Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:15][CH2:16][F:17].Cl>CN(C=O)C>[F:17][CH2:16][CH2:15][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][CH:6]=1
Reactant: FCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCF)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Under nitrogen atmosphere to a cold (5° C.) solution of 4-hydroxy-benzoic acid methyl ester (7 g, 46 mmol) in DMF (30 ml) was added NaH (60%; 2.2 g) portion wise over 20 minutes. After the addition was completed, the ice bath was removed and the resulting white suspension was heated up to room temperature and stirred for 3 hours. A prepared solution of 1-Bromo-2-fluoro-ethane (6.42 g, 50 56 mmol) in DMF (20 mL) was added and the new mixture was stirred at 50° C. for 18 hours. After cooling to room temperature the mixture was poured into a mixture of ice and 1 N HCl (1:1) and extracted with ethyl acetate. The organic extracts were washed with brine, dried over MgSO4. Evaporation and purification by flash chromatography (hexane/ethyl acetate 9/1) gave a white solid (7.75. 85% yield); 1H NMR (400 MHZ, CDCl3) δ 3.86 (s, 3H), 4.20 (m, 1H), 4.21 (m, 1H), 4.27 (m, 1H), 4.28 (m, 1H), 6.93 (d, 2H), 7.98 (d, 2H); MS m/e (M+H)+ 198; mp 77° C.
Reaction SMILES: C([O:4][CH2:5]/[C:6](/[CH3:14])=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C=C.[CH:15]1[CH:20]=CC=C[CH:16]=1>>[CH3:14][CH:6]([CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:15]([CH3:20])=[CH2:16])[CH:5]=[O:4]
Reactant: c1ccccc1
Reactant: C=CCOC/C(C)=C/c1ccccc1
Product: C=C(C)C(c1ccccc1)C(C)C=O
Temperature: 25 °C
Yield: 80 %

Procedure:
The (1E)-[3-(allyloxy)-2-methyl-1-propenyl]benzene (107.79 g, 0.571 mol), [RuCl2(PPh3)3] (3.13 g), BHT (1 g) and benzene (500 ml) were heated together in an autoclave in an oil bath at 190° C. for 4 hours. After cooling to room temperature, solvents were evaporated and the residue was distilled trough a 20-cm Widmer column to give 85.9 g of the desired compound (0.457 mol, 80%) as a 3:1 mixture of diastereoisomers. B.P.=95° C./0.032 mbar
Reaction SMILES: C(O)C.[NH2:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].Cl.[NH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]([NH:14][OH:15])=[NH:8]
Reactant: NO
Reactant: N#Cc1cccnc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1cccnc1N
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of ethanol (10 mL) and 2-amino-nicotinonitrile (590 mg) were added hydroxylamine hydrochloride (510 mg) and potassium carbonate (1.4 g) at room temperature, which was stirred for 7 hours and 30 minutes under reflux. After this, the reaction mixture was stirred for 13 hours and 30 minutes at room temperature, then water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, after which the filtrate was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the titled compound (520 mg) as a cis-trans mixture. The titled compound was used in the subsequent reaction without further purification.
Reaction SMILES: [CH:1]1([N:4]([C@@H:20]([C:22]2[CH:30]=[C:29]3[C:25]([C:26]([CH3:36])=[N:27][N:28]3[CH2:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:24][CH:23]=2)[CH3:21])[C:5]([C@@H:7]2[O:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.[ClH:37].O1CCOCC1>C(Cl)(Cl)Cl>[ClH:37].[CH:1]1([N:4]([C@@H:20]([C:22]2[CH:30]=[C:29]3[C:25]([C:26]([CH3:36])=[N:27][N:28]3[CH2:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:24][CH:23]=2)[CH3:21])[C:5]([C@@H:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCn1nc(C)c2ccc([C@@H](C)N(C(=O)[C@H]3CN(C(=O)OC(C)(C)C)CCO3)C3CC3)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COCCCn1nc(C)c2ccc([C@@H](C)N(C(=O)[C@H]3CNCCO3)C3CC3)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl (2R)-2-[(cyclopropyl{(1R)-1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}amino)carbonyl]morpholine-4-carboxylate (44.4 mg) in chloroform (2.0 mL) was added 4-normal hydrogen chloride-dioxane solution (0.75 mL) under ice-cooling, and the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in water (1 mL), and then washed with diethyl ether. The aqueous layer was freeze-dried to give (2R)-N-cyclopropyl-N-{(1R)-1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethyl}morpholine-2-carboxamide hydrochloride [Ex(3-1)] (25 mg) as a colorless powder.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[C:6]1=[O:21].[H][H]>C(O)(=O)C.[Pt]=O>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[C:6]1=[O:21]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(-c2cccn(CCN(C)C)c2=O)cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C2CCCN(CCN(C)C)C2=O)cc1
Yield: 88.4 %

Procedure:
Methyl 4-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridin-3-yl}benzoate (490 mg) was dissolved in acetic acid (20 mL), and platinum oxide (74 mg) was added, followed by stirring in a hydrogen atmosphere (1 atm.) at room temperature for 15 hours. The vapor in the reactor was purged with argon, then the reaction mixture was filtered through Celite, followed by washing with methanol. The filtrate was concentrated under reduced pressure, followed by two times azeotropy with toluene. An aqueous saturated sodium hydrogencarbonate solution was added to the residue, followed by two times extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by NH-silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:2) to obtain methyl 4-{1-[2-(dimethylamino)ethyl]-2-oxopiperidin-3-yl}benzoate (439 mg) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13])#[N:2].[SH2:14]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13])(=[S:14])[NH2:2]
Reactant: N#Cc1cccc2c1CCCC2=O
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1cccc2c1CCCC2=O

Procedure:
Analogously to Example 29a), 10.6 g (62 mmol) of 5-cyano-l-tetralone in 200 ml of pyridine and 8.6 ml of triethylamine are treated with hydrogen sulfide and worked up. There is thus obtained the title compound in the form of yellow crystals, m.p. 200°-205°.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([OH:10])=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:11]([O:10][C:5]1[C:6]([C:8]#[N:9])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1nc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1nc(Br)ccc1OCc1ccccc1

Procedure:
6-Bromo-3-hydroxypyridine-2-carbonitrile (53.8 g) obtained in Reference Example 72(1) is dissolved in acetone (550 ml), and thereto are added benzyl bromide (35.6 ml) and potassium carbonate (43.1 g). The mixture is then heated under reflux for 4 hours. After allowing to cool, water (600 ml) is added to the reaction solution, and the mixture is extracted with ethyl acetate. The aqueous layer is extracted with ethyl acetate once, and combined with the previous organic layer. The solution is washed with saturated brine and dried over sodium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1, followed by 3/1). The resulting residue is suspended in diethyl ether/n-hexane and the solid is collected by filtration to give the title compound (24.1 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]([C:14](=[O:16])[CH3:15])[C:8]=2[CH:17]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]([C:14](=[O:16])[CH3:15])[C:8]=2[CH:17]=1
Reactant: CC(=O)N1CCCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCCCc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.7 %

Procedure:
A mixture of 1-(8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone (1.3 g, 5.4 mmol) and Pd—C (10%, 100 mg) in EtOH (200 mL) was stirred under H2 (1 atm) at room temperature for 1.5 h. The mixture was filtered through a layer of Celite and the filtrate was concentrated to give 1-(8-amino-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone (DC-9) as a white solid (1 g, 90%). 1H NMR (CDCl3) δ 7.01 (d, J=6.0 Hz, 1H), 6.56 (dd, J=6.0, 1.8 Hz, 1H), 6.50 (d, J=1.8 Hz, 1H), 4.66-4.61 (m, 1H), 3.50 (br s, 2H), 2.64-2.55 (m, 3H), 1.94-1.91 (m, 5H), 1.77-1.72 (m, 1H), 1.32-1.30 (m, 1H); ESI-MS 204.1 m/z (MH+).
Reaction SMILES: Cl[C:2]1[C:6]([F:8])([F:7])[C:5]([F:10])([F:9])[C:4]([F:12])([F:11])[C:3]=1Cl.[H][H]>[Pd].C(N(CC)CC)C>[F:7][C:6]1([F:8])[CH2:2][CH2:3][C:4]([F:12])([F:11])[C:5]1([F:9])[F:10]
Reactant: [H][H]
Reactant: FC1(F)C(Cl)=C(Cl)C(F)(F)C1(F)F
Agent: [Pd]
Solvent: CCN(CC)CC
Product: FC1(F)CCC(F)(F)C1(F)F
Temperature: 40 °C
Yield: 115.5 %

Procedure:
A stainless steel reactor, the inner wall of which was lined with a fluoroplastic, was charged with 5.0 g of 1,2-dichlorohexafluorocyclopentene, 0.1 g of a 5%-palladium/carbon catalyst and 4.1 g of triethylamine, and hydrogen gas was introduced to a pressure of 5 kg/cm2. The mixture was heated to 40° C. while being stirred, and the reaction was conducted while the hyfrogen consumed was supplemented. After 7 hours' reaction, it was confirmed that the consumption of hydrogen ceased. Then the catalyst was removed from the reaction mixture and the reaction mixture was distilled to give 4.2 g of 1,1,2,2,3,3-hexafluorocyclopentane (b.p., 84.5-85° C. ).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:11].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([C:8](=[O:10])[CH3:9])=[N:7][C:2]=1[Cl:1]
Reactant: CC(=O)c1ccc(C)c(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ccc(CBr)c(Cl)n1

Procedure:
To a solution of 1-(6-chloro-5-methyl-pyridin-2-yl)-ethanone (1 eq) in CCl4 is added NBS (1 eq) and BPO (0.1 eq). The mixture is refluxed for 12 hours. After concentration, 1-(5-bromomethyl-6-chloro-pyridin-2-yl)-ethanone is isolated by flash column chromatography. MS: (ES+): 247.9 (M+1)+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:26]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:25][CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[N:27]1([C:26]2[C:21]([N:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)=[N:22][CH:23]=[CH:24][N:25]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2N2CCCCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc(N2CCNCC2)c(N2CCCCC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
Add trifluoroacetic acid (1.00 mL, 13.24 mmol, 10 eq) to a solution of 3′-piperidin-1-yl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (0.46 g, 1.32 mmol, 1 eq) in DCM (10 mL) then stir the mixture at room temperature for 4 hr. Concentrate the reaction mixture, then dissolve in methanol and load on to a 10 g SCX-2 ion exchange cartridge (pre-washed with methanol). Wash with one column volume of methanol then elute with one column volume of 3.5 M ammonia in methanol. Concentrate to give 3′-piperidin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.317 g, 0.97%). MS (m/z): 248.2 (M+1).
Reaction SMILES: Cl[CH:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][C:4]1[C:9]([CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][N:5]=1>C(O)C.[Pd]>[CH2:3]([C:4]1[C:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(CCc2cccnc2CC(Cl)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(CCc2cccnc2CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.8 %

Procedure:
Methyl 4-[2-(2-(2-chloro-2-(phenyl )ethyl)-3-pyridyl)ethyl]benzoate (0.537 g, 1.29mmol) was dissolved in ethanol (10 ml). The solution was treated with palladium on carbon (10% Pd, 0.1 g) and placed under a hydrogen atmosphere. The reaction was stirred at ambient temperature for 18 hours, then filtered and the solvent evaporated to give methyl 4-[2-(2-(phenethyl)-3-pyridyl)ethyl]benzoate (0.467 g), which was used without further purification.
Reaction SMILES: C([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:9]=1)(=O)C.Cl.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:9]=1
Reactant: CC(=O)Nc1nc(CS(=O)(=O)c2ccc(N)cc2)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc(S(=O)(=O)Cc2csc(N)n2)cc1
Temperature: 0 °C
Yield: 60.2 %

Procedure:
A solution of 2-acetylamino-4-[4-aminophenylsulfonylmethyl)thiazole (4.8 g) in a mixture of acetic acid (35 ml) and 6N-aqueous hydrochloric acid (10 ml) was refluxed for 2.5 hours with stirring. The reaction mixture was poured into ice-water and then the solution was adjusted to pH 8.0 using 10% aqueous sodium bicarbonate with stirring. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-4-(4-aminophenylsulfonylmethyl)thiazole (2.50 g, yield: 60.2%). mp: 203°-206° C. (dec.) IR (Nujol): 3450, 3350, 1630, 1595, 1530 1380 cm-1
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][CH:25]([OH:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(O)C>CCCCCC>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C@@H:25]([OH:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCCC1O
Solvent: CCO
Solvent: CCCCCC
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCC[C@H]1O

Procedure:
Racemic (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[4-(3-hydroxy-2-methyl-cyclohex-1-en-1-yl)-3-methyl-phenyl]-methanone of Example 5 was subjected to chiral HPLC (Chiralpak AD, 21.1×250 mm, 50% ethanol in hexane). The first peak which eluted displayed a positive optical rotation and was arbitrarily assigned the (R)-configuration. The title compound was isolated as a white solid, [α]D=+34.30 (c=1.0, chloroform).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([OH:14])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.F[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][CH2:3][C:4]1[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([O:14][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=Cc1ccc(F)cc1
Reactant: COCc1cc2ccccc2c(O)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCc1cc2ccccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Yield: 30 %

Procedure:
3-[(Methyloxy)methyl]-2-phenyl-1-naphthalenol (145) (46 mg, 0.17 mmol) and 4-fluorobenzaldehyde was heated with Cs2CO3 in DMF at 100° C. to give 20 mg (30%) of the title compound (146) as a light yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 3.34 (s, 3H), 4.32 (s, 2H), 6.71 (d, J=8.8 Hz, 2H), 7.16-7.20 (m, 2H), 7.20-7.30 (m, 3H), 7.45 (t, J=7.5 Hz, 1H), 7.54 (t, J=7.4 Hz, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.81 (d, J=8.4 Hz, 1H), 7.95 (d, J=9.0 Hz, 1H), 7.98 (s, 1H), 9.79 (s, 1H). LCMS (APCI): m/z 369 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[N:20]1[CH2:19][CH2:18][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:22][CH2:21]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccccc1F
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Temperature: 150 °C
Yield: 28.1 %

Procedure:
To a solution of 2-fluorobenzaldehyde (Aldrich) (1 g, 8.1 mmol) in DMF (14 mL) was added 1-Boc-piperazine (Lancaster) (2.3 g, 12 mmol). The resulting solution was treated with copper (Aldrich Chemical Company) (50 mg, 0.8 mmol) and K2CO3 (Aldrich) (5.1 g, 37 mmol). The suspension was heated in a sealed tube at 150° C. for 18 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and brine. The aqueous layer was extracted twice with EtOAc and the combined EtOAc layers were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The crude compound was purified on a Biotage 40 M column (12% EtOAc in hexanes) to give tert-butyl 4-(2-formylphenyl)piperazinecarboxylate (0.66 g) as a yellow oil. MS m/z: 291 (M+H). Calc'd for C16H22N2O3: 290.36.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[CH2:7])CCC>CN(C=O)C.C(OCC)(=O)C.Cl[Cu]>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:13]=2)=[CH2:7])=[CH2:7])=[CH:9][CH:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=C(c1ccc(OCc2ccccc2)cc1)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C(=C)c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of tributyl-[1-(4-benzyloxy-phenyl)-vinyl]-stannane (26.2 g, 52.6 mmol) in DMF (180 mL) at 0° C. was added CuCl (8.6 g, 87.7 mmol) and CuCl2 (1.00 g, 8.13 mmol), which was then stirred at 25° C. for 2 h. The reaction mixture was then diluted with ethyl acetate (500 mL) and washed with brine (3×300 mL). The reaction mixture was then dried over MgSO4 and purified by SiO2 (20% ethyl acetate/hexane) to yield 2,3-di(4-benzyloxy-phenyl)-1,3-butadiene.
Reaction SMILES: C[N+]([CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(C)C.[I-].[Cl:16][C:17]([Cl:22])([Cl:21])[C:18]([NH2:20])=[NH:19]>C(O)C>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:5][NH:19][C:18](=[NH:20])[C:17]([Cl:22])([Cl:21])[Cl:16])=[CH:7]1
Reactant: C[N+](C)(C)Cc1c[nH]c2ccccc12
Reactant: N=C(N)C(Cl)(Cl)Cl
Agent: [I-]
Solvent: CCO
Product: N=C(NCc1c[nH]c2ccccc12)C(Cl)(Cl)Cl

Procedure:
A solution of gramine methiodide (31.6 g., 0.1 mole) in 250 ml. of ethanol is treated dropwise over a period of 30 minutes with a solution of trichloroacetamidine (16.1 g., 0.1 mole) in 50 ml. of ethanol. The solution is refluxed for 15 minutes, cooled and the solvent removed in vacuo to give a crystalline residue. The residue is partitioned between 150 ml. portions of chloroform and water and the water layer back-extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo affording N-(3-indolylmethyl)-trichloroacetamidine m.p. 135.5 to 138.5 after recrystallization from benzene/hexane.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH2:6][C:5]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])(S(C3C=CC=CC=3)(=O)=O)[CH2:4]2)[O:2]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CC(C)=O>[OH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:5]1[CH2:6][CH2:7][CH2:8][C:3](=[O:2])[CH:4]=1
Reactant: O=S(=O)(c1ccccc1)C1(CCCCCCCCCCO)CCCC2(C1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C1C=C(CCCCCCCCCCO)CCC1
Yield: 77.4 %

Procedure:
Paratoluenesulfonic acid (20 mg) was added to a solution of 193 mg of 1,1-(ethylenedioxy)-3-(10-hydroxydecyl)-3-(phenylsulfonyl)-cyclohexane in 3 ml of chloroform and 0.6 ml of acetone. To the resulting mixture was added 10 ml of a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane-ethyl acetate, whereby 86 mg of 3-(10-hydroxydecyl)-2-cyclohexen-1-one were obtained in the form of a colorless oil. Yield: 77%
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1.[CH3:16][C:17]1[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:27]2[CH2:28][CH2:29][N:24]([C:18]3[C:17]([CH3:16])=[CH:22][C:21]([CH3:23])=[CH:20][N:19]=3)[CH2:25][CH2:26]2)=[O:8])=[C:4]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1
Reactant: CS(=O)(=O)Nc1cc(Br)ccc1C(=O)O
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3NS(C)(=O)=O)CC2)c(C)c1
Yield: 21 %

Procedure:
Using 4-bromo-2-methanesulfonylaminobenzoic acid (964 mg) described in Preparation Example 225 and 1-(3,5-dimethylpyridin-2-yl)piperazine (629 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (321 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([S:18]([N:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]1=2.[CH2:36]([Sn](CCCC)(CCCC)C=C)[CH2:37]CC>CN(C=O)C.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>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:21]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:18]([C:15]2[CH:16]=[CH:17][C:9]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH:36]=[CH2:37])[CH2:13][CH2:12][O:11][C:10]=3[CH:14]=2)(=[O:20])=[O:19])=[CH:29][CH:30]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2Br)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Yield: 55 %

Procedure:
A mixture of 4-(2-bromophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (1.2 g, 2.626 mmol), tributyl(vinyl)stannane (3.0 g, 10.5 mmol, Finar), Pd(PPh3)4 (303 mg, 0.131 mmol) in DMF (15 mL) was degassed with nitrogen for 10 minutes. The reaction mixture was subjected to microwave irradiation for 2 h at 100° C. After completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude material which was purified by combi flash column chromatography (column size: 12 g; elution: 0-5% ethyl acetate in hexane) to get N-(4-methoxybenzyl)-N-(thiazol-2-yl)-4-(2-vinylphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (750 mg, 68.0%) as a yellow solid. m/z (ESI) 520.1 (M+H)+.