Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@@H:7]2[C@H:11]([CH2:12][OH:13])[CH2:10][N:9]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[CH:1]1([NH:4][C:5]([C@@H:7]2[C@H:11]([CH2:12][O:13][Si:31]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32])[CH2:10][N:9]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:8]2)=[O:6])[CH2:2][CH2:3]1
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](CO)[C@@H](C(=O)NC2CC2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](c1ccccc1)N1C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](C(=O)NC2CC2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(3R,4S)-N-Cyclopropyl-4-hydroxymethyl-1-[(1S)-1-phenylethyl]pyrrolidine-3-carboxamide (7.54 g) was dissolved in N,N-dimethylformamide (180 mL). While this solution was chilled in an ice water bath, imidazole (2.67 g) and then tert-butylchlorodimethylsilane (4.72 g) were added. The mixture was stirred at room temperature for 90 min and was subsequently concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with water (2×100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate) to give (3R,4S)-N-cyclopropyl-4-(tert-butyldimethylsilyl)oxymethyl-1-[(1S)-1-phenylethyl]pyrrolidine-3-carboxamide as a pale yellow tar (7.05 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[NH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][NH:34][S:35]([C:38]1[C:47]2[C:42](=[C:43]([N:48]([CH3:50])[CH3:49])[CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36].ClCCl>C1(C)C=CC=CC=1.C(O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][NH:34][S:35]([C:38]2[C:47]3[C:42](=[C:43]([N:48]([CH3:50])[CH3:49])[CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)(=[O:37])=[O:36])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: CN(C)c1cccc2c(S(=O)(=O)NCCCOCCOCCCN)cccc12
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)c1cccc2c(S(=O)(=O)NCCCOCCOCCCNc3c([N+](=O)[O-])c(Cl)nc4ccccc34)cccc12
Temperature: 21 °C
Reaction time: 18 h
Yield: 33.9 %

Procedure:
A solution of 2,4-dichloro-3-nitroquinoline (2.71 g, 0.0115 mole) in toluene (100 mL) was cooled to 0–5° C. in an ice bath. Triethylamine (1.5 g) was added in one portion. A solution of N-(10-amino-4,7-dioxadecyl)-5-dimethylaminonaphthalene-1-sulfonamide (4.6 g, 0.01159 mole) in toluene (60 mL) was added dropwise while maintaining the temperature below 10° C. The reaction was stirred at 2–5° C. for 4 hrs and at a room temperature of 21° C. overnight (18 hours). Thin layer chromatography (dichloromethane:ethanol) showed a trace of the amine starting material, but was mostly a bright yellow spot at the solvent front assumed to be the addition product. The toluene was removed by rotary evaporation to provide a viscous oil. The oil was purified by column chromatography (silica gel, dichloromethane/ethanol) to provide 2.4 g of N-[10-(2-chloro-3-nitro-4-quinolinyl)amino-4,7-dioxadecyl]-5-dimethylaminonaphthalene-1-sulfonamide.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11](=[O:23])[NH:12][C:13]2([C:16]3[N:21]=[CH:20][C:19]([I:22])=[CH:18][N:17]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:25].O1CCOCC1>C(Cl)Cl>[ClH:25].[ClH:25].[I:22][C:19]1[CH:20]=[N:21][C:16]([C:13]2([NH:12][C:11]([C:8]3([NH2:7])[CH2:10][CH2:9]3)=[O:23])[CH2:15][CH2:14]2)=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC2(c3ncc(I)cn3)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1(C(=O)NC2(c3ncc(I)cn3)CC2)CC1
Reaction time: 1.5 h

Procedure:
{1-[1-(5-iodo-pyrimidin-2-yl)-cyclopropylcarbamoyl]-cyclopropyl}-carbamic acid tert-butyl ester (426 mg, 0.96 mmol) was dissolved in CH2Cl2 (2 mL) and 4M HCl in dioxane 3 mL, 6 mmol) was added. After 90 minutes, the volatiles were removed at 60° C. under a stream of N2. The resulting while solid was dried under vacuum overnight to yield crude 400 mg of 1-amino-cyclopropanecarboxylic acid[1-(5-iodo-pyrimidin-2-yl)-cyclopropyl]-amide dihydrochloride. This material was used without further purification.
Reaction SMILES: C(O)(=O)/C=[CH:3]\[C:4](O)=[O:5].[Cl:9][C:10]1[CH:29]=[CH:28][C:13]2[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C@@H:17]3[C@H:22]([NH2:23])[CH2:21][CH2:20][CH2:19][N:18]3[C:12]=2[CH:11]=1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[Cl:9][C:10]1[CH:29]=[CH:28][C:13]2[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C@@H:17]3[C@H:22]([NH:23][C:4](=[O:5])[CH3:3])[CH2:21][CH2:20][CH2:19][N:18]3[C:12]=2[CH:11]=1
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Reactant: O=C(O)/C=C\C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Yield: 131.3 %

Procedure:
trans-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine maleate (10 mg, 0.02 mmol), 50 μL of pyridine, and 25 μL of acetic anhydride in 1 mL of CH2Cl2 were stirred for 18 h at room temperature. The mixture was washed with 5% aqueous sodium bicarbonate and H2O, dried (Na2SO4) and evaporated to give trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin1-yl)acetamide (9.0 mg, 65%). Data: (m/z)=343 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH:7]=[CH:8]2)[C:3]1=[O:10].BrC1[C@@H]2[C@@H](CCC=C2)[C@H]1O.BrC1(Br)[C@@H]2[C@@H](CCC=C2)[C@H]1O>>[Cl:1][C:2]1([Cl:11])[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH:7]=[CH:8]2)[C@H:3]1[OH:10]
Reactant: O=C1[C@@H]2CCC=C[C@@H]2C1(Cl)Cl
Agent: O[C@@H]1[C@@H]2CCC=C[C@@H]2C1(Br)Br
Agent: O[C@H]1C(Br)[C@H]2C=CCC[C@H]21
Product: O[C@@H]1[C@@H]2CCC=C[C@@H]2C1(Cl)Cl

Procedure:
Similarly, following the procedure in paragraph 2.A. above, but substituting other ketones from Example 1 for (1S,6R)-8,8-dichlorobicyclo[4.2.0]oct-2-en-7-one, the following compounds of formula (6) are prepared: (1S,6R,7R)-8,8-dibromobicyclo[4.2.0]oct-2-en-7-ol (1S,6R,7R)-8-bromobicyclo[4.2.0]oct-2-en-7-ol
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: CON(C)C(=O)c1ccc(Br)cn1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CON(C)C(=O)c1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
Under a nitrogen atmosphere, a mixture of 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide (2.76 g), 4-chlorophenylboronic acid (2.113 g), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.920 g), sodium carbonate (3.58 g), toluene (43.3 mL) and water (13 mL) was stirred at 100° C. overnight. To the reaction mixture was added water at room temperature, the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was fractionated by HPLC(C18, mobile phase: water/acetonitrile (10 mM ammonium hydrogencarbonate-containing system)), the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.242 g).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12].F[C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23].[H-].[Na+]>C1COCC1>[F:21][C:17]1[C:18]([F:20])=[CH:19][C:14]([NH:1][C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[C:11]#[N:12])=[C:15]([N+:22]([O-:24])=[O:23])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: N#Cc1c(N)sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(Nc2cc(F)c(F)cc2[N+](=O)[O-])sc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
Combine 2-amino-benzo[b]thiophene-3-carbonitrile (3.93 g, 22.6 mmol), 2,4,5-trifluoro-nitrobenzene (4.0 g, 22.6 mmol) in 30 mL of THF, add sodium hydride (3.54 g, 88.5 mmol)) portionwise at 0˜5° C., after addition, the reaction stir overnight at RT, Pour the rection on ice water (200 mL), extract with dichloromethane (3×50 mL), the combined organic layer wash with water and brine, dry over Na2SO4. Concentrate down to a residue, purify by chromatography, gradient hexanes to hexane:CH2Cl2: EtOAc=5:5:0.5, obtain red orange solid 1.71 g as the title compound. 1H NMR (300 MHz, DMSO-d6): δ 10.34 (br, 1H), 8.41-8.35 (m, 1H), 7.96-7.94 (m, 1H), 7.85-7.79 (m, 1H), 7.64-7.61 (m, 1H), 7.52-7.49 (m, 1H), 7.42-7.36 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[C:13]3[CH2:14][CH:15]([CH2:17][OH:18])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:22]([O:21][C:19]1[C:13]2[CH2:14][CH:15]([CH2:17][O:18][S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=3)(=[O:33])=[O:32])[O:16][C:12]=2[CH:11]=[C:10]([C:8](=[O:9])[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[CH:20]=1)([CH3:24])[CH3:23]
Reactant: CC(C)Oc1cc(C(=O)Nc2ccn(C)n2)cc2c1CC(CO)O2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(OC(C)C)cc(C(=O)Nc4ccn(C)n4)cc3O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 2-hydroxymethyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (215) (506 mg, 1.530 mmol) in pyridine (10 mL) was added DMAP (20 mg), followed by p-toluenesulfonyl chloride (533 mg, 2.79 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with 3×EtOAc, dried over Na2SO4, concentrated and purified by flash column chromatography with 35-60% EtOAc in hexanes to give a white solid (580 mg, 78% yield). 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1 H) 7.78 (d, J=8.34 H) 7.35 (d, J=8.08 Hz, 2 H) 7.29 (d, J=2.27 Hz, 1 H) 6.96 (s, 1 H) 6.80 (d, J=2.27 Hz, 1 H) 6.69 (d, J=1.26 Hz, 1 H) 5.01 (dd, J=4.93, 1.89 Hz, 1 H) 4.56-4.66 (m, 1 H) 4.19 (dd, J=5.05, 2.27 Hz, 2 H) 3.81 (s, 3 H) 3.24 (dd, J=16.55, 9.73 Hz, 1 H) 2.95 (dd, J=16.42, 6.82 Hz, 1 H) 2.45 (s, 3 H) 1.30-1.35 (m, 6 H); LCMS for C24H27N3O6S m/z 486.20 (M+H+).
Reaction SMILES: O[C:2]1([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:6][C:5](=O)[CH:4]=[CH:3]1.Cl.[NH2:14]CC(OCC)=O.C(=O)(O)[O-].[Na+].C(O)C>O>[F:10][C:9]([F:12])([F:11])[C:2]1[CH:7]=[CH:6][C:5]([NH2:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN
Reactant: O=C1C=CC(O)(C(F)(F)F)C=C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 19.2 %

Procedure:
A mixture of 200 mg (11 mmol) of 4-hydroxy-4-trifluoromethyl-2,5-cyclohexadien-1-one, 461 mg (3.3 mmol) of ethyl glycinate hydrochloride, 336 mg (4.0 mmol) of sodium bicarbonate, and 3 mL of 95% ethanol was heated to reflux for 3 hours, allowed to cool to room temperature, and poured into 20 mL of water. The resulting aqueous mixture was extracted with three 10 mL portions of dichloromethane. Combination, drying (MgSO4), and concentration of the organic layers afforded a residue which was subjected to PTLC (one 2 mm silica gel plate eluted with dichloromethane) to give 102 mg (56% yield) of 4-trifluoromethylaniline.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[CH3:35].[CH2:36]([O:38][C:39]([C:41]1[CH:49]=[CH:48][C:44]2[S:45][CH:46]=[CH:47][C:43]=2[CH:42]=1)=[O:40])[CH3:37]>[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2].C(OCC)(=O)C.O.CN(C=O)C>[CH2:36]([O:38][C:39]([C:41]1[CH:49]=[CH:48][C:44]2[S:45][C:46]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=3[CH3:35])=[CH:47][C:43]=2[CH:42]=1)=[O:40])[CH3:37]
Reactant: COc1ccc(Br)c(C)c1
Reactant: CCOC(=O)c1ccc2sccc2c1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2sc(-c3ccc(OC)cc3C)cc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.6 %

Procedure:
Cesium carbonate (9.70 mmol; 3.19 g) is dried in a resealable tube at 150° C. in vacuo for 2 h and cooled to room temperature. Copper(I) iodide (9.70 mmol; 1.86 g), Pd(OAc)2 (0.24 mmol; 55 mg), triphenylphosphine (0.485 mmol; 128.50 mg), 2-bromo-5-methoxytoluene (9.70 mmol; 2.14 mL), benzo[b]thiophene-5-carboxylic acid ethyl ester (4.85 mmol; 1 g) and anhydrous DMF (24 mL) are added under nitrogen atmosphere and the mixture is stirred at 140° C. After 24 h, Pd(OAc)2 (0.24 mmol; 55 mg) and triphenylphosphine (0.485 mmol; 128.50 mg) are added and the mixture is stirred for 24 more hours. The mixture is allowed to reach room temperature and water and ethyl acetate are added. The suspension is filtered through Celite® and washed with ethyl acetate. The organic layer is separated and the aqueous layer is extracted with ethyl acetate. The organic layers are combined, washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue is chromatographed (0-10% EtOAc in hexanes) to obtain the title compound (960 mg, 61%) as a colorless waxy solid. LC-ES/MS m/e 326 (M).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([O:30][C:31]([NH:33][C:34]([CH3:41])([CH2:39][OH:40])[C:35]([O:37][CH3:38])=[O:36])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:23]([O:30][C:31]([NH:33][C:34]([CH3:41])([CH:39]=[O:40])[C:35]([O:37][CH3:38])=[O:36])=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C(C)(CO)NC(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C(C)(C=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A solution of 97.7 mg (0.23 mmol) of Dess Martin periodinane reagent (Aldrich) in 1 ml of DCM is slowly added dropwise to a solution of 56 mg (0.21 mmol) of methyl 2-benzyloxycarbonylamino-3-hydroxy-2-methylpropionate in 1 ml of DCM, and the mixture is left to stir at room temperature for 30 min. 5 ml of diethyl ether and a mixture of 4 ml of saturated NaHCO3 and 0.36 g of Na2S2O3.5H2O are then added to the solution. It is stirred for 15 min until the solid has dissolved, and then the ether phase is washed with saturated NaHCO3 and water, dried over MgSO4 and concentrated in vacuo. The crude product is purified by chromatography on 4 g of SiO2 with EtOAc/heptane (gradient 0-50%). 40 mg of the desired aldehyde are obtained.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH:16]([CH3:18])[CH3:17])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH:16]([CH3:18])[CH3:17])[CH:10]=3)[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)c1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(CCCN2CCN(c3ccccc3)CC2)n(-c2ccccc2)n1

Procedure:
36 mg (86%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-isopropyl-1H-pyrazol-5-yl)propanal (26 mg, 0.108 mmol), 1-phenylpiperazine (0.016 mL, 0.108 mmol), DIPEA (0.028 mL, 0.162 mmol) and NaBH(OAc)3 (69 mg, 0.325 mmol).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([CH3:16])=[CH2:15])[C:6]1=[O:17].Br.[CH3:19][C:20]1[CH:21]=[C:22]([C:26](=[O:34])[CH2:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[CH3:16][C:14]([N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][CH2:3][CH2:2][N:31]2[CH2:30][CH2:29][CH:28]([CH2:27][C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[CH:21]=3)=[O:34])[CH2:33][CH2:32]2)[C:6]1=[O:17])=[CH2:15]
Reactant: Cc1cccc(C(=O)CC2CCNCC2)c1
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C=C(C)n1c(=O)n(CCCN2CCC(CC(=O)c3cccc(C)c3)CC2)c2ccccc21
Yield: 100 %

Procedure:
A mixture of 5.5 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 6 parts of 1-(3-methylphenyl)-2-(4-piperidinyl)ethanone hydrobromide, 8.5 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone is stirred and refluxed overnight using a water-separator. The reaction mixture is cooled, water is added and thelayers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated, yielding 8.6 parts (100%) of 1,3-dihydro-1-(1-methylethenyl)-3-[3-[4-[2-(3-methylphenyl)-2-oxoethyl]-1-piperidinyl]propyl]-2H-benzimidazol-2-one as an oily residue.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.F[C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:20])[C:17](=[O:19])[CH3:18])=[CH:12][C:11]=1[N+:21]([O-:23])=[O:22]>CCO>[CH3:20][N:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[C:11]([N+:21]([O-:23])=[O:22])[CH:12]=1)[C:17](=[O:19])[CH3:18]
Reactant: NCC1CCOCC1
Reactant: CC(=O)N(C)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: CC(=O)N(C)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1
Yield: 96.3 %

Procedure:
4-Aminomethyltetrahydropyran (10.0 g, 86.5 mmol) was added to a mixture of N-(4-fluoro-3-nitrophenyl)-N-methylacetamide (15.6 g, 73.3 mmol) and TEA (15.3 mL, 11.1 g, 110 mmol) in EtOH (300 mL) at room temperature. The reaction mixture was heated for 6 h at reflux. Upon evaporation of ethanol, the residue was dissolved in EtOAc (400 mL), washed with H2O (3×50 mL), saturated NaCl (3×50 mL), and dried over Na2SO4. After filtration and concentration, 21.7 g (96%) of the title compound was obtained as an orange-red solid. 1H NMR (400 MHz, CHLOROFORM-D): δ 1.38-1.52 (m, 2 H), 1.72-1.81 (m, 2 H), 1.90 (s, 3 H), 1.93-2.02 (m, 1 H), 3.23 (s, 3 H), 3.23-3.27 (m, 2 H), 3.36-3.49 (m, 2 H), 4.01-4.07 (m, 2 H), 6.91 (d, J=9.18 Hz, 1 H), 7.29 (dd, J=9.08, 2.64 Hz, 1 H), 8.05 (d, J=2.34 Hz, 1 H), 8.22 (t, J=5.37 Hz, 1 H). MS (ESI) (M+H)+=309.12.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>ClCCl>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Solvent: ClCCl
Product: CCCCCCCCC=CCCCCCCCC
Yield: 42 %

Procedure:
In the 1990s, it was demonstrated that homogeneous ruthenium-based catalysts were effective in catalyzing olefin metathesis; moreover, these catalysts, in contrast to the tungsten and rhenium catalysts, often tolerate functionally substituted alkenes (Grubbs, R. H., Handbook of Metathesis, Wiley-Vch, Verlag GmbH & Co. KGaA, Weinheim (2003)). Such ruthenium-based catalysts have been used to prepare α,ω-dicarboxylate esters via metathetic routes. For example, a two-step process was reported using Grubbs catalysts to prepare long-chain unsaturated α,ω-dicarboxylate methyl esters (Warwel, S., et al., Polym. Sci. Part A: Polym. Chem., 39: 1601-1609 (2001)). Cross-metathesis of monounsaturated carboxylic acid methyl esters with ethylene in the presence of the first generation catalyst 1 (FIG. 1) in solution initially gave terminally unsaturated monocarboxylate methyl esters. The resulting terminal monounsaturated esters then underwent self-metathesis in the presence of catalyst 1 to give long-chain α,ω-dicarboxylic acid methyl esters with an overall yield between 38-40% (Warwel, S., et al., Polym. Sci. Part A: Polym. Chem., 39: 1601-1609 (2001); Warwel, S., et al., Ind. Crops & Prod., 20: 301-309 (2004); Warwel, S., et al., Macromol. Chem. Phys., 202: 1114-1121 (2001); Warwel, S., et al., Macromol. Chem. Phys., 202: 849-855 (2001); Warwel, S., et al., Chemosphere, 43: 39-48 (2001)). Self-metathesis of methyl oleate in dichloromethane was reported using the second generation Grubbs catalyst 2 (FIG. 1) and gave the long chain α,ω-dicarboxylic methyl ester 5a (FIG. 2, Eq. 1) in ˜45% conversion (Dinger, M. B., and J. C. Mol, et al., Adv. Synth. Catal., 344: 671-677 (2002)). The self-metathesis of oleic acid in the presence of Cl2(PCy3)2Ru=CH—CH═CPh2 in dichloromethane solution was reported to give 1,18-octadec-9-enedioic acid (5b) and octadec-9-ene (4) in 42% yield (U.S. Pat. No. 5,728,917). However, this process gave low conversion (about 50%) of monounsaturated fatty acids and low yields of dicarboxylic acids. In addition, the reaction was performed in a solvent, dichloromethane, which is an environmental concern.
Reaction SMILES: C1(C)C=CC(S(=S)(OCCCC(OC)(OC)OC)=O)=CC=1.[CH3:22][N:23]1[C:28](=[O:29])[C:27]2=[C:30]([S:44][CH2:45][CH2:46][CH2:47][C:48]([O:50]C)=[O:49])[N:31]([CH2:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=[CH:36][CH:35]=3)[CH:32]=[C:26]2[N:25]([CH2:52][CH:53]([CH3:55])[CH3:54])[C:24]1=[O:56].Cl>O1CCCC1.CO>[CH3:22][N:23]1[C:28](=[O:29])[C:27]2=[C:30]([S:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[N:31]([CH2:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=[CH:36][CH:35]=3)[CH:32]=[C:26]2[N:25]([CH2:52][CH:53]([CH3:54])[CH3:55])[C:24]1=[O:56]
Reactant: COC(=O)CCCSc1c2c(=O)n(C)c(=O)n(CC(C)C)c2cn1Cc1cccc2ccccc12
Agent: COC(CCCOS(=O)(=S)c1ccc(C)cc1)(OC)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC(=O)O)n(Cc3cccc4ccccc34)cc21
Reaction time: 1.5 h
Yield: 33.2 %

Procedure:
The compound of Example 2, methyl 4-[(2,3,4,6-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]-pyrimidin-5-yl)thio]butanoate (400 mg), was dissolved in 3:1:1 tetrahydrofuran/methanol/1M lithium hydroxide and stirred for 1.5 h before being acidified by dropwise addition of concentrated hydrochloric acid (HCl). The mixture was then extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate (MgSO4) and evaporated to dryness in vacuo. The resultant yellow oil was chromatographed (silica), eluting with 200:10:1 dichloromethane/methanol/glacial acetic acid. The resultant red oil was dissolved in toluene and then evaporated, then similarly with trichloromethane to yield a pink foam. The foam was recrystallised from ethyl acetate/hexane to yield 129 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH:8]=[N+:7]([O-])[CH:6]=[CH:5]2.BrC1C=C2C(=CC=1)C([Cl:25])=NC=C2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8]([Cl:25])=[N:7][CH:6]=[CH:5]2
Reactant: Clc1nccc2cc(Br)ccc12
Reactant: [O-][n+]1ccc2cc(Br)c(Cl)cc2c1
Product: Clc1cc2c(Cl)nccc2cc1Br

Procedure:
Starting with 6-Bromo-7-chloro-isoquinoline 2-oxide (10), the desired 6-Bromo-1,7-dichloro-isoquinoline was prepared by the method, described for 6-Bromo-1-chloro-isoquinoline (5). Rt=1.85 min (Method C). Detected mass: 276.1/278.2 (M+H+).