Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[CH:7]=[C:6]([N:20]3[CH:24]=[C:23](I)[N:22]=[CH:21]3)[N:5]=2)[CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH:1]1([C:4]2[N:5]=[C:6]([N:20]3[CH:24]=[C:23]([C:30]4[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=4)[N:22]=[CH:21]3)[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccc(-c2cc(C3CC3)nc(-n3cnc(I)c3)c2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C4CC4)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-cyclopropyl-6-(4-iodo-imidazol-1-yl)-4-(4-trifluoromethyl-phenyl)-pyridine (example E.17) (1.0 g, 2.2 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.628 g, 2.85 mmol) according to the general procedure VI. Obtained as an off-white solid (0.180 g, 46%). MS (ISP) 422.2 [(M+H)+]; mp 233-235° C.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)[CH:3]=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41](Cl)(Cl)([Cl:43])[Cl:42]>[Zn]>[CH3:1][C:2]([CH3:21])([CH:3]=[C:41]([Cl:43])[Cl:42])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C=O)COCc1cccc(Oc2ccccc2)c1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C=C(Cl)Cl)COCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of 2,2-dimethyl-3-(3-phenoxybenzyloxy)propan-1-al (0.25 g), triphenylphosphine (0.47 g), zinc dust (0.12 g) and carbon tetrachloride (0.2 cm3) was heated at the relux temperature for one hour. After cooling to the ambient temperature (ca 25° C.) the mixture was diluted with petroleum ether (boiling range 40°-60° C.) and the solid component removed by filtration. The filtrate was concentrated by evaporation of the solvent under reduced pressure, and the residual oil subjected to purification by flash chromatography using a silica gel column eluted with dichloromethane to yield 2,2-dimethyl-1-(3-phenoxybenzyloxy)-4,4-dichlorobut-3-ene (0.2 g).
Reaction SMILES: ClC1C=CC(C(F)(F)F)=CC=1[NH2:4].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:4][CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)C(=CN)C(=O)OCC
Temperature: 190 °C

Procedure:
A mixture of 2-chloro-5-trifluoromethylaniline (3.91 g) and diethyl ethoxymethylenemalonate (4.0 mL) is heated at 190° C. for 2 h and is then diluted with diphenyl ether (30 mL). The mixture is allowed to cool to rt, filtered, and the white solid is washed with hexane (2×10 mL) to afford 1.632 g of the diethyl amino-methylenemalonate. The resulting intermediate (2.63 g) is suspended in diphenyl ether (30 mL) and heated to reflux with a Dean-Stark trap for 3 h. The mixture is allowed to cool to rft and is then poured into hexane (50 mL). The solid is filtered and then washed with hexane (20 mL) and hexane/diethyl ether (1/1, 20 mL) to afford 1.273 g of the quinolinecarboxylate ethyl ester. Te he ester (4 00 mg) and 4-chlorobenzylamine (1.52 mL) are heated at 190° C. for 1 h. The resulting mixture is diluted with toluene (4 mL), allowed to cool to rt, and then poured into hexane (50 mL). The solvent is decanted and the remaining oil is crystallized (acetic acid, water) to afford 285 mg of the title compound as a brown solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[OH:14].[N:15]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1.C(OCC)(=O)C>[N:15]1([C:20]([O:14][C:5]2[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]([F:10])=[CH:9][C:4]=2[F:3])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Cl)N1CCCC1
Reactant: O=[N+]([O-])c1cc(O)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Oc1cc([N+](=O)[O-])c(F)cc1F)N1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
To a stirred, cold (0° C.) mixture of 1.74 g of sodium hydride (0.072 mole, 2.9 g of a 60% oil suspension) and 7.0 g (0.039 mole) of 2,4-difluoro-5-nitrophenol in 100 mL of tetrahydrofuran was added 6.4 g (0.048 mole) of 1-pyrrolidinecarbonyl chloride. The reaction mixture was allowed to warm to room temperature and was stirred for four hours. The mixture was diluted with ethyl acetate and was washed with an aqueous 10% hydrochloric acid solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and filtrate evaporated under reduced pressure leaving a semi-solid residue. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate:n-heptane (50:50) to yield 7.2 g of (2,4-difluoro-5-nitrophenyl) 1-pyrrolidinecarboxylate. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[O:18][CH3:17])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: COc1ccccc1CN
Solvent: CCN(CC)CC
Product: COc1ccccc1CNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(2-methoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-methoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[O:24][C:25]=1[CH3:26]>>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:23]1[O:24][C:25]([CH3:26])=[C:21]([CH2:20][N:11]2[C:12]3[C:8](=[CH:7][C:6]([CH2:5][C@H:4]([O:15][CH2:16][CH3:17])[C:3]([OH:2])=[O:18])=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)[N:22]=1
Reactant: CCO[C@@H](Cc1ccc2[nH]ccc2c1)C(=O)OC
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCl
Product: CCO[C@@H](Cc1ccc2c(ccn2Cc2nc(-c3ccccc3Cl)oc2C)c1)C(=O)O
Yield: 56 %

Procedure:
Starting from (S)-2-ethoxy-3-(1H-indol-5-yl)-propionic acid methyl ester and 4-chloromethyl-2-(2-chloro-phenyl)-5-methyl-oxazole, the title compound was obtained in 56% yield as a pale brown amorphous solid. MS: (M−H)− 437.2.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:25](=[O:26])[N:12]2[C:13]([C:22]([OH:24])=[O:23])=[C:14](OS(C)(=O)=O)[CH2:15][S:16][C@H:11]12)=[O:8]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:25](=[O:26])[N:12]2[C:13]([C:22]([OH:24])=[O:23])=[CH:14][CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CS(=O)(=O)OC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: CCO
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12

Procedure:
A 200 mg. portion of 7-(thien-2-ylacetamido)-3-methanesulfonyloxyl-3-cephem-4-carboxylic acid was dissolved in a working fluid containing 2.5 mg./ml. of the starting compound, 35% by volume of ethanol, and 64% by volume of 1.0 molar pH 7.0 McIlvaine buffer. The measured pH of the working fluid was 7.5. The electrolysis was carried out as described in Example 1 in the same type of cell described in Example 1, and the product was worked up as described in Example 2 to obtain about 130 mg. of crude product. The product was converted to the methyl ester, and submitted to mass spectroscopy, which revealed the presence of molecular ions of mass 337 and 338, confirming that the desired product was obtained.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][C:24]([N:26]1[CH2:33][CH:32]([O:34][CH2:35][O:36][CH3:37])[CH2:31][C@H:27]1[C:28]([OH:30])=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH:38]1([CH2:44][NH2:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.ON1C(=O)CCC1=O>O1CCOCC1>[CH2:16]([O:23][C:24]([N:26]1[CH2:33][CH:32]([O:34][CH2:35][O:36][CH3:37])[CH2:31][C@H:27]1[C:28]([NH:45][CH2:44][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)=[O:30])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCC1CCCCC1
Reactant: COCOC1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1COCCO1
Product: COCOC1C[C@@H](C(=O)NCC2CCCCC2)N(C(=O)OCc2ccccc2)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
13.4 g of dicyclohexylcarbodiimide was added, at room temperature, to a solution of 19.3 g of 1-benzyloxycarbonyl-4-methoxymethoxy-L-proline, 8.5 ml of cyclohexylmethylamine and 7.5 g of N-hydroxysuccinimide in 200 ml of dioxane. The mixture was stirred at the same temperature for 2 hours, then heated at 60° C. for 1 hour, and allowed to cool, followed by filtration. The solvent in the filtrate was removed by filtration. The resulting residue was purified by a silica gel column chromatography (eluant; 5% methanol/chloroform) to obtain 21.2 g of N-(1-benzyloxycarbonyl-4-methoxymethoxy-L-prolyl)-N-cyclohexylmethylamine as a light yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([N+:12]([O-:14])=[O:13])=[N:4][CH:3]=1.[NH2:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19].C(N(CC)CC)C>C(O)(C)C>[OH:20][CH:17]([CH2:18][OH:19])[CH2:16][NH:15][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([N+:12]([O-:14])=[O:13])=[N:4][CH:3]=1
Reactant: NCC(O)CO
Reactant: COC(=O)c1nc(Cl)cnc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COC(=O)c1nc(NCC(O)CO)cnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 1.0 g (0.004 mol) 9 in 15 ml isopropanol is added 0.36 g (0.004 mol) 10 and 0.4 g (0.004 mol) triethylamine at room temperature. The reaction mixture becomes reddish in color and is stirred at room temperature for 16 hours. The solvent is removed on the rotary evaporator and the residue is purified by flash chromatography on silica gel followed by elution with 10% methanol/chloroform. Pure 15 has Rf 0.4 and is obtained as a yellow solid, m.p. 107°-9°.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.Br[C:20]1[S:21][C:22]([N+:25]([O-:27])=[O:26])=[N:23][N:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:20]3[S:21][C:22]([N+:25]([O-:27])=[O:26])=[N:23][N:24]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: O=[N+]([O-])c1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc([N+](=O)[O-])s3)cc(C)c21
Temperature: -25 °C
Reaction time: 20 h
Yield: 35.7 %

Procedure:
To a stirred solution of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (43 g, 0.17 mol) in anhydrous acetonitrile (2000 mL) at −20° C. was added a solution of 2-bromo-5-nitro-1,3,4-thiadiazole (70 g, 0.33 mol.) in acetonitrile (1000 mL). Then Cs2CO3 (166 g, 0.51 mol, 3 eq.) as added portionwise at this temperature. The mixture was stirred at −20 to −30° C. for 20 hrs. Then, the reaction mixture was allowed to warm to r.t. and stirred at this temperature for 15 h. After filtration, the filtrate was concentrated and acidified to pH=2 at 0° C. with diluted hydrochloric acid. The mixture was extracted with EtOAc and the organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo The residue was purified by chromatography on silica gel column (petroleum ether/EtOAc/AcOH, gradient elution) to give the ethyl 2-(1-hydroxy-4-methyl-6-(5-nitro-1,3,4-thiadiazol-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate as a yellow solid (23 g, 36% yield).
Reaction SMILES: [OH-].[K+].C(O)C.[Br:6][C:7]1[CH:33]=[CH:32][C:10]2[S:11][C:12]([CH2:14][C:15]([C:27]([O:29][CH2:30][CH3:31])=[O:28])([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)C([O-])=O)=[CH:13][C:9]=2[CH:8]=1.Cl>O>[Br:6][C:7]1[CH:33]=[CH:32][C:10]2[S:11][C:12]([CH2:14][CH:15]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:13][C:9]=2[CH:8]=1
Reactant: CCOC(=O)C(Cc1cc2cc(Br)ccc2s1)(C(=O)[O-])c1ccc(OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(Cc1cc2cc(Br)ccc2s1)c1ccc(OC)cc1
Reaction time: 96 h
Yield: 91.1 %

Procedure:
A solution of 7.3 g of potassium hydroxide dissolved in 20 ml of water was added to 200 ml of an ethanol solution containing 24.2 g of 3-(5-bromobenzo[b]thien-2-yl)-2-ethoxycarbonyl-2-(4-methoxyphenyl)propionate obtained in the above step a), and the thus prepared mixture was stirred for 4 days. The resulting reaction solution was poured into cooled dilute hydrochloric acid to collect precipitated crystals by filtration. The thus collected crystals were dissolved in ethyl acetate, and then dried. After distilling off the solvent, the resulting residue was dissolved in 200 ml of ethanol, mixed With 3 ml of concentrated sulfuric acid, and then refluxed under heating for 2 hours. After cooling, the resulting reaction solution was concentrated, mixed with chloroform, washed with water, and then dried. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using chloroform as an eluant, thereby obtaining 20 g of ethyl 3-(5-bromobenzo[b]thien-2-yl)-2-(4-methoxyphenyl)propionate.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1>C(O)C>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:22]#[N:23])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(I)c1
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(I)c1
Reaction time: 2.5 h
Yield: 56 %

Procedure:
A mixture of 6.70 g (16.1 mmol) 4-[(3-iodophenyl)amino]-6-nitro-3-quinolinecarbonitrile, 300 ml ethanol, and 18.2 g (80.5 mmol) SnCl2 dihydrate was heated to reflux under N2. Removed heat at 2 hours, added ice water. Added sodium bicarbonate until pH was basic, forming a thick yellow mixture. Stirred for 2.5 hours. Extracted with chloroform, stirred organic portion with Darco and filtered through magnesium sulfate. Stripped solvent and dried in vacuo, giving 3.48 g of yellow-brown solid: mass spectrum (electrospray m/e): M+H=387.0.
Reaction SMILES: [CH:1]([N:4]([S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[NH:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)([CH3:3])[CH3:2].[C:36]1(S(NC2C=CC(C(F)(F)F)=CC=2NCC2C=CC(C(OC)=O)=CC=2)(=O)=O)C=CC=CC=1.[H-].[Na+].CI>CN(C=O)C>[CH3:36][N:15]([CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)[C:6]1[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]=1[N:4]([S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:1]([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(CNc2cc(C(F)(F)F)ccc2NS(=O)(=O)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(CNc2cc(C(F)(F)F)ccc2N(C(C)C)S(=O)(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(CN(C)c2cc(C(F)(F)F)ccc2N(C(C)C)S(=O)(=O)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Methyl 4-[2-(N-Isopropyl-phenylsulfonylamino)-5-trifluoromethylphenylaminomethyl]benzoate (200 mg) prepared by the same procedure as Example 17 by using methyl 4-(2-phenylsulfonylamino-5-trifluoromethylphenylaminomethyl)benzoate (prepared in Example 27.) was dissolved in DMF (5 ml). Sodium hydride (64 mg) and methyl iodide (200 μl) were added thereto. The mixture was stirred for 24 hours at 60° C. The reaction mixture was extracted with H2O-AcOEt, washed, dried over, filtered and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=5:1) to give the title compound (105 mg) having the following physical data.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1)=O.[O:18]=[C:19]1[CH2:24][CH2:23][CH2:22][S:21][CH2:20]1>>[O:18]=[C:19]1[CH2:24][CH2:23][CH2:22][S:21][C:20]1=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: O=C1CCCSC1
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(C=O)cc1
Product: CC(C(=O)OC(C)(C)C)c1ccc(C=C2SCCCC2=O)cc1
Yield: 29.6 %

Procedure:
By using tert-butyl 2-(4-formylphenyl)propionate (500 mg) and 3-oxothiane (500 mg), the title compound (210 mg, 30%) was obtained in the same manner as that of Example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:11][C:10](=O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1(P(=[CH:33][C:34]([O:36][CH3:37])=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:37][O:36][C:34](=[O:35])[CH:33]=[C:10]1[CH2:11][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])[CH2:9]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C=C1CC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a solution of (3-oxo-cyclobutyl)-carbamic acid tert-butyl ester (5.6 g, 30.2 mmol) in anhydrous toluene (100 mL) was added methyl (triphenylphosphoranylidene)acetate (10.7 g, 45.4 mmol) and heated to reflux overnight under N2. After cooling to room temperature, the mixture was poured into water and extracted with EA. The organic phase was dried over Na2SO4, concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (eluted with PE:EA=20:1) to give the title compound (7 g, yield 96%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[C:8]([OH:16])[CH:7]=2)[CH2:3][CH2:2]1.[C:17](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.Cl>CC(=O)CC>[CH:1]1([CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(OCC2CC2)cc1O
Agent: Cl
Agent: [K+]
Solvent: CCC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1cc(OCC2CC2)ccc1C(=O)O
Reaction time: 12 h

Procedure:
A 3.00 g portion of methyl 4-cyclopropylmethyloxy-2-hydroxybenzoate was dissolved in 70 ml of 2-butanone, and 2.80 g of potassium carbonate and 1.9 ml of dimethyl sulfate were added, followed by 12 hours of heating under reflux. After completion of the reaction, the solvent was evaporated, the resulting residue was suspended in chloroform, and insoluble matter was removed by celite filtration. The solvent was again evaporated, and then the thus obtained residue was dissolved in 20 ml of tetrahydrofuran, mixed with 30 ml of 2N sodium hydroxide aqueous solution and subjected to 3 hours of heating under reflux. After completion of the reaction, the reaction solution was poured into 1N hydrochloric acid aqueous solution, and the thus precipitated product of interest was collected by filtration, washed with water and then dried under a reduced pressure to give 2.74 g of 4-cyclopropylmethyloxy-2-methoxybenzoic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([Cl:19])=[C:16](Cl)[S:17][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>C1COCC1.CCCCCC>[CH2:1]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([Cl:19])=[C:16]([C:27](=[O:28])[C:26]([CH3:31])([CH3:30])[CH3:25])[S:17][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Clc1sc2c(c1Cl)CCN(Cc1ccccc1)CC2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1sc2c(c1Cl)CCN(Cc1ccccc1)CC2
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
The product from step (g) (109 mg, 0.35 mmol) in anhydrous THF (5 ml) was cooled to −78° C. under a nitrogen atmosphere and treated with 1.6 M n-butyl lithium in hexane (0.25 ml). The reaction mixture was stirred at −78° C. for 5 minutes followed by the addition of trimethyl acetyl chloride (0.22 ml, 1.75 mmol). After 10 additional minutes at −78° C., the reaction mixture was allowed to warm to room temperature. The reaction was quenched with saturated NaHCO3 (20 ml) and extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with brine (50 ml), dried (MgSO4), and solvent evaporated in vacuo to give the subtitled compound as an orange oil which was used in the next step without further purification. MS: ESI (positive): 362, 364 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C@H:12]4[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14][C@H:13]4[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[Cl:32]>>[Cl:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:3]=[C:4]3[C:9]4=[C:10]([C@H:12]5[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:15][CH2:14][C@H:13]5[N:8]4[CH2:7][CH2:6][CH2:5]3)[CH:11]=2)[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CCC3
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3ccc(Cl)c(Cl)c3)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 109 from tert-butyl (±)-cis-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (101.7 mg, 0.26 mmol) and 3,4-dichlorophenylboronic acid (97 mg, 0.52 mmol), after chromatographic purification (91.6 mg, 77%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ7.57 (d, 1H, J=1.8 Hz), 7.42 (d, 1 H, J=8.4 Hz), 7.31 (dd, 1H, J=2.2, 8.4 Hz), 7.12 (bs, 1H), 7.07 (bs, 1H), 3.62-3.75 (m, 1H), 3.48-60 (m, 1H), 3.15-3.35 (m, 4H), 2.65-2.80 (m, 4H), 2.10-2.20 (m, 2H), 1.85-2.00 (m, 2H), 1.46 (s, 9H) ppm.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[C:34]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:33]=[C:32]([N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.[OH-].[Na+]>C(Cl)Cl>[NH:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:30]2[CH:35]=[C:34]([N:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)[N:33]=[C:32]([N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[N:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCC1COC(=O)N1CCN(c2cc(N3CCCC3)nc(N3CCCC3)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCC1CCCN1)N1CCN(c2cc(N3CCCC3)nc(N3CCCC3)n2)CC1
Reaction time: 18 h
Yield: 80.1 %

Procedure:
0.174 ml of trifluoroacetic acid are dropped into a solution of 100 mg of (-)-N'-[(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxycarbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl)piperazine in 4 ml of methylene chloride. After about 18 hours, the reaction mixture is added with a 1N sodium hydroxide aqueous solution and it is extracted with methylene chloride (3×3 ml). The combined organic extracts are washed with water (2×2 ml), dried over sodium sulfate and solvent is evaporated off under reduced pressure. The residue is crystallized from 9:1 diisopropyl ether/ethyl acetate, to give 65 mg of (+)-N'-[(pyrrolidin-2-yl)methoxycarbonyl]-N-[2,6-bis(pyrrolidin-1-yl)pyrimidin-4-yl]piperazine, m.p. 137°-138° C., [α]D =8.7° (c=0.23 in EtOH).