Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:9])[C:2](=O)[C:3](=[O:7])[CH:4]=[CH:5][CH:6]=1.[CH3:10][C:11]([C:13]([CH3:15])=[CH2:14])=[CH2:12].[OH2:16]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:9][C:1]1[C:6](=[O:16])[C:5]2[CH2:12][C:11]([CH3:10])=[C:13]([CH3:15])[CH2:14][C:4]=2[C:3](=[O:7])[CH:2]=1
Reactant: C=C(C)C(=C)C
Reactant: CC1=CC=CC(=O)C1=O
Reactant: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC1=CC(=O)C2=C(CC(C)=C(C)C2)C1=O
Yield: 91 %

Procedure:
In toluene (30 ml) and acetic acid (10 ml), were dissolved 6.0 g (0,049 mol) of toluquinone, to which 10.0 g (0.12 mol) of 2,3-dimethyl-1,3-butadiene were added at -10° C. under stirring. Thereafter, the resultant mixture was gradually heated and stirred further for 3 hours at 40° C. The liquid reaction mixture was washed with water, and an organic layer was dried and concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) and ethanol (40 ml) were added to the residue, and the mixture was stirred for 1 hour at 40° C. After the liquid reaction mixture was concentrated under reduced pressure, the residue was dissolved in a liquid mixture of acetonitrile (70 ml) and water (20 ml). To the solution, were added 15.0 g (0.027 mol) of ceric ammonium nitrate at room temperature to stir the resultant mixture for 1 hour. The liquid reaction mixture was poured into water (200 ml) to make extraction with toluene (50 ml×2). The resulting organic layer was washed with water, dried and concentrated under reduced pressure to obtain 8.9 g of a crude product of the title compound (yield: 91%).
Reaction SMILES: C(N(CC)CC)C.C[S:9](Cl)(=O)=O.O[C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1.[O:56]1CC[CH2:58][CH2:57]1>>[C:57]([S:9][C@@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1)(=[O:56])[CH3:58]
Reactant: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
89 μl of triethylamine and 50 μl of methanesulfonyl chloride were added to a solution of 321 mg of (2S,4R)-4-hydroxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine in 3.2 ml of anhydrous tetrahydrofuran, whilst ice-cooling, and the resulting mixture was stirred at 0° to 5° C. for 30 minutes and then at room temperature for 1 hour. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was mixed with an aqueous solution of sodium hydrogencarbonate and then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate; the solvent was then removed by distillation under reduced pressure, to afford 345 mg of the title compound as a powder.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[O:34]([C:36]#[N:37])[K]>C(O)(=O)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][N:28]([C:36](=[O:34])[NH2:37])[CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: N#CO[K]
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCNCC4)n3)cc2)CC1
Solvent: CC(=O)O
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCN(C(N)=O)CC4)n3)cc2)CC1
Reaction time: 4 h
Yield: 29.4 %

Procedure:
A mixture of 2-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(piperidin-4-ylmethylamino)pyrimidine-5-carboxamide (25 mg, 0.055 mmol) and KOCN (20 mg, 0.25 mmol) in acetic acid (2 mL) was stirred at 100 C for 4 h. The mixture was then purified by HPLC to give the titled compound (8 mg). MS 496.45 (M+H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:8]([C:9]2[C:17]([Cl:18])=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)[N:7]=[CH:6][C:5]=1[C:19]#[N:20].I[CH2:22][CH3:23].O.O1CC[CH2:27][CH2:26]1>>[Cl:18][C:17]1[C:9]([N:8]2[C:4]([N:3]([CH2:22][CH3:23])[CH2:26][CH3:27])=[C:5]([C:19]#[N:20])[CH:6]=[N:7]2)=[N:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=12
Reactant: N#Cc1cnn(-c2nn3c(c2Cl)CCCC3)c1N
Reactant: C1CCOC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCN(CC)c1c(C#N)cnn1-c1nn2c(c1Cl)CCCC2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
10.45 g (0.35 mol) Sodium hydride (80%) was added to 100 ml tetrahydrofuran and cooled to 0° C. In a nitrogen atmosphere, a suspension of 43.6 g (0.17 mol) 5-amino-1-(3-chloro-4,5,6,7-tetrahydropyrazolo-[1,5-a]pyridin-2-yl)-4-pyrazolecarbonitrile in 500 ml tetrahydrofuran was added dropwise. The mixture was stirred for 1.5 hours. Then 31.4 ml (0.38 mol) iodoethane in 20 ml tetrahydrofuran was added dropwise at 15° C. After stirring for three hours at 15° C., the mixture was cooled. Water was then added dropwise and the mixture extracted with ethyl acetate. The organic phase was separated, dried and concentrated. The residue was recrystallised from ethyl acetate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])C=1.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N:47](CC)CC)C>C1COCC1.[Cu]I>[N+:15]([C:5]1[C:6]([NH:8][S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[N:47][C:2]([C:25]#[C:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:3][CH:4]=1)([O-:17])=[O:16]
Reactant: CCN(CC)CC
Reactant: C#Cc1ccccc1
Reactant: CC(C)S(=O)(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)Nc1nc(C#Cc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Add propane-2-sulfonic acid (5-chloro-2-nitrophenyl)amide (10 g, 35.7 mmol), phenylacetylene (5.9 mL, 53.6 mmol) and triphenylphosphine (0.46 g, 1.78 mmol) to a solution of triethylamine (25 mL, 178.5 mmol) in dry THF (25 mL) and flush the system with nitrogen. Add dichlorobis(triphenylphosphine)palladium(1) (0.625 g, 0.89 mmol) and copper (I) iodide (0.17 g, 0.89 mmol) to this stirring mixture. Heat the reaction to reflux for 4 h. Cool to RT and concentrate to a slurry. Filter the crude material through a plug of silica gel using EtOAc as the eluting solvent. Concentrate the filtrate and crystallize the title compound from EtOAc-hexanes (7.9 g, 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[C:2]([NH:1][S:28]([C:20]2[O:19][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH:21]=2)(=[O:29])=[O:30])[CH:7]=1
Reactant: BrCc1ccccn1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: Nc1cc(Cl)ccc1S
Agent: Br
Product: O=S(=O)(Nc1cc(Cl)ccc1SCc1ccccn1)c1cc2ccccc2o1

Procedure:
Following General Procedure A and B, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 2-bromomethyl-pyridine hydrobromide, and benzofuran-2-sulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[CH:24][S:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[CH:24][S:25][C:16]=12
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3ccsc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (336 mg, 1.75 mmol) and 60% sodium hydride (70 mg, 1.75 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 30 minutes. The solution is cooled and 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.02 mmol) is added. The reaction mixture is heated at reflux for 3.5 hours then allowed to stir at room temperature overnight. The resultant black solution is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 1:1 ethyl acetate:hexane. The fractions containing product are combined and concentrated. Diethyl ether is added and the insoluble material collected by filtration to provide 131 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a tan solid, mp 216–220° C.; 1 H NMR (DMSO-d6) δ 3.85 (s, 3H), 7.40 (3, 1H), 7.46 (d, J=5 Hz, 1H), 7.76 (s, 1H), 8.11 (d, J=5 Hz, 1H), 8.61 (s, 1H), 9.71 (s, 1H); MS 350.2 (M+H)+.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C(O)CO.CN(C)C=O.[C:39]1([SH:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>[Cu]I>[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([S:45][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:10]4[N:9]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Sc1ccccc1
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: OCCO
Product: c1ccc(Sc2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1
Temperature: 120 °C

Procedure:
Into a sealed tube was added (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine (0.125 g, 0.334 mmol), Sodium tert-butoxide (96.4 mg, 1.00 mmol), Copper(I) iodide (6.4 mg, 0.033 mmol), 1,2-Ethanediol (37.4 uL, 0.671 mmol), N,N-Dimethylformamide (4.7 mL, 6.0E1 mmol), and finally Benzenethiol (51.4 uL, 0.501 mmol). The reaction was heated at 120° C. overnight. The reaction was partitioned with DCM and water. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol) the collected fractions afforded (4-Morpholin-4-yl-phenyl)-(7-phenylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine an orange solid (72 mg, 53%). MP 143-145° C. LCMS (E/I+) 404.17 (M+H). NMR 1H (DSMO-d6)-9.33 (s, 1H), 8.97 (s, 1H), 7.45 (d, 2H, J=9.05 Hz), 7.30 (t, 2H, J=7.57 Hz), 7.18 (t, 1H, J=7.29), 7.12 (d, 2H, J=7.37 Hz), 7.01 (d, 1H, J=4.40 Hz), 6.93 (d, 1H, J=4.60 Hz), 6.75 (d, 2H, J=9.05 Hz), 3.73 (t, 4H, J=4.48 Hz), 3.00 (t, 4H, J=4.72 Hz).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].Br[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(N(CC)CCNCC)C>O1CCCC1.CCCCCC.O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:15]([CH2:16][CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(CCCCOCc1ccccc1)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CCNCCN(CC)CC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CC(CCCOCc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1

Procedure:
A solution of (R)-4-benzyl-3-(5-benzyloxypentanoyl)oxazolidin-2-one (132 g) in tetrahydrofuran (660 mL) was added dropwise to a mixture of sodium hexamethyldisilazane (1.9 M in tetrahydrofuran) (702 mL) and tetrahydrofuran (660 mL) at −78° C. The reaction temperature was rose to −40° C. To the mixture was added dropwise tert-butyl bromoacetate (85 mL) at −78° C. The reaction temperature was rose to −36° C. To the mixture was added dropwise N,N,N′-triethylethylenediamine (33 mL) at ice temperature. And then, to the mixture were added water (530 mL) and hexane (660 mL). The aqueous layer was removed, and the organic layer was washed with aqueous 20 w/v % citric acid (660 mL×3), water (660 mL), saturated aqueous sodium bicarbonate (660 mL) and brine (660 mL), then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (196 g) as a crude product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11](C(O)=O)[C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[NH2:39][C@@H:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@H:10]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24]
Reactant: Cc1cc(F)ccc1[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1C(=O)O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(F)ccc1[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Temperature: 100 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of (3R,4R)-1-(tert-butoxycarbonyl)-3-(4-fluoro-2-methylphenyl)piperidine-4-carboxylic acid (4.33 g) synthesized by a known method (WO2006/004195) in toluene (24 mL) were added DPPA (5.30 g) and triethylamine (2.7 mL) at room temperature, and the mixture was stirred at 100° C. for 1 hr. The reaction solution was cooled, 8N aqueous sodium hydroxide solution (16 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 30→70% ethyl acetate/hexane) to give the title compound (3.79 g, 96%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:12][C:13]1[C:29]([F:30])=[CH:28][C:16]2[NH:17][C:18]([S:20][C:21]3[O:25][C:24]([CH:26]=O)=[CH:23][CH:22]=3)=[N:19][C:15]=2[CH:14]=1.[C:31]1(=O)[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH2:32]1>C(O)C>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:26]([C:24]3[O:25][C:21]([S:20][C:18]4[NH:19][C:15]5[CH:14]=[C:13]([F:12])[C:29]([F:30])=[CH:28][C:16]=5[N:17]=4)=[CH:22][CH:23]=3)[C:32]3[C:33](=[O:37])[CH2:34][CH2:35][CH2:36][C:31]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: O=Cc1ccc(Sc2nc3cc(F)c(F)cc3[nH]2)o1
Reactant: O=C1CCCC(=O)C1
Reactant: CCOC(=O)c1[nH]ccc1N
Solvent: CCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3cc(F)c(F)cc3[nH]2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.5 %

Procedure:
A suspension of 308.3 mg (2.0 mmol) of 3-amino-2-ethoxycarbonylpyrrole and 560.5 mg (2.0 mmol) of 5-(5,6-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (obtained from step 1) in 10 mL of ethanol under argon is stirred at room temperature for 1 hour. 1,3-Cyclohexanedione (224.3 mg, 2.0 mmol) is then added and the reaction mixture is heated at reflux temperature for 16 h. The mixture is then cooled in an ice bath and the precipitate is filtered. The filtrate is concentrated to dryness under reduced pressure and the residue is purified by chromatography on a prepacked 90 g 15-40 μm silica gel cartridge (eluting solvent: ethyl acetate/cyclohexane 50/50 v/v; rate: 40 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is recrystallized from ethyl acetate/n-heptane and then from ethyl acetate, filtered and dried under reduced pressure. 189 mg of 9-[5-(5,6-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester are obtained as an off-white crystalline powder. mp: 160-170° C. LCMS: m/z 511: [M+H]+ (base peak); m/z 509: [M−H]− (base peak). The filtrate is concentrated to dryness under reduced pressure and the residue is purified by chromatography on a prepacked 90 g 15-40 μm silica gel cartridge (eluting solvent: ethyl acetate; rate: 40 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. 220 mg of additional 9-[5-(5,6-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester are obtained as an off-white powder. mp: 160-170° C. LCMS: m/z 511: [M+H]+ (base peak); m/z 509: [M−H]− (base peak).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH2:36]([O:43][C:44]([N:46]1[CH2:51][CH2:50][C:49]([CH2:58][C:59](O)=[O:60])([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:48][CH2:47]1)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[CH2:36]([O:43][C:44]([N:46]1[CH2:51][CH2:50][C:49]([CH2:58][C:59](=[O:60])[NH:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:48][CH2:47]1)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)CC1(c2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CC1(c2ccccc2)CCN(C(=O)OCc2ccccc2)CC1)NCc1ccccc1
Yield: 90.6 %

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.120 g, 0.271 mmol) was added to a solution of benzyl amine (0.030 mL, 0.271 mmol), 4-carboxymethyl-4-phenyl-piperidine-1-carboxylic acid benzyl ester (0.100 g, 0.247 mmol), triethylamine (0.103 mL, 0.741 mmol) in tetrahydrofuran (5 mL). After 1 hour the mixture was diluted with ethyl ether (20 mL), washed with saturated aqueous sodium bicarbonate (20 mL) followed by water (2×10 mL). Organic layer collected, concentrated under reduced pressure and crude product purified by column chromatography to give 0.099 g of 4-(benzylcarbamoyl-methyl)-4-phenyl-piperidine-1-carboxylic acid benzyl ester. LRMS m/z 443.2 (M+H)+.
Reaction SMILES: CN(C)C1C=CC(C=CC2C=CC(S(CC[CH2:22][O:23]C(C3CCCOC3)=O)(=O)=O)=CC=2)=CC=1.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([CH2:43][CH2:44][CH2:45][O:46][CH:47]2[CH2:52][CH2:51][CH2:50]CO2)(=[O:42])=[O:41])=[CH:36][CH:35]=1.[CH3:53][O:54][C:55]1[CH:62]=[C:61]([O:63][CH3:64])[CH:60]=[C:59]([O:65][CH3:66])[C:56]=1[CH:57]=O>ClCCl.C(OCC)(=O)C>[CH3:53][O:54][C:55]1[CH:62]=[C:61]([O:63][CH3:64])[CH:60]=[C:59]([O:65][CH3:66])[C:56]=1[CH:57]=[CH:33][C:34]1[CH:35]=[CH:36][C:37]([S:40]([CH2:43][CH2:44][CH2:45][O:46][CH:47]2[CH2:52][CH2:51][CH2:50][O:23][CH2:22]2)(=[O:41])=[O:42])=[CH:38][CH:39]=1
Reactant: CN(C)c1ccc(C=Cc2ccc(S(=O)(=O)CCCOC(=O)C3CCCOC3)cc2)cc1
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Reactant: Cc1ccc(S(=O)(=O)CCCOC2CCCCO2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(C=Cc2ccc(S(=O)(=O)CCCOC3CCCOC3)cc2)c(OC)c1

Procedure:
As in Example 3a 2.98 g (10 mmol) of 2a and 2.16 g (11 mmol) of 2,4,6-trimethoxybenzaldehyde give, after column chromatography [silica gel; dichloromethane/ethyl acetate mixtures], 1.28 g (27%) of yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH2:5][CH2:6][CH2:7][C:8](=[O:24])[C:9]=2[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:11]=1C(O)=O.S(=O)(=O)(O)O>C(O)C>[CH3:1][C:2]1[NH:3][C:4]2[CH2:5][CH2:6][CH2:7][C:8](=[O:24])[C:9]=2[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[CH:11]=1
Reactant: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C2=C(CCCC2=O)N1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC1=CC(c2cccc([N+](=O)[O-])c2)C2=C(CCCC2=O)N1
Yield: 39.6 %

Procedure:
2-Methyl-4-(3-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydro-3-quinolinecarboxylic acid (4.66 g) was suspended in ethanol (200 mL) with concentrated sulfuric acid (0.5 mL). The mixture was heated at reflux for 5 h, during which time all of the solid went into solution. The solvent was evaporated, and the residue was partitioned between aqueous 2N sodium hydroxide and ethyl acetate. The aqueous portion was extracted with ethyl acetate. The combined extracts were washed (water, brine), dried, and evaporated to yield a residue which was purified by chromatography, eluting with ethyl acetate, to afford the title compound as a pale yellow solid (1.6 g); mp 183°-185° C.; MS: 284 (M); 250 MHz NMR: 1.76 (s,3, CH3), 187 (m,2, CH2), 2.16 (m,2, CH2), 2.46 (m,2, CH2), 4.58 (d,1, J=4.9, CH), 4.64 (d,1, J=4.9, CH), 7.53 (t,1, 7.6, Ar), 7.62 (d, 1, J=7.6, Ar), 7.96 (s,1, Ar), 7.98 (m,1, Ar), 8.80 (s,1, NH). Analysis for C16H16N2O3 : Calculated: C, 67.59; H, 5.67; N, 9.85; Found: C, 67,44; H, 5.75; 9.56.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#N)[CH:5]=[CH:4][N:3]=1.[CH3:10][Mg]Br.[OH2:13].Cl>CCOCC>[CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:13])[CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: O
Reactant: C[Mg]Br
Reactant: Cc1cc(C#N)ccn1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)c1ccnc(C)c1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
A solution of 3.5 g. (29.7 mmoles) of 2-methyl-4-cyanopyridine in 20 ml. of dry ether was added dropwise to a cooled (5° C.) solution of 20 ml. of 3.0 M methyl magnesium bromide in ether. After addition was complete the mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was cooled to 5° C. and the excess Grignard reagent decomposed by the addition of water. The mixture was acidified with 6 N hydrochloric acid and the aqueous phase was separated. The ether phase was again extracted with 30 ml. of 1 N hydrochloric acid and the combined aqueous extracts were warmed on a steam bath for one hour. The aqueous solution was cooled, made basic with solid sodium bicarbonate and extracted with (3×100 ml.) ether. The combined ether extracts were dried and evaporated to give 2.1 g. (53%) of a yellow oil. b.p. 50°-53° C. (0.3 torr).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])C=1C#N.[CH3:11][Mg]Br.C([O:16][CH2:17][CH3:18])C>>[CH3:11][C:17]([C:18]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[F:10])=[O:16]
Reactant: CCOCC
Reactant: N#Cc1c(F)cccc1Cl
Reactant: C[Mg]Br
Product: CC(=O)c1c(F)cccc1Cl
Temperature: 35 °C
Reaction time: 8 h

Procedure:
2-chloro-6-fluorobenzonitrile (42.3 g, 0.27 mol) is dissolved in anhydrous diethyl ether (170 ml) and methyl magnesium bromide (291 ml of a 2.8 M solution, 0.82 mol) is added. The whole is warmed to reflux (35° C.) overnight (16 hrs.). Then the reaction mixture is quenched in ice-water (380 ml) followed by the addition of concentrated H2SO4 (95 ml). The resultant mixture is heated to 100° C. for 3 hours and stirred overnight at room temperature. Pure product is then extracted from the mixture using chloroform (45.0 g, 95.9%).