Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C([O-])(=O)C.[Na+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH2:26]Cl)[CH:23]=[CH:24][CH:25]=1>CS(C)=O>[F:18][C:19]([F:28])([F:29])[C:20]1[CH:21]=[C:22]([CH2:26][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Yield: 77.5 %

Procedure:
A solution of 8.0 grams (0.049 mole) of N-hydroxyphthalimide and 4.0 grams (0.059 mole) of sodium acetate in about 25 mL of dimethyl sulfoxide was stirred, and a solution of 11.5 grams (0.059 mole) of 3-trifluoromethylphenylmethyl chloride in about 15 mL of dimethyl sulfoxide was added dropwise during a 10 minute period. Upon completion of addition, the reaction mixture was heated to about 60° C. where it stirred until there was no apparent color change in the reaction mixture. The reaction mixture was then poured into an ice-water mixture. The resultant solid was collected and washed with water. The solid was then recrystallized with 100 mL of ethanol. The solid was collected by filtration and dried, yielding 12.2 grams of N-(3-trifluoromethylphenylmethoxy)phthalimide, mp 106°-108° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][O:27][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(NC3CCN(CCOc4ccc5ccccc5n4)CC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
5.5 Parts of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidineethanol and 135 parts of N,N-dimethyl-formamide were stirred at room temperature and 0.75 parts of a sodium hydride dispersion 50% were added. After stirring for one hour at room temperature, 2.5 parts of 2-chloroquinoline were added and the whole was stirred overnight at room temperature. The reaction mixture was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 4.3 parts (58%) of 1-[(4-fluorophenyl)-methyl]-N-[1-[2-(2-quinolinyloxy)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 149.9° C. (compound 77)
Reaction SMILES: [CH2:1]([C:3]([OH:16])([CH2:14][CH3:15])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10])[CH3:2].[C:17](#[N:19])[CH3:18]>>[CH2:1]([C:3]([OH:16])([CH2:14][CH3:15])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]([OH:10])[CH2:18][C:17]#[N:19])[CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: CC#N
Reactant: CCC(O)(CC)COc1cccc(C=O)c1
Product: CCC(O)(CC)COc1cccc(C(O)CC#N)c1

Procedure:
3-(2-Ethyl-2-hydroxybutoxy)benzaldehyde was reacted with acetonitrile following the method used in Example 13. Purification by flash chromatography (30, 40, 50, 75% EtOAc-hexanes step gradient) gave 3-(3-(2-ethyl-2-hydroxybutoxy)phenyl)-3-hydroxypropanenitrile as an oil. Yield (0.17 g, 79%): 1H NMR (400 MHz, CDCl3) δ 7.23 (t, J=8.0 Hz, 1H), 6.96-6.98 (m, 2H), 6.88-6.91 (m, 1H), 5.02 (t, J=6.4 Hz, 1H), 3.83 (s, 2H), 2.76 (d, J=6.8 Hz, 2H), 1.62-1.68 (m, 4H), 0.92 (t, J=7.6 Hz, 6H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=1)(=[O:3])[CH3:2].[Cl-].[NH4+]>C(O)C.[Fe]>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C(=O)c2cccc([N+](=O)[O-])c2)[nH]c2cc(Cl)ccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(=O)Nc1c(C(=O)c2cccc(N)c2)[nH]c2cc(Cl)ccc12

Procedure:
A mixture of 3-acetylamino-6-chloro-2-(3-nitrobenzoyl)indole (step 3, 2.68 g, 7.5 mmol), iron powder (1.7 g, 30 mmol) and ammonium chloride (0.8 g, 17 mmol) in 70% aqueous ethanol (70 ml) was heated at reflux for 1 h, and then cooled and filtered through a pad of Celite. The filtrate was concentrated and the residue partitioned between water (50 ml) and ethyl acetate (150 ml). The organic layer was separated, dried (MgSO4) and slovent removed by evaporation to afford 2.6 g (quant.) of the title compound as yellow amorphous solids. 1H-NMR (CDCl3) δ: 9.83 (1H, br s), 8.63 (1H, brs), 8.16 (1H, d, J=8.8 Hz), 7.35-7.21 (2H, m), 7.15-6.98 (3H, m), 6.88 (1H, dd, J=8.8, 1.8 Hz), 2.25 (3H, s) The signal due to NH2 was not observed.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([N+:31]([O-])=O)=[C:21]([CH:23]=[C:24]4[NH:28][C:27](=[O:29])[NH:26][C:25]4=O)[CH:22]=3)=[N:10][N:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.II>CN(C)C=O.[Pd]>[CH:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]4[N:31]=[C:25]5[NH:26][C:27](=[O:29])[NH:28][C:24]5=[CH:23][C:21]=4[CH:22]=3)=[N:10][N:9]=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1NC(=O)C(=Cc2cc(OCCCCc3nnnn3C3CCCCC3)ccc2[N+](=O)[O-])N1
Agent: [Pd]
Agent: II
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc3cc(OCCCCc4nnnn4C4CCCCC4)ccc3nc2[nH]1
Reaction time: 40 h
Yield: 20.4 %

Procedure:
A solution of 5-[[5-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-2-nitrophenyl]methylene-2,4-imidazolidinedione (12 g, 26 mmol) in dimethylformamide (200 mL) was hydrogenated at 55 p.s.i. over 10% palladium on charcoal (1.2 g) in a low pressure hydrogenation apparatus. After 40 hours, the mixture was filtered through kieselguhr, the solvent evaporated and the residue suspended in refluxing methanol. Iodine (6.69 g, 26 mmol) was added portionwise over 4 minutes, reflux continued for 10 minutes, and the mixture then concentrated in vacuo to approximately 70 mL. 10% Sodium thiosulate solution and 10% sodium carbonate solution was added, the mixture stirred for 5 minutes and a solid filtered off, washed with water and dried in air. This was dissolved in hot dimethylformamide and water added to precipitate a solid (4.80 g) which was dissolved in 10% hydrogen chloride in methanol. The methanol was removed and the residue crystallized from ethanol to give the hydrochloride salt of 7-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one (2.16 g, 18% overall), m.p. 288°-291° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][CH:33]([O:1][C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=2)[CH2:34][CH2:35]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: COC(=O)c1cc(O)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
To 4-hydroxy-2-(methoxycarbonyl)benzenamine (6.8 g), triphenylphosphine (14.2 g) and 4-hydroxy-N-(t-butoxycarbonyl)piperidine (9.06 g) in THF (200 mL) was added DEAD (9.51 g) drop-wise at ambient temperature. The reaction was stirred at ambient temperature for overnight, concentrated and re-dissolved in ether. The ether layer was washed with 0.5 N NaOH aqueous solution, water and brine. It was then concentrated and purified on silica gel column (ethyl acetate/hexane, gradient) to afford 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-2-(methoxycarbonyl)benzenamine (7.31 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[NH2:18])([O-:14])=[O:13]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:18][C:17]1[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Product: O=C(Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1cc(Br)ccc1O
Yield: 32.2 %

Procedure:
Using 5-bromosalicylic acid and 3,5-dinitroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:19][CH3:20])=[C:6]([CH:11]=[C:12]([Cl:18])[C:13]=1[NH:14][C:15](=[O:17])[CH3:16])[C:7]([O:9][CH3:10])=[O:8])[CH:2]=C.I([O-])(=O)(=O)=O.[Na+].C1CCCCC=1>C(O)CCC.O.O1CCOCC1.O.C(O)(C(F)(F)F)=O.C(Cl)Cl.[Os](=O)(=O)(=O)=O>[C:15]([N:14]1[C:13]2[C:4](=[C:5]([O:19][CH3:20])[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][C:12]=2[Cl:18])[CH:1]=[CH:2]1)(=[O:17])[CH3:16]
Reactant: C=CCc1c(NC(C)=O)c(Cl)cc(C(=O)OC)c1OC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1=CCCCC1
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)c2c(ccn2C(C)=O)c1OC
Reaction time: 0.5 h

Procedure:
A 2.5% solution of osmium tetroxide in butanol (0.25 ml) is added to a stirred solution of the methoxy compound from step 7 above (1.5 g) in H2O-dioxane (15 ml/45 ml) and stirred for 30 minutes. Sodium periodate (2.25 g) is added portionwise over one hour and the reaction mixture stirred for 31/2 hours. Cyclohexene (1 ml) is added, the mixture stirred for one hour, diluted with H2O and extracted with CHCl3. The organic layer is separated, dried (MgSO4) and evaporated affording a gum which is dissolved in TFA and allowed to stand for 15 minutes. The acid solution is diluted to 100 mls with CH2Cl2 and washed with H2O, saturated NaHCO3, dried (MgSO4) and evaporated affording a solid which is chromatographed on silica gel affording a colorless solid which is the indole as confirmed by NMR (270 MHz, CDCl2).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:29]=[C:28]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)[CH:27]=[CH:26][C:10]=1[CH2:11][NH:12][C:13](=[O:25])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH3:22])=[C:16]([O:23][CH3:24])[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:37][C:38]([O:40]C)=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]([CH2:37][C:38]([OH:40])=[O:39])[C:9]1[CH:29]=[C:28]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)[CH:27]=[CH:26][C:10]=1[CH2:11][NH:12][C:13](=[O:25])[C:14]1[CH:15]=[C:16]([O:23][CH3:24])[C:17]([CH3:22])=[C:18]([O:20][CH3:21])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCc2ccccc2)cc(OC)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N(CC(=O)O)Cc2ccccc2)cc(OC)c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
Compound 23a (163 mg, 0.35 mmol), methyl bromoacetate (0.166 mL, 1.75 mmol), and potassium carbonate (145 mg, 1.05 mmol) in DMF (2 mL) was sealed in a pressure tube and heated at 80° C. overnight. The reaction mixture was filtered through a silica gel pad in ethyl acetate and concentrated on a rotary evaporator. The residue was dissolved in a mixture of THF (3 mL) and MeOH (1 mL) and 10% LiOH (2 mL) was added. The reaction mixture was stirred overnight at rt. The reaction mixture was concentrated on a rotary evaporator, dissolved in water (50 mL), and acidified with conc. HCl. The white precipitate was filtered and dried invacuo to give compound 23b (155 mg, 83%). ESI-MS m/e 531.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:18][CH2:19][F:20]>CN(C)C=O>[F:20][CH2:19][CH2:18][C:8]([CH2:7][C:6]1[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: FCCBr
Reactant: COc1ccc(CC(C#N)C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CC(C#N)(C#N)CCF)cc1
Yield: 50.3 %

Procedure:
Using 0.37 g of (4-methoxybenzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.25 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.23 g of 2-(2-fluoroethyl)-2-(4-methoxybenzyl)malononitrile (the present compound (52)).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH2:37]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[CH:38]([CH3:40])[CH3:39]>ClCCl>[CH2:37]([N:41]1[CH2:46][CH2:45][N:44]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:31])[F:32])[CH3:23])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:43][CH2:42]1)[CH:38]([CH3:40])[CH3:39]
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: CC(C)CN1CCNCC1
Solvent: ClCCl
Product: CC(C)CN1CCN(Cc2cc3c(cn2)ncn3-c2cc(O[C@H](C)c3ccccc3C(F)(F)F)c(C(N)=O)s2)CC1

Procedure:
In a similar manner as described for example 58, 108 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 142.2 mg of 1-isobutylpiperazine in 2.5 ml dichloromethane give the title compound.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH3:17])[C:11]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[F:26])=[O:9])=C.Cl.[OH-].[Na+]>C(O)C.CCOC(C)=O.O>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH3:17])[C:11]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[F:26])=[O:9]
Reactant: C=COCCONC(=O)c1ccc(=O)n(C)c1Nc1ccc(C)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1ccc(Nc2c(C(=O)NOCCO)ccc(=O)n2C)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.9 %

Procedure:
To a solution of 2-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-vinyloxyethoxy)-amide (0.048 g, 0.13 mmol) in ethanol (5 mL) was added aqueous 2 M HCl (0.332 mL, 0.664 mmol). The reaction mixture was stirred for 16 hours at room temperature. The pH of the reaction mixture was adjusted with 1 M NaOH until 7. The reaction mixture was diluted with EtOAc and H2O. The organic layer was separated and washed with saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure to yield 0.044 g (100%) pure desired product as a pale yellow foamy solid. MS ESI (+) m/z 336 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 10.3 (s, 1H), 8.46 (s, 1H), 7.38 (d, 1H), 6.96-6.87 (m, 2H), 6.76 (t, 1H), 6.18 (d, 1H), 4.04 (m, 2H), 3.93 (br s, 1H), 3.75 (br s, 2H), 3.20 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(O[C:26]1[CH2:40][C@@H:39]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@H:38](/[CH:49]=[CH:50]/[C@@H:51]([O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH2:52][C@H:53]([CH3:58])[CH2:54][CH2:55][CH2:56][CH3:57])[C:27]=1[S:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])(=O)=O.C[Al](C)C.CCCCCC>ClCCCl.Cl.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.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CCOCC>[CH3:1][C:26]1[CH2:40][C@@H:39]([O:41][Si:42]([C:45]([CH3:47])([CH3:46])[CH3:48])([CH3:43])[CH3:44])[C@H:38](/[CH:49]=[CH:50]/[C@@H:51]([O:59][Si:60]([C:63]([CH3:66])([CH3:64])[CH3:65])([CH3:61])[CH3:62])[CH2:52][C@H:53]([CH3:58])[CH2:54][CH2:55][CH2:56][CH3:57])[C:27]=1[S:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35]
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(OS(=O)(=O)C(F)(F)F)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Al](C)C
Solvent: ClCCCl
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(C)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.1 %

Procedure:
To tetrakistriphenylphosphinepalladium prepared in advance in the system from tris(dibenzylideneacetone) dipalladium(0) (92 mg, 0.1 mmol) and triphenylphosphine (210 mg, 0.8 mmol) were added methyl (11R,12S,13E,15S,17R)-9-trifluoromethanesulfonyloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate 437 mg, 0.546 mmol) in 1,2-dichloroethane (5 mL) and 2M trimethylaluminum in hexane (0.423 mL, 0.846 mmol). This was agitated for 3 hours at room temperature. Ether was added to dilute the reaction solution, then the solution was poured in 1N hydrochloric acid. The desired product was extracted with ether from the mixture. The extract was washed with brine, then was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, then was purified by silica gel column chromotography (2% ethyl acetate/hexane) to obtain methyl (11R,12S,13E,15S,17R)-9-methyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (193 mg, 54%).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=O)([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][C:19](=[O:25])[NH:20]2>>[CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=[C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[CH:24][C:16]=2[CH3:15])[NH:20][C:19]1=[O:25])([CH3:3])[CH3:2]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: COc1cc(C)c(C=O)cc1C(C)C
Product: COc1cc(C)c(C=C2C(=O)Nc3cccc(C)c32)cc1C(C)C

Procedure:
5-Isopropyl-4-methoxy-2-methylbenzaldehyde was condensed with 4-methyl-2-oxindole to give 0.3 g of 3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [C:1]([N:4]1[CH2:11][CH2:10][CH2:9][C@H:5]1[C:6]([OH:8])=O)(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[C:32]([C:39]([OH:41])=[O:40])=[CH:31]2.C(N(CC)CC)C.Cl[Si](C)(C)C.N1CCC[C@H]1C(O)=O>ClCCl>[C:1]([N:4]1[CH2:11][CH2:10][CH2:9][CH:5]1[C:6]([NH:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[C:32]([C:39]([OH:41])=[O:40])=[CH:31]2)=[O:8])(=[O:3])[CH3:2]
Reactant: Nc1ccc2[nH]c(=O)c(C(=O)O)cc2c1
Reactant: CC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCC1C(=O)Nc1ccc2[nH]c(=O)c(C(=O)O)cc2c1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
A solution of 4.71 g (30 mmol) of N-acetyl-L-proline and 60 ml of dichloromethane is cooled to -18° and 3.3 ml (30 mmol) of N-methyl morpholine and 3.9 ml (30 mmol) of isobutyl chloroformate is added, and the reaction mixture is stirred for 30 minutes at -10° to -20°. A mixture of 4.08 g (20 mmol) of 6-amino-1,2-dihydro-2-oxo-3-quinolinecarboxylic acid, 150 ml of dichloromethane, 8.4 ml (60 mmol) of triethylamine, and 7.6 ml (60 mmol) of chlorotrimethylsilane is stirred at room temperature for 35 minutes. The silylation mixture is cooled to -20° and the mixed anhydride of proline is added and stirred with cooling overnight. The reaction mixture is evaporated to dryness, and the residue is treated with ethanol to yield 4.42 g of 6-[[(1-acetyl-2-pyrrolidinyl)carbonyl]-amino]-1,2-dihydro-2-oxo-3-quinolinecarboxylic acid, mp 303° dec.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=3[N:22]=[C:6]2[O:5][CH2:1][CH3:2])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Solvent: CC(=O)O
Product: CCOc1nc2cc(C)ccc2n1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 173 %

Procedure:
4-(2-Amino-4-methylphenylamino)-piperidine-1-carboxylic acid tert-butyl ester (361 mg, 1.18 mmol) was mixed with tetraethyl carbonate (272 mg, 1.20 eq) in 4 mL of acetic acid. The mixture was stirred at r.t for 4 hrs until all starting material was consumed. The solution was evaporated and the residue was extracted with ethyl acetate and concentrated NaHCO3 solution. The organic layer was dried and solvents were evaporated. The resulting residue was purified on a Biotage flash column chromatography using ethyl acetate and hexanes (1:2 ratio) to give 4-(2-ethoxy-5-methylbenzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (367 mg, 86%) as an oil. ES-MS showed m/e 360 (M++1). 1H-NMR (CDCl3) δ 7.33 (s, 1H), 7.10 (d, 1H), 6.92 (d, 1H), 4.58 (q, 2H), 4.23-4.33 (m, 3H), 2.83 (t, 2H), 2.41 (s, 3H), 2.25-2.31 (m, 2H), 1.82 (d, 2H), 1.49 (s, 9H), 1.46 (t, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[C:11]=2[CH:15]=O)[CH:6]=1)=[O:4].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][CH2:15][C:11]2[C:10]([O:17][CH3:18])=[CH:9][CH:8]=[C:7]3[C:12]=2[CH:13]=[CH:14][C:5]([C:3]([OH:2])=[O:4])=[CH:6]3)=[CH:22][CH:21]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ccc2c(C=O)c(OC)ccc2c1
Product: COc1ccc2cc(C(=O)O)ccc2c1CNCc1ccc(F)cc1

Procedure:
The title compound was prepared as a white solid (0.212 g, 34% for two steps) from 6-methoxy-5-formyl-2-naphthoic acid methyl ester using 4-fluorobenzyl amine and a procedure similar to steps 3-4 of Example 1, mp 268-270° C. (decomp.); 1H NMR (DMSO-d6) δ3.94 (s, 3H), 4.29 (s, 2H), 4.48 (s, 2H), 7.31 (t, J=8.9 Hz, 2H), 7.60 (d, J=9.2 Hz, 1H), 7.65 (dd, J=5.7, 8.6 Hz, 2H), 7.99 (dd, J=1.5, 8.9 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 8.28 (d, J=9.2 Hz, 1H), 8.60 (d, J=0.92 Hz, 1H), 9.07-9.42 (bs, 2H), 12.73-13.27 (bs, 1H); IR (neat) 3470, 3390, 2880-3080, 2820, 2760, 2680, 2610, 1710, 1630, 1600, 1595, 1515, 1485, 1465, 1445, 1270, 1260, 1235, 1210, 1195, 1185, 1095, and 1000 cm−1; mass spectrum [(+) ESI], m/z 340 (M +H)+ and [(−) ESI], m/z 338 (M−H)−; Anal. Calcd. for C20H18FNO3.HCl.0.5H2O: C, 62.42; H, 4.98; N, 3.64, Found: C, 62.07; H, 5.37; N, 3.53.