Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][C:10]2=[O:22])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:22])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C1CNCCN1Cc1ccccc1

Procedure:
A mixture of 1,4-bis(phenylmethyl)piperazinone hydrochloride (XIII, Example 39, 15.0 g.) and 10% palladium charcoal (5.0 g.) in ethanol (200 ml.) is hdyrogenated (50 lb. initial hydrogen pressure) until uptake of hydrogen ceased. The solution is filtered, the ethanol is removed under reduced pressure and the residual solid is recrystallized from methanol-isopropanol to give the title compound, m.p. 160°-161°.
Reaction SMILES: C(S[C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]2=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)C.[CH2:32]([C:34]1NC2=NC=CC(C)=C2N=1)[CH3:33]>>[CH3:12][C:11]1[CH:10]=[CH:9][N:8]=[C:7]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:4]([C:33]#[C:32][CH3:34])=[N:5][C:6]=12
Reactant: CCSc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CCc1nc2c(C)ccnc2[nH]1
Product: CC#Cc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
2-Ethylthio-7-methyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridine p0 3-{(2'-Carboxybiphenyl-4-yl)methyl{-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[F:10].[CH3:11][C:12]#[C:13][N:14]1[CH2:19][CH2:18][C@@H:17]([CH2:20][CH2:21][C:22](=[O:35])[C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)[C@@H:16]([C:36]([O:38][CH3:39])=[O:37])[CH2:15]1>C(N(CC)CC)C.O.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>[F:10][C:3]1[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[C:11]#[C:12][CH2:13][N:14]1[CH2:19][CH2:18][C@@H:17]([CH2:20][CH2:21][C:22](=[O:35])[C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)[C@@H:16]([C:36]([O:38][CH3:39])=[O:37])[CH2:15]1
Reactant: Fc1cc(F)c(F)c(Br)c1
Reactant: CC#CN1CC[C@@H](CCC(=O)c2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 80 °C

Procedure:
4.05 g of tetrakis(triphenylphosphine)palladium, 0.834 g of cuprous iodide and 7.9 cm3 of 1-bromo-2,3,5-trifluorobenzene are added at a temperature in the region of 20° C., with stirring and under an inert atmosphere, to a solution of 17.28 g of methyl (3R,4R)-1-(3-prop-2-ynyl)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 173 cm3 of triethylamine. After heating for 2 hours at a temperature in the region of 80° C., the reaction mixture is cooled to approximately 20° C., diluted with 100 cm3 of water and then extracted with 4 times 150 cm3 of ethyl acetate. The organic extracts are combined, washed with 5 times 100 cm3 of water, dried over sodium sulfate, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue is purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45μ; diameter 7 cm; mass 600 g), elution being carried out with ethyl acetate. Fractions 3 to 11 are combined and then concentrated under the above conditions. 18.4 g of methyl (3R,4R)-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@@H:16]([C:37]([O:39][CH3:40])=[O:38])[NH:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:41]([O:43][C:44]1[C:45](=O)[C:46](=[O:51])[C:47]=1[O:48]CC)[CH3:42]>C(Cl)Cl.CCOC(C)=O>[CH2:41]([O:43][C:44]1[C:47](=[O:48])[C:46](=[O:51])[C:45]=1[NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C@@H:16]([C:37]([O:39][CH3:40])=[O:38])[NH:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)[CH3:42]
Reactant: COC(=O)[C@H](COc1ccc(-c2cccc(N)c2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1c(Nc2cccc(-c3ccc(OC[C@H](NC(c4ccccc4)(c4ccccc4)c4ccccc4)C(=O)OC)cc3)c2)c(=O)c1=O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
The compound of Example 3 (1.50 g, 2.8 mmol, 1 equiv) was dissolved in 3,4-diethoxy-3 cyclobutene-1,2-dione (2.1 mL, 14.2 mmol, 5 equiv). The reaction mixture was stirred at 60-70° C. for 1 h. It was then allowed to cool to rt and diluted with CH2Cl2/EtOAc 9:1 (12 mL). The solution was filtered over a pad of silica gel and eluted with CH2Cl2/EtOAc 9:1. Unreacted 3,4-diethoxy-3-cyclobutene-1,2-dion eluted first followed by the title compound. Yield 0.68 g, 36.7%. 1H NMR (CDCl3, 7.72-7.51 (m, 8H); 7.48-7.32 (m, 3H); 7.29-7.03 (m, 10H); 6.94 (d, 2H); 4.94 (q, 2H); 4.29 (dd, 1H); 4.14 (dd, 1H); 3.85-3.69 (m, 1H); 3.23 (s, 3H); 2.90 (d, 1H); 1.55 (t, 3H). MS (ESI) 675 (M+Na), 653 (M+H), 243 (CPh3).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:14][CH:13]=1>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][N:23]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:24][CH2:25]2)=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)N1CCN(CCc2ccc(Cl)cc2)CC1
Reaction time: 1 h

Procedure:
A solution of 4.65 g of 4-chlorobenzoyl chloride in 50 ml of methylene chloride is added dropwise, over a period of 10 minutes, to a solution, stirred at room temperature, of 5 g of 1-[2-(4-chlorophenyl)-ethyl]-piperazine in 75 ml of methylene chloride. The reaction mixture is heated under reflux for 5 minutes, allowed to stand at room temperature for 1 hour and then concentrated by evaporation. The residue is made into a slurry with hot acetone and, after the addition of hexane, the whole is filtered. 1-[2-(4-chlorophenyl)-ethyl]-4-(4-chlorobenzoyl)-piperazine is obtained and can be purified and characterised via the hydrochloride which has a melting point of 254°-254.5° (decomposition).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:24]=[N:25][N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:27]=3)=[CH:13][CH:12]=2)[C:8]2[CH:47]=[CH:48][CH:49]=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>Cl.O1CCOCC1.O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:47]=[CH:48][CH:49]=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 1.5 h
Yield: 37.4 %

Procedure:
2-Butyl-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]benzimidazole (E) (400 mg) was dissolved in an 8M solution of hydrogen chloride in dioxan (5 ml) and water (0.5 ml) was added. The solution was allowed to stand for 1.5 hours and then volatile material was removed by evaporation. The residue was partitioned between sodium hydrogen carbonate solution (10 ml) and ether (10 ml). The aqueous phase was separated, washed with ether (3×10 ml) and acidified to pH4 with 20% aqueous citric acid. The precipitated solid was collected and recrystallised from ethyl acetate to give 2-butyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]benzimidazole (94 mg), as white crystals, m.p. 230°-232° C.; NMR (d6 -DMSO): 0.88(t,3H), 1.35(m,2H), 1.7(m,2H), 2.8(t,2H), 5.5(s,2H), 7.0(s,4H), 7.15(m,2H), 7.4-7.7 (complex, 6H); mass spectrum (-ve FAB, DMSO/NBA): 407 (M-H)-, 379; microanalysis found: C,73.7; H,6.2; N,20.8; C25H24N6 requires: C,73.5; H,5.9; N,20.6%.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[CH:16][CH2:17][CH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=2)=[CH:21][CH:20]=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[OH-].[Na+]>ClCCCl>[C:36]1([NH:35][CH2:16][CH2:17][CH2:18][C:19]2[CH:34]=[CH:33][C:22]([O:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NC(=O)c1ccc(Oc2ccc(CCC=O)cc2)nc1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2ccc(CCCNc3ccccc3)cc2)nc1
Yield: 8.2 %

Procedure:
Add sodium triacetoxyborohydride (0.1633 g, 0.7705 mmol) to a stirred solution of 6-[4-(3-oxo-propyl)-phenoxy]-nicotinamide (0.1341 g, 0.4962 mmol), aniline (0.047 mL, 0.5158 mmol), and 1,2-dichloroethane (7 mL). Stir the reaction for 18 h at room temperature under nitrogen. Pour the reaction mixture into 1 N sodium hydroxide (50 mL), extract with dichloromethane (3× 50 mL), dry the dichloromethane extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 0.6% concentrated ammonium hydroxide/6% ethanol/chloroform to yield 0.0142 g (8%) of 6-[4-(3-phenylamino-propyl)-phenoxy]-nicotinamide: mass spectrum (ion spray): m/z=348.1 (M+1); 1H NMR (CDCl3): 8.58 (d, 1H), 8.16 (dd, 1H), 7.26-7.1 (m, 7H), 7.10-7.04 (m, 2H), 6.97-6.94 (m, 1H), 6.79-6.51 (m, 2H), 3.19 (t, 2H), 2.76 (t, 2H), 2.04-1.97 (m, 3H).
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)=[O:4].[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([CH:2]([CH3:16])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=2)=[O:4])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(C(=O)C(C)Br)ccc1O
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1cc(C(=O)C(C)N2CCC(Cc3ccccc3)CC2)ccc1O
Reaction time: 1 h

Procedure:
300 ml of methyl ethyl ketone containing 57.4 g of 2-bromo-4'-hydroxy-3'-methoxycarbonylpropiophenone, 35 g of 4-benzylpiperidine and 30.6 g of potassium carbonate are heated under reflux for 4 hours. The precipitate is filtered off hot, the filtrate is evaporated to dryness, the residue is taken up in 3N hydrochloric acid and the mixture is extracted with diethyl ether. The ether phase is stirred for one hour; the hydrochloride crystallizes and is filtered off, rinsed with diethyl ether and transferred to a beaker containing water rendered alkaline with 3N aqueous ammonia solution, and the base freed in this way is extracted with ethyl acetate. After washing, drying and evaporation of the organic phase, 52 g of product are obtained, which is used as such.
Reaction SMILES: C(Br)C.Cl[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1.CN([CH:16]=[O:17])C>C1COCC1>[CH:9]([C:8]1[CH:11]=[CH:12][C:5]([CH:16]=[O:17])=[CH:6][CH:7]=1)=[CH2:10]
Reactant: C=Cc1ccc(Cl)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCBr
Product: C=Cc1ccc(C=O)cc1
Reaction time: 2 h
Yield: 95 %

Procedure:
7.6 gms (0.312 moles) of Mg tunings were transferred to an RB flask containing 50 ml of dry THF under nitrogen atmosphere. 2 ml of ethyl bromide was then added to the Mg metal and the reaction mixture was warmed to 50°-55° C. The mixture reacted vigorously and activated Mg metal was formed. A solution of 20 ml (0.156 moles) of 4-chlorostyrene in 50 ml of THF was added dropwise at room temperature to the activated Mg. The reaction mixture was stirred for an additional two hours. A dark gray solution appeared and was allowed to settle down. In a separate IL RB flask, a solution of 12 ml (0.15 moles) of anhydrous DMF was prepared in 300 ml of THF. The DMF solution was cooled in an icebath under dry nitrogen atmosphere for 15 mins. Grignard reagent was added dropwise to the DMF solution over a period of 1 hr with vigorous stirring. The reaction flask was then allowed to stir for three hrs. at 5° C. and RT overnight. The reaction was quenched by pouring the entire reaction mixture into 300 ml of dilute HCl in an icebath. The product was separated by solvent extraction with ether. The ether layer was dried over anhyd. MgSO4 and filtered. Finally, ether was evaporated under reduced pressure. A viscous yellow liquid was obtained and was dried under vacuum for 2 hrs and stored in a freezer at -10° C. containing a small amount of hydroquinone as an inhibitor. A yield of 65% high purity (above 95%) 4-vinyl benzaldehyde was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][CH2:6][C:7]1[C:14]([F:15])=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:16])[CH:8]=1.C(=O)([O-])[O-:22].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][CH2:6][C:7]1[C:14]([F:15])=[CH:13][C:10]([C:11]([NH2:12])=[O:22])=[C:9]([F:16])[CH:8]=1
Reactant: N#Cc1cc(F)c(COc2ccc(Cl)c(Cl)c2)cc1F
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(F)c(COc2ccc(Cl)c(Cl)c2)cc1F
Reaction time: 3 h
Yield: 37.6 %

Procedure:
To a stirred solution of 4-((3,4-dichlorophenoxy)methyl)-2,5-difluorobenzonitrile (Preparation 23, 153 mg, 0.481 mmol) in DMSO (5 mL) was added potassium carbonate (133 mg, 0.962 mmol), followed by dropwise addition of 30% aqueous hydrogen peroxide solution (0.29 mL, 2.90 mmol). After 3 hours, the reaction was quenched with saturated aqueous potassium bisulphate solution (10 mL), and extracted with DCM (3×10 mL). The combined organics were washed with brine (2×10 mL), dried over magnesium sulphate, and concentrated in vacuo to afford the title compound as a white solid (60 mg, 38%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([CH2:17][CH:18]=[CH2:19])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH2:20](Br)[CH:21]=[CH2:22].O>CN(C)C=O>[CH2:17]([C:4]1([O:3][CH2:22][CH:21]=[CH2:20])[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:8][CH2:9]1)[CH:18]=[CH2:19]
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC1(CC=C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 12 g, 0.3 mol) was added slowly to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl 4-hydroxy-4-(2-propenyl)-1-piperidinecarboxylate (Description 129, 23.1 g, 0.096 mol) in dimethylformamide (200 mL) and the mixture was stirred at 0° C. for 10 minutes. Allyl bromide (25.4 ml, 0.3 mol) was added and the mixture was stirred at 0° C. for 5 minutes, then at room temperature for 45 minutes. The mixture was cooled to 0° C. and water (200 mL) was added. The mixture was extracted with diethyl ether (2×200 mL) and the combined organic fractions were washed with water (4×200 mL) and brine (150 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (9:1), to give the title compound (5.5 g, 20%). m/z (E) 226 (M+1-C4H8).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[CH:8][C:9]2[O:21][CH2:20][CH2:19][C:12]3([S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])[C:10]=2[CH:11]=1>>[F:5][C:6]1[CH:7]=[C:8]([N+:1]([O-:4])=[O:2])[C:9]2[O:21][CH2:20][CH2:19][C:12]3([S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])[C:10]=2[CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: O=C1NC(=O)C2(CCOc3ccc(F)cc32)S1
Product: O=C1NC(=O)C2(CCOc3c([N+](=O)[O-])cc(F)cc32)S1
Temperature: 0 °C

Procedure:
Into 2.5 ml of fuming nitric acid (96%, d 1.50), which had been cooled to -20° C. while stirring, there was introduced rapidly 500 mg of (±)-6-fluoro-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione so that the temperature did not exceed -15° C. After stirring at -20° C. for 3 minutes, there was obtained a clear solution which was then poured immediately on to 15 ml of ice-water. After stirring briefly, the resulting precipitate was filtered, washed with cold water and dried. There was obtained (±)-6-fluoro-8-nitro-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione in the form of yellow crystals which melted at 192°-194° C. after recrystallization from ethyl acetate/hexane.
Reaction SMILES: Cl.[F:2][C:3]12[CH2:11][CH:7]3[CH2:8][CH:9]([CH2:10]1)[C:5]([NH2:12])([CH2:6]3)[CH2:4]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]#[N:29])=[O:22]>CS(C)=O.CCOC(C)=O>[F:2][C:3]12[CH2:11][CH:7]3[CH2:6][C:5]([NH:12][CH2:20][C:21]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[C:28]#[N:29])=[O:22])([CH2:4]1)[CH:9]([CH2:8]3)[CH2:10]2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: NC12CC3CC1CC(F)(C3)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(F)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.5 %

Procedure:
To a stirred mixture of the hydrochloride salt obtained from step II (0.19 g, 0.98 mmol) and K2CO3 (0.53 g, 4.0 mmol) in DMSO (4.0 mL) at ice bath temperature under nitrogen atmosphere (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 1.0 mmol) was added. After stirring the reaction mixture at r.t. for 3 h, the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-[N-(2-fluorohexahydro-2,5-methanopentalen-3a(1H)-yl) glycyl]pyrrolidine-2-carbonitrile as an off-white solid (0.11 g) in 38% yield. m/z (M+1) 292; 1H NMR (CDCl3) 300 MHz δ 4.80-4.73 (m, 1H), 3.77-3.32 (m, 2H), 3.52 (s, 2H), 2.50-2.42 (m, 1H), 2.87-2.08 (m, 6H), 2.0-1.60 (m, 6H), 1.50-1.42 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17].[O:20]1[CH2:23][CH:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)[CH2:21]1.C(N(CC)CC)C>C(O)(C)C>[I:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:2]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([N:27]3[CH2:28][CH2:29][N:24]([CH:22]4[CH2:23][O:20][CH2:21]4)[CH2:25][CH2:26]3)=[CH:36][CH:35]=2)[N:10]=1
Reactant: C[Si](C)(C)CCOCn1cnc2c(Cl)nc(I)nc21
Reactant: Nc1ccc(N2CCN(C3COC3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C[Si](C)(C)CCOCn1cnc2c(Nc3ccc(N4CCN(C5COC5)CC4)cc3)nc(I)nc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
A mixture of 117b (2.05 g, 5.0 mmol), 117e (1.17 g, 5.0 mmol), and triethylamine (1.01 g, 10 mmol) in i-propanol (30 mL) was stirred at 80° C. for 4 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 117f (1.82 g, 60%) as a yellow solid. MS-ESI: [M+H]+ 608.1
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:9][N:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.[CH3:20][N:21]([CH:23](OC)OC)[CH3:22]>CN(C=O)C.CCOCC>[F:8][C:7]1[C:2]([N:1]=[CH:20][N:21]([CH3:23])[CH3:22])=[N:3][C:4]([O:9][N:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:5][CH:6]=1
Reactant: COc1ccc(C=NOc2ncc(F)c(N)n2)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(C=NOc2ncc(F)c(N=CN(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a magnetically stirred suspension of 4-methoxybenzaldehyde O-(4-amino-5-fluoropyrimidin-2-yl)oxime (0.075 g, 0.29 mmol) in anhydrous DMF (0.2 mL) was added DMF-DMA (0.068 g, 0.57 mmol) and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with Et2O (10 mL) and then was cooled to 0° C. The resulting solid was collected by vacuum filtration, and the cake was washed with cold Et2O followed by hexanes. The precipitate that formed in the filtrate was collected by vacuum filtration and the combined solids were dried under vacuum to give N′-{5-fluoro-2-[1-(4-methoxyphenyl)-methylideneaminooxy]pyrimidin-4-yl}-N,N-dimethylformamidine (0.069 g, 76%) as a white solid: mp 243-245° C. dec; 1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.60 (s, 1H), 8.26 (d, J=2.7 Hz, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.05 (d, J=8.6 Hz, 2H), 3.82 (s, 3H), 3.21 (s, 3H), 3.10 (s, 3H); ESIMS m/z 318 ([M+H]+).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:32][C:29]2[CH:28]=[CH:27][C:26]([O:25][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:31][CH:30]=2)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCOc1ccc(O)cc1
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(OCCCCCC)cc2)cc1
Reaction time: 8 h
Yield: 50.4 %

Procedure:
In tetrahydrofuran were dissolved 1.0 g of p-octyloxybenzoic acid chloride and 800 mg of p-hexyloxyphenol, and 500 mg of triethylamine was added to the solution and reaction was carried out with stirring overnight. The precipitate was removed by filtration, and the filtrate was concentrated, purified by using a silica gel column and recrystallized from ethanol to obtain 800 mg of 4-hexyloxyphenyl 4-octyloxybenzoate. The phase transition temperatures of the so-obtained compounds are as follows. ##STR142##
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:27]=1[CH:28]=[CH:29][C:30]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:31]
Reactant: O=C(O)C=Cc1c(F)cccc1F
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1c(F)cccc1F
Yield: 86.1 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 2,6-difluorocinnamic acid (2.6 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (3.9 g, 85%) as an oily product.