Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:18][C:19]1[CH:20]=[N:21][N:22]([CH2:24][C@H:25]2[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2)[CH:23]=1>O1CCOCC1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:20]=[N:21][N:22]([CH2:24][C@H:25]3[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]3)[CH:23]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(N)cn2)C1
Reactant: Clc1ncnc(Cl)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(Cl)n3)cn2)C1
Temperature: 110 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine (1.8 g, 6.4 mmol) in dioxane (20 mL) was added diisopropylethylamine (4 mL), followed by the addition of (S)-tert-butyl 2-((4-amino-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (1.2 g, 7.2 mmol). The reaction mixture was stirred at 110° C. for 1 hour, and LCMS (liquid chromatography-mass spectrometry) showed the reaction was completed. The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with petroleum ether:ethyl acetate=5:1, to afford (S)-tert-butyl 2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate as a yellow solid (1.8 g, 70%). MS (ES+) C16H22ClN7O3 requires: 395, 396, found: 396, 397 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9](C(OC)=O)#[C:10][C:11](OC)=[O:12]>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[CH:9][CH:10]=[C:11]2[OH:12]
Reactant: Nc1ccccc1Cl
Reactant: COC(=O)C#CC(=O)OC
Product: Oc1ccnc2c(Cl)cccc12

Procedure:
In the manner of Examples III.A. and B., 8-chloro-4-hydroxyquinoline was prepared from 2-chloroaniline and dimethyl acetylenedicarboxylate.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CCCCCC.C([Li])CCC.[Cl-:25].[Cl-].[CH3:27][C:28]1([Zr+2:33][C:34]2([CH3:39])[CH:38]=[CH:37][CH:36]=[CH:35]2)[CH:32]=[CH:31][CH:30]=[CH:29]1>C(OCC)C>[Cl-:25].[CH3:27][C:28]1([Zr+:33]([C:34]2([CH3:39])[CH:38]=[CH:37][CH:36]=[CH:35]2)[C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)[CH:29]=[CH:30][CH:31]=[CH:32]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC1([Zr+2]C2(C)C=CC=C2)C=CC=C1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1([Zr+](c2cccc3c2Cc2ccccc2-3)C2(C)C=CC=C2)C=CC=C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
About 2.4 mmol of fluorene was dissolved in 50 ml of diethylether and mixed with 1.5 ml of a 1.6M hexane solution of butyllithium and stirred for 2 hrs at room temperature. Then 0.77 g of bis(methylcyclopentadienyl) zirconium dichloride was added. The reaction mixture was then stirred for an addition 90 mins. Then the solvent was removed using a vacuum. The residue was extracted with toluene and a suspension filtered over sodium sulfate. The filtrate was freed from solvent and taken up in 50 ml of diethylether. Crystallization at -30° C. yields the product bis(methylcyclopentadienyl) (fluorenyl) zirconium chloride, referred to hereinafter as Catalyst No. 79. The x-ray analysis of the solid Catalyst No. 79 is believed to demonstrate that the fluorenyl is a σ-bound ligand rather than a π-bound ligand.
Reaction SMILES: [F:1][C:2]1[N:3]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=[C:5]([CH:7]=O)[N:6]=1.[CH2:28](P(=O)(OCC)OCC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[H-].[Na+].O>COCCOC>[F:1][C:2]1[N:3]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=[C:5](/[CH:7]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:6]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1nc(/C=C/c2ccccc2)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
To a stirred mixture of 2-fluoro-4-formyl-1-triphenylmethylimidazole (0.356 g.) and diethyl benzylphosphonate (0.228 g.) in 1,2-dimethoxyethane under an argon atmosphere at room temperature was added sodium hydride (0,048 g.). Stirring was continued for 18 hours and then water (15 ml.) was added. The precipitate was filtered and dried to give 2-fluoro-1-triphenylmethyl-4-(2-phenyl-trans-vinyl)imidazole (0.415 g.), m.p. 167°-170°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([N+:8]([O-:10])=[O:9])[C:6](=O)[CH:5]=[C:4]([CH3:12])[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:6]1[CH:5]=[C:4]([CH3:12])[N:3]=[C:2]([CH3:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC1=CC(=O)C([N+](=O)[O-])C(C)=N1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)c([N+](=O)[O-])c(C)n1

Procedure:
By the method of Yakugaku Zasshi, 87, 387 (1967), 2,6-dimethyl-3-nitro-4-pyridone (11.23 g, 66.8 mmol) and phosphorus oxychloride (57 ml) were heated together at reflux for 11/2 hours. The excess reagent was removed under reduced pressure, and the residue dissolved in dichloromethane (150 ml). This solution was treated with dilute aqueous sodium bicarbonate until the aqueous layer was at pH 7, and then the organic phase was separated, dried (MgSO4) and concentrated under reduced pressure to give a pale yellow solid, (9.8 g, 79%). Caution: this compound is believed to be a powerful skin irritant.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[N:8][N:9]([CH2:14][CH3:15])[C:10]=1[C:11](O)=[O:12]>>[Cl:5][C:6]1[CH:7]=[N:8][N:9]([CH2:14][CH3:15])[C:10]=1[C:11]([Cl:3])=[O:12]
Reactant: CCn1ncc(Cl)c1C(=O)O
Reactant: O=S(Cl)Cl
Product: CCn1ncc(Cl)c1C(=O)Cl
Temperature: 80 °C

Procedure:
Thionyl chloride (5 ml) was added to 4-chloro-1-ethyl-1H-pyrazole-5-carboxylic acid (1 g) and the reaction was heated at 80° C. for 6 h then cooled to room temperature overnight. The reaction was evaporated, then azeotroped with toluene to give title compound, 970 mg.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]=[C:21]([CH3:24])[NH:22][CH:23]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[N:20]=[C:21]([CH3:24])[N:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:23]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: Cc1nc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)nc1C
Temperature: 50 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)-4-[(2-methyl-1H-imidazol-4-yl)carbonyl]piperazine (0.50 g, 1.53 mmol), methyl bromoacetate (0.28 g, 1.84 mmol) and potassium carbonate (0.63 g, 4.6 mmol) in N,N-dimethylformamide (5 mL) was stirred at 50° C. for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate 50:50). The residue was washed with hexane-ethyl acetate and purified by silica gel column chromatography (hexane/ethyl acetate 50:50 to 0/100 then ethyl acetate/methanol 100/0 to 90/10) to give the title compound (0.25 g, 40%) as a white solid.
Reaction SMILES: Br[C:2]1[O:6][C:5]2[C:7]([O:13]C(=O)C)=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:17](=[O:30])[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1.[C-:31]#[N:32].[Na+]>CS(C)=O>[C:31]([C:2]1[O:6][C:5]2[C:7]([OH:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:17](=[O:30])[C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=1)#[N:32]
Reactant: [C-]#N
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(C(=O)c2c(C#N)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 3.5 h

Procedure:
A mixture of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzo[b]furan (25 mg, 0.05 mmol) and sodium cyanide (15 mg, 0.38 mmol) in dry DMSO (1 mL) under nitrogen at room temperature was stirred for 3.5 hours (tlc), quenched with saturated ammonium chloride solution and diluted with ethyl acetate (20 mL). The organic layer was separated, dried over magnesium sulfate and solvent was distilled to afford the crude material which was purified over silica gel column (eluent-Hexane: diethyl-ether 1:1 to 0:100) to afford 2-cyano-7-hydroxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzo[b]furan as pale cream solid; (13 mg, 65%); 1H NMR (300 MHz, CDCl3) δ: 7.29(d, 1H, J=8.71 Hz), 7.19(s, 2H, benzoyl Hs), 6.06(d, 1H, J=8.77 Hz), 5.82(b, 1H, OH), 3.99(s, 3H, OMe), 3.96(s, 3H, OMe), 3.88(s, 6H, 2×OMe).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[I:12].[CH3:13]C([O-])(C)C.[K+].IC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([CH3:13])[N:6]=[C:5]2[I:12]
Reactant: Clc1cc2[nH]nc(I)c2cc1Cl
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2cc(Cl)c(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of 5,6-dichloro-3-iodo-1H-indazole (820 mg, 2.62 mmol) in THF (8 ml) at 0° C. was added KOt-Bu (412 mg, 3.67 mmol). The reaction mixture was stirred at 0° C. for 30 min then added iodomethane (0.23 ml, 3.67 mmol). Stirred at 0° C. for 30 min then warmed to room temperature and stirred for 1.5 hr. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated. The crude residue was absorbed on silica gel and purified by chromatography with 20% to 30% EtOAc/hexanes to afford 585 mg (68%) of 5,6-dichloro-3-iodo-1-methyl-1H-indazole as a light yellow solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.61 (s, 1H), 7.56 (s, 1H), 4.09 (s, 3H). The minor 5,6-dichloro-3-iodo-2-methyl-1H-indazole regioisomer was also observed but not isolated.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1.O.[NH2:33][NH2:34]>>[NH:33]([C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1)[NH2:34]
Reactant: CCc1nc2c(C)cc(Br)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: NN
Solvent: O
Product: CCc1nc2c(C)cc(NN)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of 5-Bromo-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine. (2.0 g), and hydrazine hydrate (15 mL) was heated to 120° C. for 24 hours. Concentration and purification (SiO2, 85/14/2 CH2Cl2 /MeOH/NH4OH) gave 1.80 g of 5-hydrazino-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine. Reduction in methanol (50 mL) under 1 atm. H2 with W-2 Raney nickle (1 mL, 50% dispersion/water) at RT for 48 hours gave the title compound (1.44 g) after purification (SiO2, 85/14/2 CH2Cl2 /MeOH/NH4OH).
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].Cl[CH2:6][C:7]1[CH:12]=[C:11]([C:13]([NH:15][C:16]2[S:17][C:18]([C:26]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[O:14])[CH:10]=[CH:9][N:8]=1.O>CN(C=O)C>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:19]1[N:20]=[C:16]([NH:15][C:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([CH2:6][O:4][CH3:3])[CH:12]=2)=[O:14])[S:17][C:18]=1[C:26]([CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]
Reactant: CO
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccnc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1cc(C(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)ccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under ice-cooling, 60% sodium hydride (10.0 mg, 0.250 mmol) was dissolved in DMF (1.0 mL), methanol (110 μL, 2.72 mmol) was slowly added dropwise thereto, and the mixture was stirred at 0° C. for 10 min. Then, 2-(chloromethyl)-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-4-carboxamide (81.0 mg, 0.189 mmol) obtained in step 1 of Reference Example 6, which was dissolved in DMF (1.0 mL), was slowly added dropwise thereto, and the mixture was stirred at room temperature for 5 hr. To the mixture were added water and a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50), and recrystallized from ethanol-water to give compound (IJ) (45.0 mg, 56%) as white crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[C:9]([C:18]#[N:19])=[N:10][CH:11]=[C:12]([NH:14][CH2:15][CH2:16][OH:17])[N:13]=1.Cl.[CH2:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][CH2:24][NH:23][CH2:22]1>CN(C)C=O>[OH:17][CH2:16][CH2:15][NH:14][C:12]1[N:13]=[C:8]([N:23]2[CH2:22][CH2:21][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][CH2:24]2)[C:9]([C:18]#[N:19])=[N:10][CH:11]=1
Reactant: c1ccc2c(c1)CCNCC2
Reactant: N#Cc1ncc(NCCO)nc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ncc(NCCO)nc1N1CCc2ccccc2CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
0.415 g (3.00 mmol) of potassium carbonate were added slowly at room temperature to a solution of 0.243 g (1.0 mmol) of the 3-bromo-5-(2-hydroxy-ethylamino)-pyrazine-2-carbonitrile and 0.220 g (1.2 mmol) of the 2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (J. Heterocycl. Chem. 1971, 8(5), 779-83) in 10.0 ml of N,N-dimethyl-formamide. The reaction mixture was stirred at room temperature for 64 hours and at 80° C. for 5 hours. It was subsequently poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 9:1 to 0:10 v/v gradient of hexane and ethylacetate as the eluent giving 0.308 g (1.0 mmol, 100% of theory) of the 5-(2-hydroxy-ethylamino)-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile as light yellow amorphous solid; MS: 310 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:3]=12.[CH3:16][C:17]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:18]=1[CH2:19][NH:20][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)CCC>[CH3:16][C:17]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:18]=1[CH2:19][N:20]([CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:3]=12
Reactant: Cc1ccc(C)c(CNC2CCCC2)c1
Reactant: Clc1ncnc2c1cnn2C1CCCO1
Solvent: CCCCO
Product: Cc1ccc(C)c(CN(c2ncnc3c2cnn3C2CCCO2)C2CCCC2)c1

Procedure:
A mixture of 7.8 g. (35 mmole) 4-chloro-1-(tetrahydrofuran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine, 20.3 g. (100 mmole) N-(2,5-dimethylbenzyl)-cyclopentylamine and 100 ml. n-butanol is heated under reflux for 16 hours. The reaction mixture is evaporated, the residue is taken up in water and extracted with dichloromethane and the extract is washed with dilute acetic acid and dilute aqueous sodium hydrogen carbonate solution, dried, evaporated and chromatographed on silica gel. 5.0 g. (37% of theory) of the title compound are eluted with dichloromethane/methanol (98:2 v/v) which, after trituration with diethyl ether, melts at 173°-174° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:34]=[CH:33][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.Cl>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([N:30]1[CH2:29][CH2:28][N:27]([CH2:26][C:25]2[CH:33]=[CH:34][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:32][CH2:31]1)=[O:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)O
Reactant: Fc1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)N1CCN(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
(E)-3-(2-tert-Butoxycarbonylamino-4-chlorophenyl)-acrylic acid (150 mg, 0.5 mmol), 1-(4-fluorobenzyl)-piperazine (98 mg, 0.5 mmol) and EDCl.HCl (96 mg, 0.5 mmol) were dissolved in CH2Cl2 and stirred at room temperature for 18 hours. The reaction mixture was purified via chromatography (SiO2, EtOAc) to yield the title compound as a white foam (150 mg, 63%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:19][S:20][C:21]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[N:22]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[C:3]([CH2:19][S:20][C:21]2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: Cc1c(SCCNCc2ccccc2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN(CCSc1ccnc(CSc2nc3ccccc3[nH]2)c1C)Cc1ccccc1

Procedure:
2-((3-Methyl-4-(2-benzylaminoethylthio)pyridin-2-yl)-methylthio)-1H-benzimidazole (2 g) was dissolved in dimethylformamide and reacted with methyl chloroacetate (0.45 ml) in the presence of potassium carbonate (0.71 g) at 50°-60° C. After the completion of the reaction, the dimethylformamide was distilled away and the residue was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to give an oily product. The oily product was purified by column chromatography to give 2-((3-methyl-4-(2-(N-benzyl-N-methoxycarbonylmethylamino)ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[C@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][C@H:12]([OH:22])[C@@H:11]1[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:32]1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.CI>C(#N)C>[Si:1]([O:8][CH2:9][C@H:10]1[C@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][C@H:12]([OH:22])[C@@H:11]1[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1
Reactant: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CC#N
Solvent: CI
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.5 %

Procedure:
A solution of (Z)-7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenoic acid (24) (261 mmol) in acetonitrile (1000 ml) was cooled on ice. Diazabicycloundecene (156.0 ml, 1044 mmol) was added thereto and methyl iodide (65.0 ml, 1044 mmol) was added drop wise to the solution. The reaction mixture was warmed to room temperature, and stirred for 14 hours. The reaction mixture was cooled on ice, diazabicycloundecene (39.0 ml, 261 mmol) and methyl iodide (16.3 ml, 261 mmol) were added, then, the mixture was stirred at room temperature for 1.25 hours. The reaction mixture was again cooled on ice, and diazabicycloundecene (39.0 ml, 261 mmol) and methyl iodide (16.3 ml, 261 mmol) were added. After stirring at room temperature for one hour, the reaction mixture was concentrated under reduced pressure. Ethyl acetate (400 ml) and water (400 ml) were added to the residue and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (400 ml), the organic layers were combined and sequentially washed with 1N-hydrochloric acid (600 ml), saturated sodium bicarbonate water (800 ml) and saturated aqueous sodium chloride (800 ml). After drying with anhydrous magnesium sulfate, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2000 g; ethyl acetate:hexane=1:3), the fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300: 190 g; ethyl acetate:hexane=1:3) to give methyl (Z)-7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenate (25) (110.4 g, 233.5 mmol, 89.5%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[Cl:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15].FC1C=CC=CC=1CBr.C1(C(Cl)=O)CCC1>>[Cl:10][CH2:11][CH2:12][CH2:13][C:14](=[O:15])[CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1]
Reactant: O=C(Cl)CCCCl
Reactant: Clc1ccccc1CBr
Agent: Fc1ccccc1CBr
Agent: O=C(Cl)C1CCC1
Product: O=C(CCCCl)Cc1ccccc1Cl
Yield: 79 %

Procedure:
Following a procedure similar to that described in Preparation 13, except that equivalent amounts of 2-chlorobenzyl bromide and 4-chlorobutyryl chloride were used in place of the 2-fluorobenzyl bromide and cyclobutanecarbonyl chloride, the title compound was obtained as a yellow oil in a yield of 79%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH:19]=[O:20])=[C:17]2[C:12]([C:13](=[O:32])[C:14]([CH3:31])=[C:15]([CH:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:23][CH2:22]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([Mg]Br)[CH2:35][CH2:34]1.Cl.O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:18]([CH:19]([CH:33]2[CH2:35][CH2:34]2)[OH:20])=[C:17]2[C:12]([C:13](=[O:32])[C:14]([CH3:31])=[C:15]([CH:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:23][CH2:22]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: CCC(=O)N1CCC(c2oc3c(C=O)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)N1CCC(c2oc3c(C(O)C4CC4)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 7-(benzyloxy)-3-methyl-4-oxo-2-(1-propanoylpiperidin-4-yl)-4H-chromene-8-carbaldehyde (200 mg, 0.46 mmol) obtained in Example 34-2 in tetrahydrofuran (6 mL), a 1 N solution of cyclopropyl magnesium bromide in tetrahydrofuran (1.5 mL, 1.50 mmol) was added dropwise at −30° C., and the mixture was gradually heated to 0° C. over 45 minutes and then stirred at 0° C. for 2 hours. A 1 N aqueous hydrochloric acid solution (5 mL) was added dropwise to the reaction solution, and then water was added to the mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=60/40→0/100) to obtain 159 mg of the title compound (yield: 68%) as an oil.