Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[N:28][N:27]=[N:26]2)=[CH:21][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:6].B(Br)(Br)Br.CO.ClCCl.C1(C)C=CC=CC=1.CO>ClCCl>[OH:2][C:3]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[N:28][N:27]=[N:26]2)=[CH:21][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCO)(c2ccccc2)C1
Agent: BrB(Br)Br
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: O=C(c1cc(-n2cnnn2)ccc1O)N1CCC(CCO)(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Combine 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (2.0 g, 5.1 mmol) and anhydrous dichloromethane (100 mL). Cool in an ice bath. Add a solution of boron tribromide (17.8 mL, 1 M, 17.8 mmol) and stir. After 2 hours, pour the reaction mixture into ice-water and stir vigorously. After 18 hours, separate the layers and extract the organic layer with water. Saturate the aqueous layer with sodium chloride and extract with dichloromethane. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia to give a residue. Combine the residue and toluene/methanol. Evaporate invacao to give a residue, dissolve in dichloromethane, filter, evaporate, combine with dichloromethane, again evaporate to remove residual toluene to give the title compound: mp; 86-96° C. Rf=0.37 (silica gel, 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:4]=2[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:6](=[O:17])[CH:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:8]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[N:44][CH:45]=2)O1.[OH-].[Cs+]>O1CCOCC1.O.CCOC(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>[NH2:46][C:42]1[CH:41]=[C:40]([C:2]2[C:3]3[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:4]=3[N:5]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:6](=[O:17])[CH:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[N:8]=2)[CH:45]=[N:44][CH:43]=1
Reactant: CC1(C)OB(c2cncc(N)c2)OC1(C)C
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(Cl)c3cc(Cl)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3cncc(N)c3)c3cc(Cl)ccc32)cc1
Temperature: 90 °C
Yield: 33.4 %

Procedure:
5,7-Dichloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (240 mg) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (134 mg, 1.2 eq) were suspended in dioxane/water (6 mL/2 mL), and then cesium hydroxide (170 mg, 2 eq) was added and the mixture was degassed by pulling vacuum until bubbling occurred, and then introducing nitrogen gas. The degassing procedure was repeated twice, and then tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.05 eq) was added. The degassing procedure was repeated once, and then the reaction was heated to 90° C. for three hours. The crude mixture was then diluted with EtOAc (20 mL) and then washed with water, then brine, and then it was dried over sodium sulfate, and concentrated onto silica gel. The product was purified by chromatography (gradient: 75:25 hexanes:EtOAc to EtOAc) delivering the product as a solid (90 mg, 33% yield). MS (ES+) m/z 531.0 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Cl:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][Cl:22])=[CH:17][CH:16]=1>C(#N)C>[Cl-:13].[Cl-:13].[Cl:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N+:1]2[CH:6]=[CH:5][C:4]([C:7]3[CH:12]=[CH:11][N+:10]([CH2:21][C:18]4[CH:19]=[CH:20][C:15]([CH2:14][Cl:13])=[CH:16][CH:17]=4)=[CH:9][CH:8]=3)=[CH:3][CH:2]=2)=[CH:16][CH:17]=1
Reactant: c1cc(-c2ccncc2)ccn1
Reactant: ClCc1ccc(CCl)cc1
Solvent: CC#N
Product: ClCc1ccc(C[n+]2ccc(-c3cc[n+](Cc4ccc(CCl)cc4)cc3)cc2)cc1
Product: [Cl-]
Yield: 79.1 %

Procedure:
34.3 g (0.22 mol) of 4,4′-bipyridyl and 106 g (0.66 mol) of α,α′-dichloro-p-xylene are stirred in 500 ml of acetonitrile at 90° C. for 4 hours under an argon atmosphere. After cooling, the precipitate is filtered off and washed sufficiently with acetonitrile. Drying gives 88.1 g of 1,1′-di[p-(chloromethyl)benzyl]-4,4′-bipyridinium dichloride.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C:14](=[O:15])[O:13][CH2:12][CH2:11][N:10]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.COC(=O)C(N)C1C=CC(F)=CC=1>>[CH2:16]([N:10]1[CH:11]=[CH:12][O:13][C:14](=[O:15])[C@@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Agent: COC(=O)C(N)c1ccc(F)cc1
Agent: Cl
Product: O=C1OC=CN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Temperature: 65 °C
Reaction time: 72 h

Procedure:
To a solution of 3-(4-fluorophenyl)-4-phenylmethyl-2-morpholinone (i.e. N-benzyl-4-fluorophenyl-1,4-oxazin-2-one) (10 g) in isopropyl acetate (110 ml) at room temperature was added a solution of (-)-3-bromocamphor-8-sulphonic acid ((-)-3BCS) (12 g) in acetonitrile (24 ml). Crystallisation began after 2-3 min. The slurry was stirred for 1 h at room temperature. Trifluoroacetic acid (7 ml) was added and the mixture stirred at 65° C. for 3 days. The mixture was cooled to 0°-5° C., aged for 1 h. and the solid collected, washed with isopropyl acetate and dried in vacuo at 40° C., to give the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt: yield 17.24 g, ee 98.6% (S) isomer. The chiral composition of the remaining liquors was determined as 79%(R), 21%(S). The liquors were stirred at 65° C. for 3 days, then cooled to 0°-5° C. The solid was collected, washed with isopropyl acetate and dried in vacuo to give a further batch of the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt: yield 0.84 g, ee 98.6% (S) isomer. The chiral composition of the remaining liquors was determined as 64%(R), 36%(S). The liquors were stripped in vacuo and the residue was dissolved in isopropyl acetate (20 ml) containing trifluoroacetic acid (1 ml) and stirred at 65° C. for 20h. The mixture was cooled to 0°-5° C. for 1 h and the solid collected, washed with isopropyl acetate and dried in vacuo to give a further batch of the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt: yield 2.2 g, ee 99.2% (S) isomer. Total weight of (-)-3BCS salt: 20.28 g, 97% yield. A sample (0.5 g) of the (-)-3BCS salt was retained and the remainder converted back to free base. The salt was partitioned between isopropyl acetate (50 ml) and water (100 ml) containing 0.88 ammonia soln. (3 ml). The layers were separated and the aqueous phase extracted with isopropyl acetate (25 ml). The combined organic phases were washed with water (25 ml). The organic phase was concentrated to residue and flushed with isopropyl acetate to give the 3-(S)-(4-fluorophenyl)-4-phenylmethyl-2-morpholinone (i.e. N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one) as the free base: yield 8.7 g, 93% recovery, ee 98.4% (S) isomer.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][N:13]=2)=[C:6]([NH2:21])[CH:5]=1.C(N(CC)CC)C.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](Cl)=[O:36].[OH-].[Na+].Cl>C1COCC1.CO>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:22])=[CH:5][C:6]=2[NH:21][C:35]([C:31]2[O:30][CH:34]=[CH:33][CH:32]=2)=[O:36])=[N:13]1
Reactant: COC(=O)c1ccc(C=Cc2n[nH]c3ccccc23)c(N)c1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)c(NC(=O)c2ccco2)c1
Reaction time: 4 h
Yield: 83 %

Procedure:
A solution of 3-amino-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid methyl ester (0.30 g, 1.0 mmol) obtained in Step 1 of Example 217 and triethylamine (0.43 ml, 3.1 mmol) in THF (10 mL) was added with furan-2-carbonyl chloride (0.11 mL, 1.1 mmol), followed by stirring for 4 hours. The reaction mixture was extracted with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was concentrated under reduced pressure to obtain crude product. Further, the product was dissolved in methanol (20 mL) and added with 2 mol/L aqueous sodium hydroxide solution (5.0 mL), followed by stirring at 60° C. for 1 hour. The reaction mixture was acidified by hydrochloric acid (6 mol/L) and the precipitated crystal was collected by filtration to obtain (E)-4-[2-(1H-indazol-3-yl) vinyl]-3-[(furan-2-carbonyl)amino]benzoic acid (0.31 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH:8]2[CH2:16][N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:10]3[CH2:9]2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[N:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C@@H:8]2[CH2:16][N:11]3[CH2:12][CH2:13][N:14]([C:23]4[N:22]=[N:21][C:20]([Cl:19])=[CH:25][CH:24]=4)[CH2:15][C@@H:10]3[CH2:9]2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(OCC2CC3CNCCN3C2)cc1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: Fc1ccc(OC[C@H]2C[C@H]3CN(c4ccc(Cl)nn4)CCN3C2)cc1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A mixture of 0.500 g (2.00 mmol) of (7SR,8aSR)-7-(4-fluorophenoxy)methyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 3), 1.49 g (10.0 mmol) of 3,6-dichloropyridazine, and 0.508 g (4.79 mmol) of sodium carbonate in 50 mL of isoamyl alcohol was heated to reflux for 48 hours. The reaction was cooled to ambient temperature, the solvent removed in vacuo, the residue taken up in ethyl acetate and water, the pH was adjusted to 11 with sodium carbonate and the layers were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic layers were dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 90:10 ethyl acetate:hexane gave 0.478 g (66%) of the title compound. Mp (.HCl) 229° C. (dec). HRMS calc'd for C18H21ClFN4O (MH+): 363.1388, found: 363.1404.
Reaction SMILES: C1([C:7]2[C:11]([C:12](NC)=[O:13])=[C:10](C)ON=2)C=CC=CC=1.[CH2:17]([C:19]1[C:23]([C:24](NC)=[O:25])=[C:22]([CH3:28])ON=1)[CH3:18]>>[CH:24](=[O:25])[C:23]1[CH:22]=[CH:28][CH:18]=[CH:17][CH:19]=1.[CH3:10][C:11]([CH:12]=[O:13])([CH3:17])[CH3:7]
Reactant: CCc1noc(C)c1C(=O)NC
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C
Product: CC(C)(C)C=O
Product: O=Cc1ccccc1

Procedure:
Again following the above procedure and using in place of 3-phenyl-5,N-dimethyl-isoxazole-4-carboxamide an equivalent amount of 3-ethyl-5,N-dimethyl-isoxazole-4-carboxamide and in place of benzaldehyde an equivalent amount of pivaldehyde there is obtained
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(Cl)(Cl)Cl.[CH3:22][CH2:23][CH2:24][CH2:25]CCC.[O:29]1CCCC1.C(C1C=CC=CC=1)C>O1CCCC1>[C:9]([NH:13][S:14]([CH2:17][CH2:22][CH2:23][C@H:24]([OH:29])[CH3:25])(=[O:16])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCCCCCC
Reactant: CC(C)(C)NS(C)(=O)=O
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: ClC(Cl)Cl
Product: C[C@@H](O)CCCS(=O)(=O)NC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2.0 M lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (100 ml) was slowly added dropwise to a solution of N-t-butylmethanesulfonamide (15.1 g) in tetrahydrofuran (100 ml) under nitrogen atmosphere taking about 1 hour at −50 to −20° C. After stirring for 1 hour at 0° C. and cooling to −50° C., (R)-1-methyloxethane (8.51 g) was added dropwise thereto. After stirring for 5 days at room temperature, the solution was extracted with water and ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate: hexane/ethyl acetate=½) to obtain crude (R)-N-t-butyl-4-hydroxy-1-pentanesulfonamide (6.6 g) as solid. This solid was dissolved by adding chloroform and concentrated under reduced pressure. The residue thus obtained was crystallized by adding diethyl ether. The crystals were separated by filtration and dried under reduced pressure to obtain (R)-N-t-butyl-4-hydroxy-1-pentanesulfonamide (3.39 g) as white crystals.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.[Cl-].[NH4+]>O1CCCC1>[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[NH:12][CH:2]=[CH:1]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Brc1cccc2cc[nH]c12
Reaction time: 0.67 h

Procedure:
100 ml (100 mmol) of a tetrahydrofuran solution containing 1.0 M vinylmagnesium bromide was added to a tetrahydrofuran solution (250 ml) containing 5.05 g (25 mmol) of 2-bromonitrobenzene at −40° C. in nitrogen atmosphere, followed by stirring as it was for 40 minutes. The reaction mixture was poured into 500 ml of an aqueous saturated ammonium chloride, and the mixture was extracted with ethyl ether. The extract was dried over magnesium sulfate and concentrated. Then, the residue was purified by silica gel column chromatography, to give 2.89 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:31][Si:32]([CH3:41])([CH3:40])[C:33]#[C:34][C:35](OCC)=[O:36]>C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:12]([O:14][CH3:15])=[O:13])[C:35](=[O:36])[C:34]#[C:33][Si:32]([CH3:41])([CH3:40])[CH3:31])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(OC)c(Cc2ccc(Cl)nn2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)c(C(C(=O)C#C[Si](C)(C)C)c2ccc(Cl)nn2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-[(6-chloropyridazin-3-yl)methyl]-4-methoxybenzoate (10.03 g, 34.2 mmol) in THF (400 mL) was added LHMDS (100 mL, 1M solution in THF) and ethyl 3-(trimethylsilyl)propynoate (6.66 mL, 35.5 mmol) at −78° C. The reaction was warmed to 0° C. and stirred for 0.5 hr until the reaction was complete by LCMS analysis. The reaction was quenched with aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with 0.5 N HCl, brine, dried over MgSO4, and condensed in vacuo to yield an oil. The crude material was purified via silica gel chromatography (CH2Cl2) to yield the title compound.
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH:2]=O.[Na+].C([O-])(=O)C.[NH4+:11].[C:12]1([C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15])[OH:13]>O>[OH:13][C:12]1[CH:19]=[C:18]([NH:11][CH2:2][C:1]([OH:5])=[O:4])[CH:17]=[CH:16][C:14]=1[OH:15]
Reactant: O=CC(=O)[O-]
Reactant: [NH4+]
Reactant: Oc1ccccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CNc1ccc(O)c(O)c1

Procedure:
36.9 g of sodium glyoxylate, 75 g of ammonium acetate, 72 g of catechol and 130 ml of water are treated in the same manner as described in Example 1. 11.0 g of DL-(3,4-dihydroxyphenyl)glycine are thereby obtained as crystals. Yield: 18.5 g M.p. 185°-188° C. (decomp.).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]=O)=[CH:25][CH:24]=1.N1CCCCC1>C(O)C>[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]=[C:18]2[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])=[CH:25][CH:24]=1
Reactant: O=CCCc1ccc(F)cc1
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1SC(=CCCc2ccc(F)cc2)C(=O)N1CCCCSc1cccc2nccn12

Procedure:
To a solution of 964 mg (3.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 609 mg (4.0 mmol) of 3-(4-fluorophenyl)-1-propanal in 20 ml of ethanol, 26 mg (0.3 mmol) of piperidine was added, followed by refluxing for 4.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1) to yield 0.88 g (64.2%, yellow oily substance) of the desired product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[CH2:11]([Li])CCC.COS(OC)(=O)=O.[Cl-].[NH4+]>C(OCC)C>[CH3:11][C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1
Reactant: [Li]CCCC
Reactant: c1csc(-c2cccs2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Product: Cc1ccc(-c2cccs2)s1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere a stirred solution of 32.0 grams (0.193 mole) of 2,2'-bithienyl in 150 mL of diethyl ether was cooled to -5°0 C., and 90.5 mL (0.226 mole--2.6M in hexanes) of n-butyllithium was added slowy dropwise. Upon completion of addition the reaction mixture was stirred at -5° C. for one hour, and then a solution of 27.8 grams (0.220 mole) of dimethylsulfate in 75 mL of diethyl ether was added very slowly dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred for 18 hours. After this time the reaction mixture was poured into 350 mL of an aqueous 10% ammonium chloride solution. The mixture was extracted with diethyl ether, and the combined extracts were washed with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure to yield 30.0 grams of 5-methyl(2,2'-bithienyl); b.p. 108°-113° C./1.9 mm.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[I:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]([CH3:24])[CH:19]=[C:20]([CH2:22][NH2:23])[N:21]=2)=[CH:13][CH:12]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:23][CH2:22][C:20]2[N:21]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([I:10])=[CH:12][CH:13]=3)[N:18]([CH3:24])[CH:19]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(CN)nc1-c1ccc(I)cc1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1cc(CNC(=O)c2ccc(Cl)s2)nc1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-thiophene-2-carboxylic acid (23 mg, 0.14 mmol), (2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl amine prepared above (21 mg, 0.067 mmol) and TEA (0.050 mL, 0.36 mmol) in DMF (2 mL) was added BOP (70 mg, 0.16 mmol). The mixture was stirred at room temperature overnight. It was then purified by HPLC to give 5-chloro-N-((2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (14 mg). MS 457.9 and 459.9 (M+H).
Reaction SMILES: [Cl-].COC[P+]([C:18]1[CH:23]=[CH:22]C=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[C:25](C)([O-:27])C.[K+].[CH2:30]([C@H:33]1[CH2:38][CH2:37][C@H:36]([C@H:39]2[CH2:44][CH2:43][C@H:42](CC=O)[CH2:41][CH2:40]2)[CH2:35][CH2:34]1)[CH2:31][CH3:32].C1(C)C=CC=CC=1>C(OC)(C)(C)C.O>[CH3:25][O:27][CH:22]=[CH:23][CH2:18][C@H:42]1[CH2:41][CH2:40][C@H:39]([C@H:36]2[CH2:35][CH2:34][C@H:33]([CH2:30][CH2:31][CH3:32])[CH2:38][CH2:37]2)[CH2:44][CH2:43]1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CC=O)CC2)CC1
Reactant: CC(C)(C)[O-]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Solvent: O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CC=COC)CC2)CC1
Reaction time: 24 h

Procedure:
Commerically available methoxymethyltriphenylphosphonium chloride (102.7 g, 0.300 mol) was added to methyl t-butyl ether (1 l), followed by adding potassium t-butoxide (33.7g, 0.300 mol) in argon atmosphere at -10° C. in 10 minutes with stirring, agitating the reaction mixture at 0° C. for one hour, dropwise adding a solution of trans-4-(trans-4-propylcyclohexyl)cyclohexylacetaldehyde (50 g, 0.200 mol) prepared in item (ii) of Example 7, in methyl t-butyl ether (200 ml), at -10° C. in 15 minutes, agitating the reaction mixture at 0° C. for one hour, adding toluene (0.3 l) and water (0.3 l), four times washing the toluene solution with water (0.3 l) in a washing and separating manner, drying the organic layer over anhydrous sodium sulfate, separating the drying agent, distilling off toluene, dissolving the residue in ethyl acetate (100 ml) on heating, allowing the solution to stand still at room temperature for one day, filtering off deposited crystals, concentrating the mother liquor, dissolving the concentrate in heptane and purifying the solution with silica gel column chromatography to obtain trans-1-(3-methoxy-2-propenyl)-4-(trans-4-propylcyclohexyl)cyclohexane (42.6 g, 0.153 mol), adding to the total quantity thereof, tetrahydrofuran (330 ml) and 2N-hydrochloric acid (90 ml), heating the mixture under reflux with stirring for one hour, cooling the reaction mixture, adding toluene (300 ml) and water (1 l), three times washing the toluene solution with water (1 l) in a washing and separating manner, drying the organic layer over anhydrous sodium sulfate, separating the drying agent, distilling off toluene and drying the residue under reduced pressure to obtain 3-[trans-4-propylcyclohexyl)cyclohexyl]-1-propanal (35.6 g, 0.135 mol).