Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>ClCCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1
Solvent: ClCCCl
Product: CS(=O)(=O)Nc1ccc(-c2ccc(O)cc2)cc1
Yield: 46 %

Procedure:
The procedure of Preparation Example 2 was repeated, except that 55 mg of N-(4′-methoxybiphenyl-4-yl)methanesulfonamide was used in place of 4′-methoxy-2-biphenylacetonitrile, and 1,2-dichloroethane was used in place of methylene chloride. The resulting crude product was purified by TLC (using a 6:1 mixture of chloroform and acetone as the developing solvent) to obtain 24 mg of N-(4′-hydroxybiphenyl-4-yl)-methanesulfonamide.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH2:15][CH2:16][CH2:17][CH:18]3[N:23]([CH3:25])[CH3:24])C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][CH:18]2[N:23]([CH3:24])[CH3:25]
Reactant: CN(C)C1CCCc2c(OCCCN3C(=O)c4ccccc4C3=O)cccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C)C1CCCc2c(OCCCN)cccc21

Procedure:
4.4 ml of 99% hydrazine hydrate are added to a stirred solution of 5-(3-phthalimidopropoxy)-1-dimethylamino-1,2,3,4-tetrahydronaphthalene (26.8 g prepared in the preceding step) in absolute ethanol (270 ml). The reaction mixture is stirred and heated to reflux for 3 hours, allowed to cool, filtered and the filtrate evaporated in vacuo. The yellow residue is triturated in 5% HCl (250 ml), the suspension filtered and the solid washed with 5% HCl. The clear yellow filtrate is extracted with diethyl ether. The aqueous acidic layer is made strongly alkaline with 50% NaOH solution, resulting in an oily precipitate which is extracted with diethyl ether. The combined organic extracts are dried over sodium sulfate, filtered and the filtrate evaporated in vacuo, yielding 14.7 g of a light yellow oil identified by NMR as the desired 3-aminopropoxy compound.
Reaction SMILES: C(OC(=O)CN1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-])=O)=[CH:16][C:15]([C:21](=[O:26])[NH:22][CH:23]3[CH2:25][CH2:24]3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)C.[CH2:28]([OH:30])[CH3:29]>[Pd]>[CH2:28]([O:30][C:21](=[O:26])[CH2:15][CH:14]1[CH2:7][CH2:8][N:9]([C:12]2[C:17]([NH2:18])=[CH:16][C:15]([C:21](=[O:26])[NH:22][CH:23]3[CH2:24][CH2:25]3)=[CH:14][N:13]=2)[CH2:10][CH2:11]1)[CH3:29]
Reactant: CCOC(=O)CN1CCN(c2ncc(C(=O)NC3CC3)cc2[N+](=O)[O-])CC1
Reactant: CCO
Agent: [Pd]
Product: CCOC(=O)CC1CCN(c2ncc(C(=O)NC3CC3)cc2N)CC1
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 0.33 g (0.93 mmol) of [4-(5-cyclopropylcarbamoyl-3-nitro-pyridin-2-yl)-piperazin-1-yl]-acetic acid ethyl ester in ethanol is added 0.050 g (0.023 mmol) of 5% palladium on carbon. The mixture is placed under an atmosphere of hydrogen and stirred overnight. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to provide 0.39 g (97%) of (3′-amino-5′-cyclopropylcarbamoyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester as a red oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Si:23]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][N:45]=[C:44]([CH:48]=[O:49])[CH:43]=1)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Si:23]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][N:45]=[C:44]([C:48](=[O:49])[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:43]=1)([C:36]([CH3:38])([CH3:39])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Reactant: CC(C)(C)[Si](OCc1ccnc(C=O)c1)(c1ccccc1)c1ccccc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCc1ccnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a solution of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (1.00 g) in ethanol (15 mL) were added 4-({[tert-butyl(diphenyl)silyl]oxy}methyl)pyridine-2-carbaldehyde (1.40 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (95.0 mg) and triethylamine (190 μL), and the mixture was stirred with heating under reflux for 4 hr under argon atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.90 g, yield 88%) was obtained as a brown oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 698 (MH+).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:12]2=[O:30])[S:5]([CH3:8])(=[O:7])=[O:6].C(Br)(Br)(Br)[Br:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:32][CH2:2][CH2:3][N:4]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:12]2=[O:30])[S:5]([CH3:8])(=[O:7])=[O:6]
Reactant: BrC(Br)(Br)Br
Reactant: CS(=O)(=O)N(CCO)c1ccc2c(c1)C(=O)N(CC(=O)OCc1ccccc1)C2=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)N(CCBr)c1ccc2c(c1)C(=O)N(CC(=O)OCc1ccccc1)C2=O
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a solution of benzyl 2-(5-(N-(2-hydroxyethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (0.690 g, 1.595 mmol) in DCM (18 ml), CBr4 (0.688 g, 2.075 mmol) was added stirring at room temperature. After few minutes triphenylphosphine (0.544 g, 2.075 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum and the crude was purified by flash chromatography on silica gel column (petroleum ether:ethyl acetate=60:40) affording benzyl 2-(5-(N-(2-bromoethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (0.759 g, 1.532 mmol, 96% yield, MS/ESI+ 494.8-496.7 [MH]+).
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:35]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[N:34]=[CH:33][N:32]=1)(=[O:3])[CH3:2].[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[C:1]([S:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:35]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[N:34]=[CH:33][N:32]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)Cn1ncnc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1SC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1ncnc1/C=C1\CNCCC1SC(C)=O
Yield: 29 %

Procedure:
Following a procedure similar to that described in Example 132-(f), the crude (E)-4-(acetylsulfanyl)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,4-triazol-5-yl]methylidene}-1-(triphenylmethyl)piperidine (1.57 g) obtained in Example 166-(c) was treated with trifluoroacetic acid in dichloromethane and the product was purified by silica gel chromatography using dichloromethane and methanol (20:1 to 10:1) as eluents to afford the title compound (330 mg, yield: 29%) as a yellow amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:21]([C:23]3[S:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[N:27]=3)[CH3:22])=[C:9]([CH:11]([OH:20])C(C3C=CC=CC=3)O)[N:10]=2)[CH:7]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:21]([C:23]3[S:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[N:27]=3)[CH3:22])=[C:9]([CH:11]=[O:20])[N:10]=2)[CH:7]=1
Reactant: CN(c1nc(-c2ccc(F)cc2)cs1)c1c(C(O)C(O)c2ccccc2)nc2ccc(Br)cn12
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: ClCCl
Product: CN(c1nc(-c2ccc(F)cc2)cs1)c1c(C=O)nc2ccc(Br)cn12
Temperature: -4 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(6-bromo-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-2-yl)-2-phenylethane-1,2-diol (Gen-5-ab) (10.8 g, 20 mmol, 1 eq.) in DCM (500 mL) was cooled to −4° C. Lead tetraacetate (dried before use, 13.3 g, 30 mmol, 1.5 eq.) was added and stirred at −4° C. for 0.5 h. The reaction was quenched by addition of water (500 mL). The mixture was filtered and the layers in the filtrate were separated. The aqueous layer was extracted with DCM (2×200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel (elution with heptane/EtOAc 100/0 to 50/50) to give an additional amount of Intermediate Gen-5-q 6-bromo-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridine-2-carbaldehyde.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:8][C:7](=[O:18])[C:6]=2[CH:5]=[C:4]([CH3:19])[CH:3]=1.[CH:20]([O:22]CCCC)=[CH2:21].C(N(CC)CC)C.Cl>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][C:4]1[CH:3]=[C:2]([C:20](=[O:22])[CH3:21])[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:8][C:7](=[O:18])[C:6]=2[CH:5]=1
Reactant: Cc1cc(Br)c2oc(-c3ccncc3)cc(=O)c2c1
Reactant: C=COCCCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(C)cc2c(=O)cc(-c3ccncc3)oc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 2.5 %

Procedure:
A mixture of 8-bromo-2-(4-pyridinyl)-6-methyl-4H-1-benzopyran-4-one (0.12 g, 0.36 mmol), n-butyl vinyl ether (0.047 ml, 0.36 mmol), triethylamine (0.050 ml, 0.36 mmol) in DMF (5 ml) was purged with N2 and then treated with PdCl2(dppf) (27 mg, 0.036 mmol). The mixture was heated to 90° C. overnight. The mixture was cooled to room temperature and treated with 1N aqueous HCl (30 ml) and stirring was continued overnight. The mixture was then diluted with water (50 ml), and lyophilized to dryness. The residue was eluted through a C8-HPLC column and the product isolated as an off-white solid (2.5 mg). The product was identical to that described above.
Reaction SMILES: [OH:1][CH:2]([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)[C:3]1[CH:4]=[C:5]([C:24]([OH:26])=[O:25])[C:6]2[O:10][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:7]=2[CH:23]=1>CC(C)=O.CS(C)=O>[C:17]1([C:9]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:8][C:7]3[CH:23]=[C:3]([C:2]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[O:1])[CH:4]=[C:5]([C:24]([OH:26])=[O:25])[C:6]=3[O:10]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1cc(C(O)c2ccncc2)cc2c1OC(c1ccccc1)(c1ccccc1)O2
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: O=C(c1ccncc1)c1cc2c(c(C(=O)O)c1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 6-(hydroxy-pyridin-4-yl-methyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (128 mg, 0.324 mmol, 1 eq.) in a mixture of 10 mL acetone and 3 mL DMSO, IBX (273 mg, 0.973 mmol, 3 eq.) was added and the reaction mixture was stirred 3 h at 50° C. The mixture was partitioned between H2O and EtOAc, and the organic layer was washed with saturated NaCl solution before being dried over MgSO4 and evaporated under reduced pressure to yield the title compound as a yellowish solid.
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH2:15][CH:16]=[CH2:17])[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C=C.C(O)(C)C.[OH-].[Na+]>C1(C)C=CC=CC=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1.C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1.C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[CH2:8]([O:7][CH2:6][CH:5]1[CH2:15][CH2:16][CH:17]=[CH:1][O:4]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=CCOC(CC=C)COCc1ccccc1
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: C1=COC(COCc2ccccc2)CC1
Temperature: 120 °C

Procedure:
Benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, bis(tricyclohexylphosphine) benzylidine ruthenium(IV) chloride—Grubbs 1 generation catalyst (0.5 g, 0.54 mmol) was added in one portion to a stirred solution of ((2-(allyloxy)pent-4-enyloxy)methyl)benzene (12) (4 g, 17.2 mmol) in toluene (200 mL). The resulting mixture was heated at 50° C. under N2 for 2 hours before isopropanol (18 mL) and NaOH (0.17 g) were added. The mixture was then heated at 120° C. overnight. The solvent was evaporated and the residue was purified over silica gel using Et2O and hexane to give 2-(benzyloxymethyl)-3,4-dihydro-2H-pyran (13).
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:30][O:31][CH3:32])[C:12]([NH:14][C@H:15]2[C@@H:18]([CH2:19][O:20]C(=O)CCl)[N:17]([S:25]([O-:28])(=[O:27])=[O:26])[C:16]2=[O:29])=[O:13])[N:10]=1)=O.[Na+:33].CSC(=S)N.[Na]>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:30][O:31][CH3:32])[C:12]([NH:14][C@H:15]2[C@@H:18]([CH2:19][OH:20])[N:17]([S:25]([O-:28])(=[O:26])=[O:27])[C:16]2=[O:29])=[O:13])[N:10]=1.[Na+:33]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1COC(=O)CCl)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1CO)c1csc(N)n1

Procedure:
In 2 ml of water is dissolved 70 mg of sodium cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-chloroacetoxymethyl-2-oxoazetidine-1-sulfonate (syn-isomer), and under ice-cooling and stirring, 39 mg of sodium monomethyldithiocarbamate is added. The mixture is stirred at room temperature for one hour. After addition of 10 mg of sodium monomethyldithiocarbamate, the mixture is stirred for 30 minutes. The reaction mixture is then filtered and the filtrate is washed with ether. The aqueous layer is chromatographed on an Amberlite XAD-II column and lyophilized to give sodium cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-hydroxymethyl-2-oxoazetidine-1-sulfonate (syn-isomer).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][CH2:29][CH:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:31])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:28]([C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:29][CH:30]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH3:31])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNCC(C)c4ccccc4)cc3)cc2)CC1
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN(CC(C)c4ccccc4)C(=O)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-(4′-{3-methyl-4-[(2-phenyl-propylamino)-methyl]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester and benzoyl chloride.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7]CC)=[O:6].[N:24]([CH2:27][C:28]([O:30]CC)=[O:29])=[C:25]=[O:26].N1C=CC=CC=1.[OH-].[Na+].Cl>CN(C=O)C>[C:28]([CH2:27][NH:24][C:25](=[O:26])[NH:2][C@H:3]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:15][CH:16]=1)[CH2:4][C:5]([OH:7])=[O:6])([OH:30])=[O:29]
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: CCOC(=O)CN=C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(O)CNC(=O)N[C@@H](CC(=O)O)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Intermediate 8-1 (90 mg, 0.254 mmol) and ethyl isocyanatoacetate (Intermediate 16-1: 39.4 mg, 0.305 mmol) in DMF (3 mL) is added pyridine (2.93 g, 37.1 mmol) and the mixture is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residue is used directly in the next step. Next, the above residue is dissolved in EtOH (1 mL) and 1N NaOH (3 mL, 3 mmol) is added. The mixture is stirred at room temperature for 2 hours then is acidified with 1N HCl. The mixture is extracted with EtOAc and the organic phase is washed with water, brine then dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (+0.1% TFA). Lyophilization of the proper fractions gives the title compound; HPLC Retention time 0.98 minutes (condition C); MS 391.3 (M+1); 1H NMR (400 MHz, DMSO-d6): δ ppm 2.34 (d, J=7.33 Hz, 2H), 2.79 (d, J=6.57 Hz, 2H), 3.67 (d, J=5.56 Hz, 2H), 4.04-4.12 (m, 1H), 6.15 (t, J=5.81 Hz, 1H), 6.23 (d, J=8.34 Hz, 1H), 7.28-7.30 (m, 2H), 7.39-7.42 (m, 1H), 7.48 (t, J=7.83 Hz, 1H), 7.62-7.65 (m, 3H), 7.71 (t, J=1.77 Hz, 1H), 12.32 (s, br, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1.C(C=C)=O>ClC1C=CC=CC=1Cl>[F:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]2[C:6]([CH:12]=[CH:11][CH:16]=[N:5]2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1c(N)cccc1F
Agent: C=CC=O
Solvent: Clc1ccccc1Cl
Product: COc1c(F)ccc2cccnc12
Temperature: 170 °C
Reaction time: 1 h
Yield: 361 %

Procedure:
A solution of 3-fluoro 2-methoxyaniline (5.0 g) in 1,2-dichlorobenzene (50 ml) was heated to 170° C. and treated with p-toluenesulphonic acid (0.7 g). A solution of acrolein (4.0 g) in 1,2-dichlorobenzeue (20 ml) was added dropwise over 20 minutes. The reaction was stirred for 1 hour at 170° C. before being allowed to cool. The mixture was extracted with 2N hydrochloric acid (3×200 ml) and the combined extracts washed with dichloromethane (20 ml), basified with 25% aqueous sodium hydroxide, and extracted with ethyl acetate (3×200 ml). The combined extracts were dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with 50% ethyl acetate in hexane to yield the desired product (2.6 g) as a clear oil.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11]CC)=[O:10])=[N:4]1)[CH3:2].[OH-].[Na+].C(O)C.Cl>O>[CH2:1]([N:3]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([OH:11])=[O:10])=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1nn(CC)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1cc(C)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.3 %

Procedure:
A mixture of ethyl 1-ethyl-4-methyl-1H-pyrazole-3-carboxylate (8.60 g, 47.2 mmol), 8N aqueous sodium hydroxide solution (11.8 mL) and ethanol (30 mL) was stirred at room temperature for 15 hr. The reaction mixture was neutralized with 1N hydrochloric acid, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (5.19 g, 71%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.Cl>CC(C)=O>[Cl:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccnc1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCC(c2nccnc2Cl)CC1
Temperature: 25 °C

Procedure:
2-Chloro-3-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazine (0.29 g, 1.14 mmol) was dissolved in acetone (8 mL) and 1M aqueous hydrochloric acid (1.0 mL, 1.0 mmol) was heated to 50° C. for 4 h, then cooled to RT. The acetone was removed under vacuum and the solution was then diluted with EtOAc. This mixture was transferred to a reparatory funnel and washed with sat. aqueous sodium bicarbonate (1×), brine (1×), dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give 4-(3-chloropyrazin-2-yl)cyclohexanone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11]O)=[NH:10])=[CH:4][CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].CCO.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:18]([O:17][C:13]([C:14]1[N:10]=[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[NH:11][CH:15]=1)=[O:16])[CH3:19]
Reactant: N=C(Cc1ccc(Br)cc1)NO
Reactant: C#CC(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c(Cc2ccc(Br)cc2)n1
Temperature: 190 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
2-(4-bromophenyl)-N-hydroxyacetamidine (5.0 g, 21.8 mmol) and ethyl propiolate (2.4 mL, 24.0 mmol) were dissolved in EtOH (100 mL, 2 mol). The mixture was heated to reflux for 7 hours, cooled and then concentrated. The residue was then dissolved in diphenyl ether (75 mL, 470 mmol), heated at 190° C. for 2 hours, cooled, combined with 400 mL of hexanes, and allowed to sit overnight. The solvent was decanted and the precipitant was dissolved in DCM and purified by column chromatography (0-10% MeOH in DCM) to yield 2-(4-bromobenzyl)-1H-imidazole-4-carboxylic acid ethyl ester (3.3 g).
Reaction SMILES: [F:1][C:2]1[CH:42]=[C:41]([N+:43]([O-])=O)[CH:40]=[CH:39][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][Si:9]([CH3:38])([CH3:37])[O:10][Si:11]([CH3:36])([CH3:35])[O:12][Si:13]([CH3:34])([CH3:33])[O:14][Si:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:24]=1[F:32])([CH3:17])[CH3:16]>[Pd]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][Si:15]([CH3:16])([CH3:17])[O:14][Si:13]([CH3:34])([CH3:33])[O:12][Si:11]([CH3:36])([CH3:35])[O:10][Si:9]([CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:39]=[CH:40][C:41]([NH2:43])=[CH:42][C:2]=2[F:1])([CH3:37])[CH3:38])=[C:24]([F:32])[CH:25]=1
Reactant: C[Si](C)(CCCCOc1ccc([N+](=O)[O-])cc1F)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Product: C[Si](C)(CCCCOc1ccc(N)cc1F)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.18 g of the above (2f) (3.09 mmol) and 10 mL of a 10 wt % of Pd/C (0.0233 g) ethyl acetate solution were mixed, and stirred for 2 days in a nitrogen atmosphere at room temperature. The solution was filtrated by Celite and then concentrated to obtain a colorless oily material of 1,7-bis[4-(4-amino-2-fluorophenoxy)butyl]-1,1,3,3,5,5,7,7-octamethyltetrasiloxane (30 (1.98 g, 99% of yield) represented by the following formula. Various measurements were carried out with regard to the obtained (3f), and results are shown below.