Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].C[Si](C)(C)O[SiH](C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1C=CC=CC=1.C1COCC1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:2]([OH:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[SiH](C)O[Si](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COc1ccc(C(C)O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
A 30-mL eggplant flask equipped with a magnetic stirrer was heat dried while pumping to a vacuum of 5 Pa before its interior was purged with nitrogen atmosphere. To the flask, 4-methoxyacetophenone (151 mg, 1.0 mmol) and 1,1,1,3,3-pentamethyldisiloxane (372 mg, 2.5 mmol) were added through a syringe, and dissolved in benzene (0.5 mL). To the solution, iron complex A (5.0 mg, 0.01 mmol) was added as catalyst. The solution was stirred at room temperature for 6 hours. At 0° C., tetrabutylammonium fluoride in THF (1 M, 1 mL) was then added to the solution, which was stirred at 0° C. for 1 hour. The solvents were distilled off in vacuum. The crude product was purified by silica gel-packed column chromatography using hexane/ethyl acetate (3/1) as developing solvent, obtaining 1-(4-methoxyphenyl)ethanol (140 mg, 0.92 mmol, 92%). The results are shown as Entry 1 in Table 7. The resulting alcohol was identified for geometry by 1H and 13C-NMR spectroscopy.
Reaction SMILES: Cl[C:2](Cl)([CH3:6])[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:15]([NH:23][NH2:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O.CCOCC>[CH2:15]([NH:23][N:24]=[C:2]([CH3:6])[C:3]([OH:5])=[O:4])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(Cl)(Cl)C(=O)O
Reactant: NNCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CC(=NNCCc1ccccc1)C(=O)O
Temperature: 90 °C

Procedure:
To a solution of 5.7 g. 2,2-dichloropropionic acid and 2.8 g. potassium carbonate in 40 ml water is added a solution of 6.9 g. phenethylhydrazine hydrochloride and 5.6 g. potassium carbonate in 20 ml water. The mixture is heated with stirring to 90° C., a further solution of 5.6 g. potassium carbonate in 20 ml water is dropped in over 30 minutes and further stirred for 60 minutes at 90° C. Afterwards the still alkaline solution is cooled to ambient temperature, shaken out with ether and acidified with concentrated hydrochloric acid. 2-(phenethylhydrazono)-propionic acid crystallizes out and is recrystallized from toluene. The yield is 3.3 g. (40% of theory); m.p. 74°-76° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)=[O:2].C[Li].[CH2:14](OCC)C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH:1]([OH:2])[CH3:14])[CH:8]=[CH:9]1
Reactant: CCOCC
Reactant: O=Cc1cccc2cc[nH]c12
Agent: O=C([O-])O
Agent: [Li]C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)c1cccc2cc[nH]c12
Yield: 94.5 %

Procedure:
Add 7-formylindole (1.0 g, 6.89 mmol) in anhydrous tetrahydrofuran (15 ml) dropwise to a solution of 1.4M methyllithium in diethyl ether (12.2 ml, 17.1 mmol) at −78° C. After 15 minutes add saturated aqueous sodium bicarbonate (15 ml). Dilute with 1:1 ethyl acetate:diethyl ether, wash with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride, dry over magnesium sulfate, and concentrate under reduced pressure to provide desired compound (1.05 g, 94%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.CN(C1C=CC=CN=1)C.[C:26]1(=[O:36])[O:31][C:29](=[O:30])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12>ClCCl>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:26](=[O:36])[C:27]1[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:29]([OH:31])=[O:30]
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: O=C(O)c1ccccc1C(=O)Nc1ccccc1-c1cc2ccccc2[nH]1
Reaction time: 0.17 h

Procedure:
958 mg (4.6 mmol) 2-(2-Aminophenyl) indole and 675 mg (5.52 mmol, 1.2 eq) DMAP (dimethylamino pyridine) were dissolved in 35 ml anhydrous dichloromethane. The mixture was stirred for 10 min. 954 mg (6.44 mmol, 1.4 eq) of phthalic anhydride in 3 ml anhydrous dichloromethane were added and the mixture was stirred at 23° C. for three hours. To the mixture were added 20 ml dichloromethane. It was extracted with 50 ml aqueous 1 M HCl. The aqueous phase was re-extracted with 30 ml dichloromethane. The combined organic phases were dried over magnesium sulfate. The crude product was chromatographed on silica using an ethylacetate/hexane gradient (10%–90%) as mobile phase. The solvent was removed and the product was re-crystallized from ethylacetate:hexane (70:30) to obtain 654 mg of ivory colored crystals in 40% overall yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([CH3:18])=[CH:16][C:12]([C:13](O)=O)=[CH:11][C:10]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:24][C:25]1[C:26](=[S:40])[NH:27][C:28]([C:31]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:33][CH2:32]2)=[CH:29][CH:30]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:17]([CH3:18])=[CH:16][C:12]([C:13]2[S:40][C:26]3[C:25]([N:24]=2)=[CH:30][CH:29]=[C:28]([C:31]2([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:32][CH2:33]2)[N:27]=3)=[CH:11][C:10]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Reactant: Nc1ccc(C2(c3ccccc3)CC2)[nH]c1=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1OCc1ccccc1
Temperature: 70 °C

Procedure:
A mixture of 4-(benzyloxy)-3,5-dimethylbenzoic acid (238.0 mg, 929 μmol) and thionyl chloride (2.5 mL, 34.25 mmol) was heated at 70° C. for 1 h and then concentrated in vacuo. 3-Amino-6-(1-phenylcyclopropyl)pyridine-2(1H)-thione (225 mg, 0.929 mmol) was added to the residue, and the resulting mixture was and heated in toluene (9.0 mL) at 100° C. for 10 min. (±)-10-Camphorsulfonic acid (194 mg, 836 μmol) was subsequently added, and the resulting mixture was heated at 100° C. for 30 min. The reaction solution was then cooled to 25° C. and concentrated onto silica gel. Chromatographic purification (silica gel, 0-40% ethyl ether/hexanes) provided 2-(4-(benzyloxy)-3,5-dimethylphenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine as a white solid. MS (ESI) m/z: Calculated: 462.2; Observed: 463.2 (M++1).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)CCC(Cl)=O.C(Cl)(=O)CCCCC(Cl)=O.C(OC(=O)OCC(C)C)C(C)C.C(Cl)(=O)COCCOCCOCC(Cl)=O.C(OC(=O)OCC(C)C)C(C)C.C(O)(=O)COCCOCCOCC(O)=O>>[C:4]1([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: Nc1cccc(B(O)O)c1
Agent: CC(C)COC(=O)OCC(C)C
Agent: O=C(Cl)CCC(=O)Cl
Agent: O=C(Cl)CCCCC(=O)Cl
Product: OB(O)c1ccccc1

Procedure:
Phenylboronic acid reagents of General Formula IX are prepared by condensation of (3-aminophenyl)boronic acid with an activated dicarboxylic acid preferably selected from, but not limited to, either succinyl chloride, adipoyl chloride, adiptic acid diisobutylcarbonate, suberoyl chloride,3,3'-dithiopropionyl chloride and 3,6,9-trioxaundecanedioyl chloride and 3,6,9-trioxaundecanedioic acid diisobutylcarbonate. The preparation of a single reagent of General Formula IX has been previously reported (Burnett, T. J., Peebles, H. C. and Hageman, J. H. (1980) Biochem. Biophys. Research Commun., 96, 157-162). ##STR11##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH:13]=[CH:12][C:11](/[C:14](/[CH3:19])=[CH:15]\[C:16](O)=[O:17])=[CH:10]1.[CH3:20][NH:21][OH:22]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH:13]=[CH:12][C:11](/[C:14](/[CH3:19])=[CH:15]\[C:16]([N:21]([OH:22])[CH3:20])=[O:17])=[CH:10]1
Reactant: C/C(=C/C(=O)O)c1ccn(-c2c(C)cccc2C)c1
Reactant: CNO
Product: C/C(=C/C(=O)N(C)O)c1ccn(-c2c(C)cccc2C)c1

Procedure:
Condensation of (Z)-3-[1-(2,6-dimethylphenyl)-1H-pyrrol-3-yl]-2-butenoic acid is condensed with N-methylhydroxylamine as described in example 1(a) to yield (Z)-3-[1-(2,6-dimethylphenyl)-1H-pyrrol-3-yl]-N-hydroxy-N-methyl-2-butenamide, m.p. 158°-160°.
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[C:6]2[CH:8]=[CH:9][C:10]([C:12](OCC)=[O:13])=[CH:11][C:5]2=[N:4]1)[CH3:2].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[N:7]=[C:6]2[CH:8]=[CH:9][C:10]([CH2:12][OH:13])=[CH:11][C:5]2=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1ccc2nn(CC)nc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CCn1nc2ccc(CO)cc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
Ethyl 2-ethylbenzotriazole-5-carboxylate (0.7 g, 3.06 mmol) was dissolved in dry toluene (10 mL) and cooled to 0° C. under nitrogen. A solution of DIBAL-H (1.5M in toluene, 3 mL, 4.5 mmol) was then added dropwise to the cooled solution over 15 minutes. The reaction was stirred at 0° C. for one hour when further DIBAL-H (1.5 mL, 2.25 mmol) was added. A further aliquot of DIBAL-H (0.75 mL, 1.12 mmol) was added after 2 hours and the reaction was stirred for further 30 min. The reaction was quenched by addition of a saturated solution of sodium potassium tartrate, diluted with water and extracted with AcOEt. The organic layer was dried over sodium sulfate to give a crude oil (440 mg) which was used directly in the following step.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([CH:16]1[C:29]3[CH:28]=[CH:27][C:26]([C:30](=[NH:36])[N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:25][C:24]=3[O:23][C:22]3[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12]2)=O)(C)(C)C.O.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>ClC(Cl)C>[CH:13]12[NH:8][CH:9]([CH2:15][CH2:14]1)[CH2:10][CH:11]([CH:16]1[C:29]3[CH:28]=[CH:27][C:26]([C:30]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[NH:36])=[CH:25][C:24]=3[O:23][C:22]3[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12]2.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: CCN(CC)C(=N)c1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Solvent: CC(Cl)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=N)c1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To solution of crude 3-[3-(N,N-diethyl-carbamimidoyl)-9H-xanthen-9-yl]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, 3m (0.34 g) in dichloroethane (2 mL) was added H2O (0.1 mL) and TFA (2 mL). The mixture was stirred at rt for 1 h and evaporated. The residue was purified via reverse phase HPLC (eluent: CH3CN in water containing 0.1% TFA), yielding 0.263 g (56%) for two steps) of 9-(8-aza-bicyclo[3.2.1]oct-3-yl)-N,N-diethyl-9H-xanthene-3-carboxamidine, 4m as a TFA salt (MS m/z (MH+) 390.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]3[CH2:36][CH2:35][CH2:34]3)[CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]3[CH2:36][CH2:35][CH2:34]3)[CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:2]1[N:1]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1ncccn1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3ncccn3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 189 using pyrimidin-2-yl-acetic acid and 3(S)-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine (Example 7, Compound 95) as starting materials. Product as an oil. LC/MS (Method B) 2.51 min, [M+1]+ 473. Potency class A.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O1CCOCC1>[CH2:18]([S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=[C:2]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:3]=[C:4]2[N:10]=1)[CH3:19]
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCSc1ccccc1-c1nc2cc(-c3ccccc3)cnc2n1C
Temperature: 70 °C
Yield: 106.6 %

Procedure:
A mixture of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (0.35 g), tripotassium phosphate (0.42 g), phenylboronic acid (0.13 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.03 g), tris(dibenzylideneacetone)dipalladium(0) (0.01 g), and 1,4-dioxane (3 ml) was stirred with heating at 70° C. for 2 hours, and then heated to 90° C., and stirred with heating for further 2 hours. Into the reaction mixture cooled to room temperature, saturated aqueous ammonium chloride solution was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.37 g of 2-(2-ethylsulfanylphenyl)-3-methyl-6-phenyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 56).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C:11]([C:12]3[CH2:13][CH2:14][C@@H:15]4[C@:20]([C:22]=3[CH2:23][CH2:24]2)([CH3:21])[CH2:19][CH2:18][C@H:17]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C:16]4([CH3:36])[CH3:35])=[CH:10][CH2:9]1)[CH3:7].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Si:28]([O:27][C@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@@H:15]([CH2:14][CH2:13][C:12]3[C:11]4[C@:25]([CH3:26])([CH2:24][CH2:23][C:22]=32)[C@@H:8]([C@H:6]([CH3:7])[CH2:5][CH2:4][CH2:3][OH:2])[CH2:9][CH:10]=4)[C:16]1([CH3:35])[CH3:36])([C:31]([CH3:34])([CH3:32])[CH3:33])([CH3:30])[CH3:29]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CCCO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Yield: 91.4 %

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid methyl ester (5.29 g) is reduced with lithium aluminium hydride (1.75 g) in 300 ml of THF at room temperature. After aqueous work-up and crystallisation from ethanol/water, 4.58 g of 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-ol is isolated.
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:11])=[CH:8]/[CH2:9][OH:10].[OH-].[Na+].C(O)(=O)C.[BH4-].[Na+]>O1CCCC1>[OH:1][CH2:2]/[C:3](/[CH2:12][CH2:13]/[CH:14]=[C:15](/[CH3:22])\[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:11])=[CH:8]/[CH2:9][OH:10]
Reactant: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)CO
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C\CC/C(=C\CC/C(C)=C/CO)CO
Temperature: -20 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
In 125 ml of anhydrous tetrahydrofuran was suspended 18 g of (E)-4-methyl-(-acetoxy-4-hexen-1-yltriphenylphosphonium iodide, and to this suspension was added dropwise two molar equivalents of a n-butyllithium-hexane solution at -20° C. in a stream of nitrogen. The resulting mixture was stirred at -20° C. for one hour and to this was further added 8.4 g of (Z)-1,1-diethoxy-6,10-dimethyl-5,9-undecadien-2-one (prepared in Referential example 3) in 25 ml of anhydrous tetrahydrofuran. The mixture was then stirred at room temperature for 3 hours and, after addition of ice-water, extracted with n-hexane, and from the extract was obtained an oil. The oil was treated with a sodium hydroxide solution and acetic acid and reduced with 150 mg of sodium borohydride in the same manner as in Example 13, yielding 3.0 g of a mixture of the (E,Z,Z) and (E,E,Z) isomers.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[F:12])(=[O:3])[CH3:2].[CH3:13][C:14]1[CH:15]=[C:16]([NH:23][C:24](=[O:30])[C@:25]([OH:29])([CH3:28])[CH2:26]Br)[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21]>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:28][C@@:25]([OH:29])([CH3:26])[C:24]([NH:23][C:16]2[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:14]([CH3:13])[CH:15]=2)=[O:30])=[CH:7][C:6]=1[F:12])(=[O:3])[CH3:2]
Reactant: Cc1cc(NC(=O)[C@@](C)(O)CBr)ccc1[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(O)cc1F
Product: CC(=O)Nc1ccc(OC[C@](C)(O)C(=O)Nc2ccc([N+](=O)[O-])c(C)c2)cc1F

Procedure:
(2S)-3-(4-Acetylamino-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared according to the method B as described in Example 3e starting from 4-acetylamino-3-fluorophenol and N-[3-methyl-4-(nitro)phenyl]-(2R)-3-bromo-2-hydroxy-2-methylpropanamide. 1H NMR (DMSO-d6): 1.42 (3H, s), 2.02 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J=9.7 Hz), 4.21 (1H, d, J=9.7 Hz), 6.23 (1H, bs), 6.72 (1H, m), 6.90 (1H, m), 7.56 (1H, m), 7.88 (1H, dd, J=9.0 Hz and 2.2 Hz), 7.93 (1H, d, J=2.2 Hz), 8.03 (1H, d, J=9.0 Hz), 9.51 (1H, s), 10.15 (1H, bs).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:13]=1[C:14](OC)=O.S(Cl)(Cl)=O.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([O-:36])=[O:35])=[CH:30][CH:29]=1.[Na+].C([O-])(=O)C.[K+]>[Cl-].[Na+].O.C(Cl)(Cl)Cl.C(Cl)Cl.CCCCCC>[Cl:11][C:12]1[C:13]([CH2:14][S:34]([C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])=[CH:18][C:19]([Cl:22])=[CH:20][N:21]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Agent: CC(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: O=S(=O)(Cc1cc(Cl)cnc1Cl)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At −78° C., diisobutylaluminum hydride (a 1M hexane solution; 1.92 ml) was added dropwise to a methylene chloride (10 ml) solution of methyl 2,5-dichloronicotinate (188 mg, 0.912 mmol). The resulting mixture was stirred at 0° C. for 30 minutes. The reaction mixture was added with brine, and the mixture was filtered through Celite. The filtrate was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate (=3:1) eluate was concentrated under reduced pressure. To a chloroform (10 ml) solution of the residue (128 mg) was added thionyl chloride (0.26 ml, 3.60 mmol), followed by stirring at 50° C. for 6.5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in butanol (10 ml). To the resulting solution were added sodium 4-chlorobenzenesulfinate (171 mg, 0.863 mmol) and potassium acetate (212 mg, 2.16 mmol) and the mixture was stirred at 70° C. for 19 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, followed by successive washing with water and brine and drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting solid was washed with hexane-diisopropyl ether, and collected by filtration, whereby the title compound (108 mg, 35%) was obtained as a white powder.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][S:16][CH2:17][CH:18]=3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+].[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:27])=[CH:29][CH:30]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][S:16][CH2:17][CH:18]=3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN
Reactant: CCc1sc(C2=CCSCC2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCc1sc(C2=CCSCC2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
To a mixture of 4-({cyclohexyl[5-(3,6-dihydro-2H-thiopyran-4-yl)-2-ethylthiophen-3-yl]methyl}amino)benzoic acid (246 mg) synthesized above, ethyl β-alaninate hydrochloride (98.8 mg), 1-hydroxybenzotriazole monohydrate (98.5 mg) and triethylamine (90 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (123 mg), and the mixture was stirred at room temperature for 8 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give a brown oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 2.5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (145 mg, 47%) as a brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:23][C@@H:24]([CH3:27])[CH2:25][OH:26])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])#[N:2].[H-].[Na+].F[C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:23][C@@H:24]([CH3:27])[CH2:25][O:26][C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])#[N:2]
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CO)cc1OC
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)COc2ccc(C#N)cc2)cc1OC
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
To a solution of (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)benzamide (177 mg) in dimethylformamide (4 mL) was added sodium hydride (19.2 mg) at ambient temperature. After stirring for 20 minutes, 4-fluorobenzonitrile (63.8 mg) was added to the mixture. After stirring for an hour at 60° C., the mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with the mixture of chloroform and ethyl acetate (9:1) to give (S)-5-cyano-2-[2-(4-cyanophenoxy)-1-methylethylamino]-N-(3,4-dimethoxybenzyl)benzamide (76 mg) as a solid substance.