Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:18])[C:10]3[CH:16]=[C:15](Br)[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].[CH3:19][Zn]C.C1(C)C=CC=CC=1>O1CCOCC1.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]>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:18])[C:10]3[CH:16]=[C:15]([CH3:19])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2c3sc(Br)cc3C(C)C2C1
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)N1CC2c3sc(C)cc3C(C)C2C1
Temperature: 22 °C
Yield: 95 %

Procedure:
A solution of the product from step j) (284 mg, 0.86 mmol) in dioxane (4.3 ml) was treated with Pd(dppf)2Cl2 (42 mg, 0.051 mmol) and a 2M solution of dimethylzinc in toluene (0.86 ml, 1.72 mmol) at 102° C. for 1 hour. The reaction was cooled to 22° C. and carefully quenched with sat. NH4Cl (3 ml). After the effervescence subsided, the reaction was extracted with EtOAc (3×50 ml). The combined organic layers were dried (MgSO4) passed through a plug of silica-gel eluting with 50:50 hexanes:EtOAc to provide the subtitle compound (216 mg, 95% over 3-steps). MS calculated for C14H19NO2S +H 266, observed 266.
Reaction SMILES: C[O:2][C:3](=[O:25])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1(/[CH:5]=[C:4](\[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=2)/[C:3]([OH:25])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C(=C/C1CCCCC1)c1ccc(S(C)(=O)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)O)cc1[N+](=O)[O-]
Temperature: 47.5 °C
Reaction time: 15 h
Yield: 89.8 %

Procedure:
A solution of (E)-3-cyclohexyl-2-(4-(methanesulfonyl)-3-nitro-phenyl)-acrylic acid methyl ester (597 mg, 1.62 mmol) in ethanol (10 mL) was treated with a 1N aqueous sodium hydroxide solution (8 mL). The solution was heated at 45-50° C. For 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (20 mL) and extracted with diethyl ether (1×50 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-3-cyclohexyl-2-(4-(methanesulfonyl)-3-nitro-phenyl)-acrylic acid (0.514 g, 90%) as a white solid: mp 244-247° C.; EI-HRMS m/e calcd for C16H19NO6S (M+) 353.0933, found 353.0929.
Reaction SMILES: C([C:6](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[C:7](=[O:9])[CH3:8])(OCC)=O.C(O)(=O)C.Cl>O=[Pt]=O.O>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:6][C:7](=[O:9])[CH3:8])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=Cc1ccc(C)cc1)C(C)=O
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)CCc1ccc(C)cc1

Procedure:
3-Carboethoxy-4-(4-methylphenyl)but-2-one (20 g), (prepared by hydrogenation over PtO2 at 1 atmosphere of 3-carboethoxy-4-(4-methylphenyl)but-3-en-2-one) was heated under reflux for 3.5 h in a mixture of glacial acetic acid (48 ml), concentrated hydrochloric acid (5.6 ml) and water (30 ml). The solvent was evaporated, the residue dissolved in xylene, washed with water, dried and evaporated. The residue was distilled to give 4-(4-methylphenyl)butan-2-one, 11.0 g, bp 80-90/1 mm).
Reaction SMILES: C([NH:8][C:9]1[C:18]([Cl:19])=[C:17]2[C:12]([C:13](=[O:41])[C:14]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:15][N:16]2[C:20]2[CH:25]=[C:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([F:34])=[CH:22][C:21]=2[F:35])=[CH:11][C:10]=1[F:42])C1C=CC=CC=1.C(O)(=O)C.[H][H]>ClCCCl.[OH-].[Pd+2].[OH-]>[NH2:8][C:9]1[C:18]([Cl:19])=[C:17]2[C:12]([C:13](=[O:41])[C:14]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:15][N:16]2[C:20]2[CH:25]=[C:24]([NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C:23]([F:34])=[CH:22][C:21]=2[F:35])=[CH:11][C:10]=1[F:42]
Reactant: [H][H]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(NCc3ccccc3)c(F)cc2c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(N)c(F)cc2c1=O
Temperature: 25 °C
Yield: 91.9 %

Procedure:
Ethyl 7-benzylamino-1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (3.2 g) was dissolved in 1,2-dichloroethane (40 ml). An acetic acid suspension (10 ml) of 20% palladium hydroxide (300 mg) was added to this solution, and the mixture was stirred overnight at 60° C. in a hydrogen atmosphere. An acetic acid suspension (4 ml) of 20% palladium hydroxide (100 mg) was additionally added, and the resultant mixture was stirred overnight at the same temperature. After the reaction mixture was cooled back to room temperature, palladium hydroxide was removed by filtration. After the solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue, and solids were collected by filtration to obtain the title compound (2.5 g) as an amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:26])[C:11]([C:13]1[C:14]([F:25])=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)=[O:12].[F:27][C:28]([Si](C)(C)C)([F:30])[F:29].[F-].C[N+](C)(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:26])[C:11]([C:13]1[C:14]([F:25])=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)([OH:12])[C:28]([F:30])([F:29])[F:27]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(C(C)C(=O)c2cc3c(cc2F)OCC(=O)N3C)c(Cl)c1
Agent: C[N+](C)(C)C
Agent: [F-]
Product: COc1ccc(C(C)C(O)(c2cc3c(cc2F)OCC(=O)N3C)C(F)(F)F)c(Cl)c1

Procedure:
In analogy to Example 1, step 3, 6-[2-(2-chloro-4-methoxy-phenyl)-propionyl]-7-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as a colorless solid. MS (m/e)=448.1 [M+H+].
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1.[C-:14]#[N:15].[Na+]>CN(C=O)C.O>[N:13]1[C:12]2[NH:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:3][CH2:2][C:14]#[N:15]
Reactant: [C-]#N
Reactant: ClCCc1ccc2c(n1)NCCC2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCc1ccc2c(n1)NCCC2
Temperature: 85 °C
Yield: 21 %

Procedure:
7-(2-chloroethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (500 mg) and NaCN (150 mg) were dissolved in DMF (in 15 mL) and the mixture was heated at 85° C. for 6 hrs. Cooled to 25° C. and the reaction was diluted with H2O, extracted with CHCl3, and the solution was washed with H2O, dried with MgSO4. The solution was concentrated to a yellow oil. Column purification (Ethyl acetate: Hexane=1:1) to yield a yellow solid 100 mg (8.9%). 1H NMR (DMSO-d6) δ 7.06 (d, 1H), 6.45 (m, 2H), 3.33 (1, 2H), 2.75 (m, 4H), 2.63 (t, 2H), 1.75 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:65][CH2:66][CH:67]([OH:70])[CH2:68][OH:69]>CN(C=O)C.CCOC(C)=O>[OH:70][CH:67]([CH2:68][OH:69])[CH2:66][NH:65][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)=[CH:10][C:2]=1[F:1]
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)ccc1-c1ccccc1C
Reactant: NCC(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cc(-c2nc(-c3ccc(C(=O)NCC(O)CO)c(F)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoic acid (75 mg, 0.18 mmol) was dissolved in anhydrous DMF (1 mL). N-ethyldiisopropylamine (65 μl, 0.38 mmol) was added followed by HATU (72 mg, 0.19 mmol) and the reaction was stirred at RT for 15 minutes. 3-Amino-1,2-propanediol (17 mg, 0.19 mmol) was added and the reaction stirred at RT overnight. EtOAc was added and the organic phase was washed three times with a 1N aqueous solution of HCl and brine. It was dried on MgSO4, filtered and concentrated. It was purified on preparative HPLC to afford the title compound as a brown solid. LC/MS (Method B): 492.2 (M+H)+, 490.3 (M−H)−. HPLC (Method A) Rt 4.82 min (Purity: 95.9%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[Cl:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccc(Cl)c(Cl)c2)s1
Yield: 4 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, using 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.055 mmol) and 3,4-dichlorophenylboronic acid (11 mg, 0.06 mmol). The title compound was obtained in 4% yield (0.8 mg). MS (ESI+) m/z 452 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].FC(F)(F)S(O)(=O)=O>ClC(Cl)(Cl)C(=N)OCC#CC>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:2][C:1]#[C:3][CH3:4])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: CC#CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CC#CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CC1OC
Temperature: 25 °C
Yield: 63.8 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (50 mg in 1.5 ml 33% methylene chloride in cyclohexane), 2-butynyl trichloroacetimidate (20 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 16 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (17 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O(C1C=CC(P2(=S)SP(=S)(C3C=CC(OC4C=CC=CC=4)=CC=3)[S:32]2)=CC=1)C1C=CC=CC=1>COCCOC.C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](=[S:32])[NH2:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(N)=O)cc1
Reactant: S=P1(c2ccc(Oc3ccccc3)cc2)SP(=S)(c2ccc(Oc3ccccc3)cc2)S1
Solvent: C1CCOC1
Solvent: COCCOC
Product: CCCCCCCOc1ccc(C(N)=S)cc1
Yield: 105.3 %

Procedure:
To stirring suspension of 4-(heptyloxy)benzamide (1.24 g, 5.29 mmol) in DME (20 mL) and THF (10 mL) was added 2,4-bis(4-phenoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (2.80 g, 5.29 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated onto silica and purified by column chromatography (0-60% EA in iso-hexanes) to afford 1.4 g (62%) of 4-(heptyloxy)benzothioamide as a yellow waxy solid. LCMS-ESI (m/z) calculated for C14H21NOS, 251.4. found 252.0 [M+H]+, tR=3.13 min. (Method 6).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21]([O:23][C:24](=[O:30])[CH:25](Br)[CH:26]([CH3:28])[CH3:27])[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[CH2:21]([O:23][C:24](=[O:30])[CH:25]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:26]([CH3:28])[CH3:27])[CH3:22]
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Reactant: CCOC(=O)C(Br)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Oc1cccc2c1cc(C)n2Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
1-Benzyl-2-methyl-1H-indol-4-ol 3 (0.3 g 1.26 mmole) was dissolved in anhydrous dimethylformamide (20 mL). To the solution sodium hydride 60% in mineral oil (66 mg 1.65 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture ethyl-2-bromoisovalerate (0.344 mL, 1.65 mmole) was added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (300 mL) and washed with H2O (4×100 mL) and brine (1×100 mL). The organic layer was separated, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (10:1 Hexane:EtOAc) to afford a 1:1 mixture of 7: ethyl-2-bromoisovalerate. Further purification by column chromatography (10:1 Hexane:EtOAc) afforded 7 (0.09 g, 19%) as a yellow oil.
Reaction SMILES: [SH:1][C@@H:2]([CH3:13])[C:3]([N:5]1[C@H:9]([C:10]([OH:12])=[O:11])[CH2:8][S:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22][CH:21]=1>O>[CH3:29][C:20]1[CH:25]=[CH:24][C:23]([C:26]([S:1][C@@H:2]([CH3:13])[C:3]([N:5]2[C@H:9]([C:10]([OH:12])=[O:11])[CH2:8][S:7][CH2:6]2)=[O:4])=[O:27])=[CH:22][CH:21]=1
Reactant: C[C@H](S)C(=O)N1CSC[C@H]1C(=O)O
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(C(=O)S[C@@H](C)C(=O)N2CSC[C@H]2C(=O)O)cc1
Temperature: 25 °C

Procedure:
2.2 g of (4R)-3-[(2S)-2-mercaptopropanoyl]-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate are dissolved in 50 ml of water. To this solution, 1.6 g of p-toluoyl chloride is added dropwise with stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour and at room temperature for additional 1 hour. The reaction solution is washed with ethyl acetate, and acidified with conc. hydrochloric acid to give crystals. The crystals (the titled compound) are collected by filtration, yield 3.3 g (97%), mp. 166°-166.5° C. (ethyl acetate), [α]D25 -148.6° (c=1.1, methanol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[OH-].[CH2:9]([N+](C)(C)C)[C:10]1[CH:15]=CC=[CH:12][CH:11]=1.CC(Cl)(C)C#C.[OH-].[Na+]>CO.C(Cl)Cl.O>[CH3:9][C:10]1([CH3:15])[O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:12]=[CH:11]1
Reactant: Oc1ccncc1
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: C#CC(C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC1(C)C=Cc2cnccc2O1
Temperature: 25 °C
Reaction time: 90 h

Procedure:
p-Hydroxypyridine (32.0 g), 40% benzyltrimethylammonium hydroxide in MeOH (50.7 g) and 3-methyl-3-chlorobut-1-yne (37.4 g) were dissolved in CH2Cl2 (150 mL). To this stirred solution was added NaOH pellets (14.5 g) dissolved in H2O (150 mL) and the resulting mixture stirred vigorously at room temperature for 3.75 days. The layers were separated and the aqueous layer further extracted with CHCl3. The combined organic layers were evaporated and the resulting brown oil was taken up in Et2O and washed with 10% NaOH solution, H20 and brine before drying over anh. MgSO4. Filtration and evaporation yielded an orange oil (21.0 g) which was boiled in o-dichlorobenzene under N2 for 1 h. Evaporation of the solvent and distillation gave the title pyranopyridine (9.2 g): bp 110° C. /0.18 mmHg; NMR (CDCl3) δ 1.47 (s, 6H)
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([S:11][CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:13](Cl)(=[O:15])[CH3:14]>C(Cl)Cl>[CH3:14][C:13]([C:8]1[CH:9]=[CH:10][C:5]([S:11][CH3:12])=[CH:6][CH:7]=1)=[O:15]
Reactant: CC(=O)Cl
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
123 g (0.92 mol) of AlCl3 are added with a spatula to a mixture of 100 g (0.8 mol) of thioanisole, 750 ml of CH2Cl2 and 63 ml (0.9 mol) of acetyl chloride, cooled to 0° C. beforehand, said addition being carried out so that the temperature does not exceed 10° C. The mixture is stirred for 1 h at room temperature, heated for 1 h at 40° C. and then poured into 800 ml of an ice/water mixture. The resulting mixture is separated and extracted with CH2Cl2. The organic phases are combined, washed with water and then dried over MgSO4 and concentrated to give 117.1 g of 4-(methylthio)acetophenone.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@:19]([O:49][Si:50]([CH3:53])([CH3:52])[CH3:51])([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][Si:32]([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:26]=4)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.CCOC(C)=O.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@:19]3([O:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][Si:32]([C:45]([CH3:48])([CH3:46])[CH3:47])([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:26]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](Oc1cccc(C[C@]2(O[Si](C)(C)C)CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)[Si](Oc1cccc(C[C@]2(O[Si](C)(C)C)CCCC[C@@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 87.3 %

Procedure:
A mixture of (R)-2-(4,5-diphenyloxazol-2-yl)-1-trimethylsilyloxy-1-[3-(tertbutyldiphenylsiloxy)benzyl]-2-cyclohexene (24 g) and 10% Pd/C (10 g) in a mixture of MeOH (200 ml) and EtOAc (500 ml) was stirred under H2 for 8 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel to give (1R, 2S)-2-(4,5-diphenyloxazol-2-yl)-1-trimethylsilyoxy-1-[3-(tertbutyldiphenylsiloxy)benzyl]cyclohexane (21 g).
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH3:19])=[C:4]([CH3:17])[C:5]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:35])(=O)=O)=CC=1.[Cl-].[NH4+]>O1CCCC1>[Si:10]([O:9][CH2:8][C:5]1[C:4]([CH3:17])=[C:3]([O:18][CH3:19])[C:2]([F:35])=[CH:7][N:6]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: COc1c(Br)cnc(CO[Si](C)(C)C(C)(C)C)c1C
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(F)cnc(CO[Si](C)(C)C(C)(C)C)c1C
Temperature: -68 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
The above 5-bromo-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methoxy-3-methylpyridine (734 mg) was dissolved in tetrahydrofuran (30 ml), and butyllithium (1.59 M solution, 2.42 ml) was then added dropwise to the solution at −110° C. The resulting mixture was stirred at the same above temperature for 1 hour, and a tetrahydrofuran (5 ml) solution of N-fluorobenzenesulfonimide (3.03 g) was then added dropwise to the reaction solution at the same temperature. The temperature of the resulting mixture was gradually raised to −68° C. over 3 hours, and the mixture was then stirred at room temperature for 30 minutes. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was then concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain the title compound (353 mg) as an oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][I:10])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](C2C=CC(CCO)=CC=2)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][I:10])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Brc1ccc(CCI)cc1
Reactant: OCCc1ccc(-c2ccc(F)cc2)cc1
Product: Fc1ccc(-c2ccc(CCI)cc2)cc1
Yield: 100 %

Procedure:
The title compound (650 mg, 100%) was prepared following the general procedure of step 1, Preparation 2, outlined for 1-bromo-4-(2-iodoethyl)benzene except that 2-(4′-fluorobiphenyl-4-yl)ethanol (430 mg, 1.99 mmol) was used in place of 2-(4-bromophenyl)ethanol. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.23 (t, J=7.69 Hz, 2H) 3.39 (t, J=7.69 Hz, 2H) 7.13 (t, J=8.72 Hz, 2H) 7.24-7.30 (m, 2H) 7.48-7.58 (m, 4H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][S:7][CH2:6][C@@H:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(OCC)(=O)C>C1CCCCC1>[CH2:28]([O:27][C:25]([CH:24]([NH:1][C@H:2]1[CH2:8][S:7][CH2:6][C@@H:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(OCc1ccccc1)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSC[C@H]1c1cccs1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(CCc2ccccc2)C(=O)OCc2ccccc2)CSC[C@H]1c1cccs1

Procedure:
282 mg of t-butyl α-[6(R)-amino-5-oxo-3(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in Example 16(g)] were N-alkylated with 684 mg of benzyl 2-bromo-4-phenylbutyrate in the same manner as in Example 1(h). The reaction product was subjected to silica gel column chromatography using a 1:4 by volume mixture of ethyl acetate and cyclohexane, to separate it into two isomers, A and B (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).