Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]=[CH:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH:18]([NH2:21])([CH3:20])[CH3:19]>C(O)(C)C>[C:1]([NH:4][CH:5]=[CH:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]([OH:15])[CH2:14][NH:21][CH:18]([CH3:20])[CH3:19])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC=Cc1ccc(OCC2CO2)cc1
Reactant: CC(C)N
Solvent: CC(C)O
Product: CC(=O)NC=Cc1ccc(OCC(O)CNC(C)C)cc1

Procedure:
11.6 g (0.05 mol) of 1-[p-(2-acetylaminovinyl)-phenoxy]-2,3-epoxy-propane are dissolved in 100 ml of isopropanol, 4.25 ml (0.05 mol) of isopropylamine are added and thereafter the mixture is heated to the boil for 3 hours under reflux. It is then evaporated in vacuo and the resulting crude base is crystallised from ethyl acetate. 1-[p-(2-Acetylaminovinyl)-phenoxy]-2-hydroxy-3-isopropylaminopropane of melting point 144°-146° C. is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.F[C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-(4-pyridyl)piperazine (9.78 g), ethyl 4-fluorobenzoate (9.7 ml) and powdered potassium carbonate (9.9 g) in dried dimethylsulphoxide (60 ml) was heated at 95° C. for 18 hours. The mixture was poured into water (1200 ml) and stirred for 30 minutes. The precipitate was filtered off, washed with water and dried. The solid was purified by flash column chromatography on alumina (ICN alumina N32-63) using 1% methanol/dichloromethane as eluent, to give ethyl 4-[4-(4-pyridyl)-1-piperazinyl]benzoate (4.85 g) as a cream solid, mp 162-164° C.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:5][N:4]=1.[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH2:22][S:23][CH2:24][CH2:25][NH2:26]>>[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH2:22][S:23][CH2:24][CH2:25][NH:26][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:5][N:4]=1
Reactant: CSc1nnc(Cc2cccnc2)c(=O)[nH]1
Reactant: NCCSCc1nccs1
Product: O=c1[nH]c(NCCSCc2nccs2)nnc1Cc1cccnc1

Procedure:
3-Methylthio-6-(3-pyridylmethyl)-1,2,4-triazin-5-one (3.28 g) and 2-(2-thiazolylmethylthio)ethylamine (2.7 g) were heated together on an oil bath (160°-170°) for 1 hour. The cooled mixture was triturated with isopropanol and the solid was twice recrystallised from ethanol to give the title compound as pale yellow plates (3.1 g) m.p. 158°-59°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]([CH3:18])[C:11](=[O:19])[CH:10]=2)=[C:4]([F:20])[CH:3]=1.FC1C=C(I)C=CC=1NC1C([N+]([O-])=O)=CNC(=O)C=1.C1C(=O)N([Cl:47])C(=O)C1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]([CH3:18])[C:11](=[O:19])[C:10]=2[Cl:47])=[C:4]([F:20])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1cc([N+](=O)[O-])c(Nc2ccc(Br)cc2F)cc1=O
Agent: O=c1cc(Nc2ccc(I)cc2F)c([N+](=O)[O-])c[nH]1
Solvent: CN(C)C=O
Product: Cn1cc([N+](=O)[O-])c(Nc2ccc(Br)cc2F)c(Cl)c1=O
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 77 %

Procedure:
A suspension of 4-(4-Bromo-2-fluoro-phenylamino)-1-methyl-5-nitro-1H-pyridin-2-one (451 mg, 1.323 mol), synthesized using the same procedures as for the synthesis of 4-(2-Fluoro-4-iodophenylamino)-5-nitropyridin-2(1H)-one, and NCS (286 mg, 2.14 mmol) in dry DMF (13 mL) was heated to 50° C. The solution became clear in 5 minutes, and the solution turned into light orange. The heating was continued over the 48 hours. At this time, LC/MS indicated there was 77% of the title product in the reaction mixture. The heating temperature was then raised to 70° C. and kept at that temperature for additional 4 hours. Water was added until the yellow precipitate formed. The stirring was continued at r.t. for 30 min. The precipitate was then filtered, washed with water (5 mL) and dried under high vacuum overnight. The title compound was used for the next reaction without further purification. (424 mg, 85% yield).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:5]1)([OH:3])=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.OC1C2N=NNC=2C=CC=1.CN1CCOCC1>CCOCC>[C:25]1([NH:24][C:1]([CH:4]2[CH2:9][CH2:8][CH2:7][N:6]([C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)=[O:11])[CH2:5]2)=[O:3])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)C1CCCN(C(=O)C2CCN(c3ccncc3)CC2)C1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: O=C(Nc1ccccc1)C1CCCN(C(=O)C2CCN(c3ccncc3)CC2)C1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
Dicyclocarbodiimide (620 mg) was added to a stirred mixture of the crude 3-carboxy-1-[4-pyridylpiperidin-4-ylcarbonyl]piperidine product from step (b) (1 g), aniline (0.17 ml), hydroxybenztriazole, (236 mg), N-methylmorpholine (0.29 ml) under an atmosphere of argon with cooling to 0 to 5° C. The mixture was stirred at 0° C. for 30 minutes and then allowed to warm to ambient temperature and stirred overnight. The mixture was quenched with water and the solvent removed by evaporation. The residue was partitioned between dichloromethane and water. The aqueous phase was seperated and washed with dichloromethane. The aqueous phase was evaporated and the residue purified by flash chromatography on silica gel using 15% MeOH/CHCl2 as eluent to give a crude product which was further purified by flash chromatography on silica gel using a gradient of 4 to 10% MeOH/CH2Cl2 as eluent to give an oil. Ether was added and then evaporated to yield 3-(phenylaminocarbonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperidine as a foam (200 mg; 80% pure);
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][O:7][CH2:8][C@:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:12][C@@H:11]([N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10]1.NN>C1(C)C=CC=CC=1>[F:1][C:2]([F:38])([F:39])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][O:7][CH2:8][C@:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:12][C@@H:11]([NH2:14])[CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CC[C@](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Agent: NN
Solvent: Cc1ccccc1
Product: N[C@@H]1CC[C@](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Temperature: 80 °C
Yield: 94.5 %

Procedure:
To a solution of 2-((1R,3R)-3-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-3-phenylcyclopentyl)isoindoline-1,3-dione (68 mg), available from Example 7, in toluene (0.50 mL) was added anhydrous hydrazine (41 μL), and the reaction mixture was heated at 80° C. for 12 h. The precipitate was removed by filtration, and the filtrate was evaporated in vacuo to give the title compound (49 mg). 1H NMR (CDCl3, 400 MHz) δ 1.46 (1H, m), 1.60 (2H, broad s), 1.74 (1H, dd, J=6.0, 12.8 Hz), 2.09 (2H, m), 2.19 (1H, m), 2.48 (1H, dd, J=6.8, 12.8 Hz), 3.40 (1H, d, J=8.8 Hz), 3.44 (1H, d, J=8.8 Hz), 3.53 (1H, quintet, J=7.2 Hz), 4.43 (2H, s), 7.25 (5H, m), 7.55 (2H, s), and 7.73 (1H, s). HRMS m/z calcd for C21H22F6NO (M+H)+ 418.1607. found 546.1621.
Reaction SMILES: O.O.[CH3:3][C:4]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[N:5]=1.C(CC(=O)C)(=O)C.Cl.C(N)(=[NH:22])C.[C:24]1([CH3:37])[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=1[S:32]([O:35]N)(=[O:34])=[O:33]>ClCCl>[C:24]1([CH3:37])[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=1[S:32]([O-:35])(=[O:34])=[O:33].[NH2:22][N+:5]1[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[N:9][C:4]=1[CH3:3]
Reactant: Cc1cc(C)nc(C)n1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: CC(=N)N
Agent: Cl
Solvent: O
Solvent: CC(=O)CC(C)=O
Solvent: ClCCl
Product: Cc1cc(C)[n+](N)c(C)n1
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Reaction time: 5 h

Procedure:
2,4,6-trimethylpyrimidine dihydrate (0.79 g, 5.0 mmole, prepared from acetylacetone and acetamidine hydrochloride according to A. Bowman, J. Chem. Soc. 1937;494-495) in dichloromethane (10 mL) was dried over Na2SO4 and filtered. Separately, O-(mesitylenesulfonyl)hydroxylamine containing ca. 25% water (1.57 g, ca. 5.4 mmole) was dissolved in dichloromethane (10 mL) and dried over Na2SO4 and filtered. The dry O-(mesitylenesulfonyl)hydroxylamine filtrate was added dropwise to the dry 2,4,6-trimethylpyrimidine filtrate at 0 C. Stirring was continued 5 hr at 0 C. and then 16 hr at 4 C. The reaction mixture was concentrated at reduced pressure to ca. 10 mL and treated with ca. 3 mL ether to cause separation of a white powder, which was filtered, washed with 10 mL 1:1 dichloromethane/ether, and dried to yield 1.27 of crude product in two crops. Recrystallization from methanol/dichloromethane/ether gave 1.18 g of the title compound, mp 183-185 C.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](=[S:11])=[S:10].Br[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:14]#[N:15].O>C1COCC1>[C:9]([S:11][CH:13]([C:14]#[N:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[S:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(Br)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Reactant: S=C=S
Solvent: C1CCOC1
Solvent: O
Product: N#CC(SC(=S)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100 ml round bottom flask was added 5 ml phenyl magnesium bromide (3M solution in ethyl ether) and diluted to 20 ml with anhydrous THF. 1.2 g carbon disulfide was added dropwise to this mixture and stirred for ½ h at room temperature. Then to the dark red solution was added 3 g α-bromobenzeneacetonitrile dropwise and the mixture stirred for another 3 h. Water was added to the mixture and the organic product was extracted with diethyl ether (3×50 ml), dried with magnesium sulfate overnight and filtered. After removal of solvent and column chromatography (3:1 mixture of hexane and ethyl ether), pure α-cyanobenzyl dithiobenzoate was obtained as a red odorless solid (77% yield). Proton and carbon NMR spectra were consistent with the expected structure, CTA-CP-1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([NH:9][CH:10]1[CH2:14][CH2:13][O:12][CH2:11]1)=[O:8])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([NH:9][CH:10]1[CH2:14][CH2:13][O:12][CH2:11]1)=[O:8]
Reactant: O=C(NC1CCOC1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(=O)NC2CCOC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
3-Nitro-N-(tetrahydrofuran-3-yl)benzamide (0.24 g, 1.016 mmol) was taken in methanol (5 ml), added Pd—C (10%, 0.108 g) and the reaction mixture was stirred under hydrogen atmosphere for 2 hr at room temperature. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under vacuum to afford the crude product, which was purified by column chromatography eluting with 0-100% ethyl acetate in hexane to obtain the title compound (180 mg).
Reaction SMILES: [C:1]([CH:3]([OH:18])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)#[CH:2].[F:19][C:20]1[CH:28]=[CH:27][C:23]([CH:24]([OH:26])[CH3:25])=[CH:22][C:21]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]=[CH:44][CH:45]([CH:49]([CH3:51])[CH3:50])[C:46](O)=[O:47])=[CH:39][CH:38]=1>>[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH:43]=[CH:44][CH:45]([CH:49]([CH3:51])[CH3:50])[C:46]([O:18][CH:3]([C:1]#[CH:2])[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:5]=2)=[O:47])=[CH:41][CH:42]=1.[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH:43]=[CH:44][CH:45]([CH:49]([CH3:51])[CH3:50])[C:46]([O:26][CH:24]([CH3:25])[C:23]2[CH:27]=[CH:28][C:20]([F:19])=[C:21]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:22]=2)=[O:47])=[CH:41][CH:42]=1
Reactant: CC(C)C(C=Cc1ccc(F)cc1)C(=O)O
Reactant: C#CC(O)c1ccc(F)c(Oc2ccccc2)c1
Reactant: CC(O)c1ccc(F)c(Oc2ccccc2)c1
Product: C#CC(OC(=O)C(C=Cc1ccc(F)cc1)C(C)C)c1ccc(F)c(Oc2ccccc2)c1
Product: CC(OC(=O)C(C=Cc1ccc(F)cc1)C(C)C)c1ccc(F)c(Oc2ccccc2)c1

Procedure:
Each of α-ethynyl-4-fluoro-3-phenoxybenzyl alcohol and 4-fluoro-α-methyl-3-phenoxybenzyl alcohol is reacted with 4-(4-fluorophenyl)-2-isopropyl-3-butenoic acid to yield α-ethynyl-4-fluoro-3-phenoxybenzyl 4-(4-fluorophenyl)-2-isopropyl-3-butenoate and 4-fluoro-α-methyl-3-phenoxybenzyl 4-(4-fluorophenyl)-2-isopropyl-3-butenoate.
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:8]2[CH2:33][C:34](OC)=[O:35])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[C:8]2[CH2:33][CH2:34][OH:35])=[CH:38][CH:39]=1
Reactant: COC(=O)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)Sc1c(CCO)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12
Reaction time: 1 h

Procedure:
The compound from Step A (192 mg) was dissolved in 3 mL of THF at RT under an argon atmosphere and treated with 30 mg of lithium aluminum hydride. After 1 hr, the reaction was poured onto 10 mL of 0.5N Na,K tartrate solution and extracted with 3×10 mL of EtOAc. The organic layer was washed with 10 mL of H2O, dried (MgSO4) and evaporated to dryness to yield the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:16][N:15](C(OCC2C=CC=CC=2)=O)[CH2:14]1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1.C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: O=C(OCc1ccccc1)N1CCC(Oc2ccccc2)C(OCc2ccc3ccccc3c2)C1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(OC2CCNCC2OCc2ccc3ccccc3c2)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 47 %

Procedure:
30 mg, 0.065 mmol) of benzyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-phenoxy-piperidine-1-carboxylate were dissolved in 1.6 ml of tetrahydrofuran, cooled to 0° C. and treated in succession within 25 minutes with a solution of 95 ml (0.32 mmol, approximately 5 eq.) of a 70% sodium dihydrido-bis-(2-methoxyethoxy)-aluminate solution (SDMA) in toluene and 1.6 ml of tetrahydrofuran. This reaction solution was stirred at 0° C. for 2.5 hours. Subsequently, it was poured into a mixture of saturated potassium sodium tartrate solution and ice and extracted four times with 50 ml of methylene chloride each time. The organic phases were washed twice with water, evaporated under reduced pressure and dried in a high vacuum. The orange coloured resin was separated on silica gel using a 95:5 mixture of methylene chloride and methanol as the eluent. There were obtained 10 mg (47% of theory) of (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-phenoxy-piperidine as a colourless, amorphous solid; Rf : 0.38 (SiO2, methylene chloride:methanol=9:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([OH:16])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](I)[CH3:25]>CN(C=O)C.Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([O:16][CH2:24][CH3:25])[CH:5]=1
Reactant: CCI
Reactant: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)cc(N2CCCC2=O)c1
Temperature: 50 °C
Yield: 95 %

Procedure:
To 3-hydroxy-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D37) (0.80 g, 3.4 mmol, 1 equiv) dissolved in DMF (10 ml) was added K2CO3 (0.94 g, 6.8 mmol, 2 equiv) and ethyl iodide (1.1 g, 6.8 mmol, 2 equiv). The resulting mixture was heated at 50° C. for 4 h, cooled to room temperature, diluted with 2N aqueous HCl solution (50 ml) and extracted with Et2O (50 ml). The organic phase was then washed with water (50 ml), dried over MgSO4 and concentrated in vacuo to give of 3-ethoxy-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (B11) (0.85 g, 95%) as a brown oil which slowly solidified to a tan solid.
Reaction SMILES: [C:1]1([CH:7]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:8][C:9](O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:23])=O.CN(C)[CH:28]=[O:29]>>[Cl:23][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[S:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]=1[CH:28]=[O:29]
Reactant: COc1cccc(SC(CC(=O)O)c2ccccc2)c1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Product: COc1ccc2c(c1)SC(c1ccccc1)C(C=O)=C2Cl

Procedure:
As in example 18, but using 4.3 g 3-phenyl-3-(3-methoxyphenylmercapto)propionic acid, 40 ml dimethylformamide and 15 ml phosphorous oxychloride. After hydrolysis and work-up the residual oil is purified by column chromatography and the best fractions are recrystallized in diisopropylether. Pure 4-chloro-3-formyl-7-methoxy-thioflav-3-ene is obtained as yellow crystals; m.p. 84°-87° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(#N)C.[CH3:12][C:13]1([CH3:25])[CH2:17][C:16]2[C:18]([CH3:24])=[CH:19][C:20]([CH3:23])=[C:21]([CH3:22])[C:15]=2[O:14]1>O>[Br:1][C:19]1[C:20]([CH3:23])=[C:21]([CH3:22])[C:15]2[O:14][C:13]([CH3:25])([CH3:12])[CH2:17][C:16]=2[C:18]=1[CH3:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)c2c(c1C)OC(C)(C)C2
Solvent: O
Solvent: CC#N
Product: Cc1c(C)c2c(c(C)c1Br)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
N-bromosuccinimide (12.5 g, 70.0 mmol) was added to a solution of acetonitrile (165 mL) containing 2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran (11.1 g, 58.3 mmol) synthesized in Reference Example 3 under ice-cooling condition, and the mixture was warmed to room temperature. After stirring for 5 hours, water was added to the reaction solution. The generated precipitate was collected by filtration and washed with a mixture of acetonitrile/water (1/2). The solid was dried to give 13.5 g of the title compound (yield: 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([SH:10])=[C:6]([CH:9]=1)[CH:7]=O.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+].Cl>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH:13]([C:12]([F:11])([F:21])[F:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:9]=1
Reactant: Cc1ccc(S)c(C=O)c1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(C)ccc2SC1C(F)(F)F
Yield: 69.4 %

Procedure:
The 5-methyl-2-mercaptobenzaldehyde (Step 1) (3.25 g, 21.3 mmol) was added to DMF (5 mL) and ethyl 4,4,4-trifluorocrotonate (4.32 g, 25.7 mmol). With stirring, K2CO3 (3.78 g, 27.3 mmol) was added causing the reaction to become a deep red. The reaction was stirred at room temperature for 20 hours, acidified with 3N HCl, diluted with ethyl acetate and washed with water, saturated NaHCO3 solution, brine, dried over MgSO4, filtered and concentrated in vacuo yielding an oil. The oil was crystallized from diethyl ether-petroleum ether to give ethyl 6-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylate as a light yellow solid (4.47 g, 69%): mp 93.1-94.7° C. 1H NMR (acetone-d6/300 MHz) 7.94 (s, 1H), 7.41 (s, 1H), 7.31 (d, 1H, J=7.9 Hz), 7.25 (d, 1H, J=7.9 Hz), 4.96 (q, 1H, J=8.5 Hz), 4.33 (m, 2H), 2.34 (s, 3H), 1.35 (t, 3H, J=7.0 Hz). FABLRMS m/z 309 (M+Li).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1.[OH-].[K+]>CN(C=O)C.O.[Cu-]=O>[CH3:8][C:6]1[CH:7]=[C:2]([S:20][C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH:3]=[C:4]([CH3:12])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1c(C)cc(I)cc1C
Reactant: Cc1ccc(S)cc1
Agent: O=[Cu-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(C)cc(Sc2ccc(C)cc2)cc1C
Yield: 78.2 %

Procedure:
A mixture of 1-(4-iodo-2,6-dimethylphenyl)ethanone (1.5 g, 5.5 mmol, 1.0 equiv), 4-methylbenzenethiol (1.02 g, 8.2 mmol, 1.5 equiv), copper(I) oxide (39.2 mg, 0.3 mmol, 0.05 equiv), and potassium hydroxide (614.1 mg, 11.0 mmol, 2.0 equiv) in DMF (4.4 mL) and H2O (1.1 mL) was heated at reflux for 20 h. The mixture was quenched with H2O (10 mL) and extracted with ether (2×20 mL). The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3.0% EtOAc in hexanes as eluant) to provide 1-(2,6-dimethyl-4-(p-tolylthio)phenyl)ethanone (1.16 g, 4.3 mmol) as yellow oil in 79% yield: 1H NMR (CD3OD, 500 MHz) δ 7.29 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 6.88 (s, 2H), 2.45 (s, 3H), 2.35 (s, 3H), 2.15 (s, 6H); ESI-MS: m/z 271.8 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:52])([CH3:51])/[CH:3]=[CH:4]/[C@H:5]1[O:10]C(C)(C)[O:8][C@@H:7]([C@@H:13]([O:48][CH3:49])[C:14]([NH:16][C@@H:17]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:21][C@H:20]([O:32][C:33](=[O:47])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:19][CH2:18]2)=[O:15])[C@@H:6]1[OH:50]>C(O)(C(F)(F)F)=O.C1COCC1.O>[O:24]=[C:23]1[N:22]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:21][C@H:20]([O:32][C:33](=[O:47])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:19][CH2:18][C@@H:17]1[NH:16][C:14](=[O:15])[C@H:13]([O:48][CH3:49])[C@H:7]([OH:8])[C@@H:6]([OH:50])[C@H:5]([OH:10])/[CH:4]=[CH:3]/[C:2]([CH3:1])([CH3:51])[CH3:52]
Reactant: CCCCCCCCCCCCCC(=O)O[C@@H]1CC[C@H](NC(=O)[C@H](OC)[C@@H]2OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@H]2O)C(=O)N(Cc2cccnc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCC(=O)O[C@@H]1CC[C@H](NC(=O)[C@H](OC)[C@H](O)[C@@H](O)[C@H](O)/C=C/C(C)(C)C)C(=O)N(Cc2cccnc2)C1
Yield: 69 %

Procedure:
To a solution of TFA/THF/H2O (3/3/2) (30 mL) at 0° C. is added tetradecanoic acid (3R,6S)-6-{(R)-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetylamino}-7-oxo-1-pyridin-3-ylmethyl-azepan-3-yl ester (0.3 g, 0.42 mmol). After 30 min the reaction is evaporated under high vacuum, toluene is added (20 mL) and evaporated under high vacuum to remove remaining TFA. The residue is dissolved in CH2Cl2 at 0° C. and neutralized by adding NH4OH dropwise. The solution is concentrated and chromatographed on silica (98% CH2Cl2/2% CH3OH) to give 0.2 g (70.7%) of tetradecanoic acid (3R,6S)-7-oxo-1-pyridin-3-ylmethyl-6-((2R,3R,4S,5R)-(E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-non-6-enoylamino)-azepan-3-yl ester as a with solid. 1H NMR 300 MHz δ 8.62 (s, 2H), 8.17 (d, 1H), 7.67 (d, 1H), 7.33 (m, 1H), 5.83 (d, 1H), 5.42(dd, 1H), 4.69 (m, 1H), 4.54 (m, 1H), 4.33 (d, 1H), 4.32 (t, 1H), 3.83 (dd, 2H), 3.67 (d, 1H), 3.25 (s, 3H), 3.17 (m, 1H), 2.94 (d, 1H), 2.29 (t, 2H), 2.13 (m, 2H), 2.00 (m, 1H), 1.60 (m, 3H), 1.29 (m, 24H), 1.04 (s, 9H), 0.89 (t, 3H); MS (ESI) 690.3 (M+H)+.