Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[OH:9]O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N+:3]=1[O-:9]
Reactant: OO
Reactant: Brc1cccc(Br)n1
Solvent: O=C(O)C(F)(F)F
Product: [O-][n+]1c(Br)cccc1Br
Temperature: 100 °C
Yield: 90 %

Procedure:
To an ice-cold solution of 2,6-dibromopyridine (50 g, 0.21 mol) in trifluoroacetic acid (250 mL) was added 30% H2O2 solution (70 mL) drop wise over 1 h. The reaction mixture was washed, heated to 100° C. for 16 h then cooled to rt, poured into 1.50 L of water and the precipitate filtered. The solid thus obtained (10 g) was the starting material (2,6-dibromopyridine). The filtrate was extracted with dichloromethane (3×1 L) and the combined organic layer was washed with 0.50 M K2CO3 solution (3×500 mL). The organic layer was then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was treated with hexane then filtered to obtain the desired product as an off white solid (38.50 g, 72% and 90% yield based on the recovery of the starting material).
Reaction SMILES: Br[CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6])=[CH:13][CH:12]=1
Reactant: CC(C)(CF)C(=O)CBr
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CF)C(=O)COc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
157 g (0.79 mol) of 1-bromo-3,3-dimethyl-4-fluoro-2-butanone were added dropwise to a stirred mixture of 102 g (0.79 mol) of p-chlorophenol and 110 g (0.79 mol) of powered potassium carbonate in 500 ml of acetone at 20° to 30° C., while cooling. The mixture was subsequently stirred at 20° C. for 2 hours, the inorganic salt was filtered off and the filtrate was concentrated. The residue was distilled under a high vacuum. 175 g (90% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone of boiling point 112° to 119° C./0.05 mm Hg were obtained. ##STR15##
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>C(Cl)Cl>[C:31]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:19][CH2:20]1)(=[O:34])[CH:32]=[CH2:33]
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
To a solution of N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzene sulfonamide (1045 mg, 3 mmol) in CH2Cl2 was added triethylamine (0.418 ml, 3 mmmol) and acryloyl chloride (0.244 ml, 3 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. After quenching with water (5 ml), the mixture was extracted by CHCl3 (50 ml×2), washed with brine (50 ml×2). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (AcOEt/n-hexane=4/1) to afford the title compound 1 (648 mg, yield 54%). LC: 100%. MS: m/z=402.39, 403.18 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:20])([CH2:15][O:16]C(=O)C)[CH2:10][O:11][C:12](=[O:14])[CH3:13].C([O-])(=O)C>C1CCCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:20])([CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH2:15][OH:16]
Reactant: CC(=O)OCC(O)(COC(C)=O)c1ccc(F)cc1F
Agent: CC(=O)[O-]
Solvent: C1CCCCC1
Product: CC(=O)OC[C@](O)(CO)c1ccc(F)cc1F
Temperature: 30 °C
Reaction time: 47 h
Yield: 95.8 %

Procedure:
A 10 l reaction vessel was charged with 110 g of 2-(2,4-difluorophenyl)-1,3-diacetoxy-2-propanol, 11 g of Lipase made by SEIKAGAKU CORPORATION, (derived from Rhizopus delemar, Enzyme No. 3), 2.8 l of 50 mM acetate buffer (pH 5 ) and 2.8 l of cyclohexane. The resulting mixture was stirred at 30° C. for 47 hours. The obtained reaction mixture was extracted twice with 3 l of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 90 g of (R)-2-(2,4-difluorophenyl)-3-acetoxy-1,2-propanediol.
Reaction SMILES: Br[C:2]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH:6]=[CH:5][C:4]=2[CH:3]=1.C([Li])CCC.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C.Cl>C(OCC)C.CCCCCC>[CH:19]1[C:14]2[C:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[CH:6]=[CH:5][C:4]=3[CH:3]=[C:2]([B:25]([OH:30])[OH:26])[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: Brc1cc2ccc3ccccc3c2c2ccccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1cc2ccc3ccccc3c2c2ccccc12
Temperature: -40 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A flask was charged with 10.1 g of 5-bromobenzo[c]phenanthrene in an argon atmosphere. 400 mL of dehydrated diethyl ether was then added to the flask. After cooling the reaction solution to −40° C., 22 mL of a 1.6 M hexane solution of n-butyllithium was added to the reaction solution. The mixture was heated to 0° C., and stirred for 1 hour. After cooling the reaction solution to −60° C., a dehydrated diethyl ether (10 mL) solution of 14.4 g of triisopropyl borate was added dropwise to the reaction solution. The reaction solution was stirred for 5 hours while warming the reaction solution up to room temperature. After the addition of 100 mL of a 10% hydrochloric acid aqueous solution, the mixture was stirred for 1 hour. After removing the aqueous phase, the organic phase was washed with water and a saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate by filtration, the organic phase was concentrated. The resulting solid was washed with hexane to obtain 5.37 g of the target benzo[c]phenanthrene-5-boronic acid (yield: 60%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12]C(=O)C)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.OS(O)(=O)=O>CO>[C:1]1([C:7]2[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1nc(-c2ccccc2)c[nH]1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: Nc1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Yield: 41.9 %

Procedure:
To a solution of the above 0.5 g (2.4 mmol) N-(4-phenyl-1H-imidazol-2-yl)-acetamide in MeOH (20 mL) was added water (20 mL) and conc. H2SO4 (1 mL). The mixture was refluxed under nitrogen for 2 days. After cooling to rt, the organic solvent was removed under vacuum. The reaction mixture was neutralized with saturated sodium bicarbonate aq. solution (50 mL) and extracted with ethyl acetate (150 mL). The organic layer was dried and condensed. The residue was purified by a flash column chromatography eluting with EtOAc then EtOAc/MeOH=7:1 to give 4-phenyl-1H-imidazol-2-ylamine (160 mg, 41%). LCMS: 160 (M+1)+.
Reaction SMILES: [CH3:1][C:2](=[CH2:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+].OO.C(OCC)(=[O:19])C>C1COCC1>[CH3:12][CH:2]([CH2:3][NH:4][C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])[CH2:1][OH:19]
Reactant: C=C(C)CNC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(CO)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
The tert-butyl N-(2-methylallyl)carbamate (213 mg, 1.24 mmol) was diluted with THF (12 mL) and the mixture was cooled to 0° C. Borane-dimethylsulfide complex (0.9 mL, 1.8 mmol) was added. After 1.5 hours, the reaction was cooled to −40° C. and 1 N NaOH (5 mL) and 30% hydrogen peroxide (5 mL) were carefully added. After 15 minutes, the reaction was warmed slowly until the frozen mixture melted. Ethyl acetate (100 mL) was then added, and the mixture was washed with brine (3×10 mL). The combined aqueous layers were extracted with ethyl acetate (100 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography (about 20 g silica, 10% EtOAc/CH2Cl2 through 15% EtOAc/CH2Cl2) to give the desired product (209 mg, 1.10 mmol, 89%).
Reaction SMILES: [C:1]1(=[N:13]O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(=N[OH:22])CCCCC1.C1(=O)CCCCC1.C1(=O)CCCCCCCCCCC1.S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O>>[C:1]1(=[O:22])[NH:13][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: ON=C1CCCCCCCCCCC1
Reactant: ON=C1CCCCC1
Agent: O=C1CCCCCCCCCCC1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O=C1CCCCC1
Product: O=C1CCCCCCCCCCCN1

Procedure:
Patent Reference 2 has described the following process. A mixture of cyclododecanone and cyclohexanone is blended with an aqueous solution of hydroxylamine to produce oximes. Cyclohexanone oxime produced has a low melting point and is a good solvent for cyclododecanone oxime, so that the reaction can be conducted at 100° C. or lower and at an ambient pressure. Furthermore, cyclohexanone oxime is adequately hydrophilic for the oxime-forming reaction to quickly proceed, and the mixture is transferred to the rearrangement step without residual cyclohexanone or cyclododecanone. A rearrangement catalyst used is concentrated sulfuric acid or oleum. Whereas laurolactam produced has a high melting point, it is highly soluble in caprolactam having a low melting point which is simultaneously produced. Therefore the reaction can be carried out even at a temperature of 100° C. or lower. The resulting rearrangement reaction solution is neutralized with ammonia water and then extracted with an organic solvent. Caprolactam can be dissolved in water to some extent, but is extracted into an organic solvent due to salting-out effect of ammonium sulfate formed by neutralization. Next, a large amount of water is added to the solution containing extracted laurolactam and caprolactam, and caprolactam is extracted into the aqueous phase. From the separated organic phase, the organic solvent is recovered and laurolactam is purified by distillation. On the other hand, the aqueous phase is concentrated and after removing impurities, caprolactam is purified.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Br[CH2:31][CH3:32].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH2:31][CH3:32])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: CCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CC)C3)cc1
Temperature: 100 °C
Yield: 56.4 %

Procedure:
To a solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (130 mg, 0.33 mmol) in DMF (2.5 mL) was added bromoethane (29 μL, 0.39 mmol) and DIPEA (69 μL, 0.39 mmol). The reaction mixture was then heated by microwave at 100° C. for 1 h. The crude reaction mixture was then partitioned between water and EtOAc, the phases separated and the organic layer washed with NaHCO3 and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (2-10% MeOH/DCM) to give a light brown solid (79 mg, 57%).
Reaction SMILES: [OH-].[NH4+:2].CO[C:5](=[O:29])[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)(=[O:20])=[O:19])=[CH:14][C:13]=2[CH3:28])[CH2:8]1>CO>[F:27][C:23]1[CH:22]=[C:21]([S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH:9]3[CH2:10][CH2:11][N:7]([CH2:6][C:5]([NH2:2])=[O:29])[CH2:8]3)=[C:13]([CH3:28])[CH:14]=2)(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)CN1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2C)C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(CC(N)=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A concentrated solution of ammonium hydroxide (2 mL) was added to a solution of {3-[4-(3-fluoro-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidin-1-yl}-acetic acid methyl ester (130 mg, 0.3321 mmol) in methanol (2 mL) and the resulting mixture was stirred at room temperature for 16 hours. Solvent was evaporated under reduced pressure and the crude material was purified via flash chromatography (DCM/MeOH/NH4OH) to give 0.102 g of 2-{3-[4-(3-fluoro-benzenesulfonyl)-2-methyl-phenyl]-pyrrolidin-1-yl}-acetamide of a white foam: MS (M+H)=377.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[N:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[N:3]=1.[CH2:13]([N:15]=[C:16]=[S:17])[CH3:14]>C(#N)C>[CH2:13]([NH:15][C:16](=[S:17])[NH:1][C:2]1[CH:6]=[N:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[N:3]=1)[CH3:14]
Reactant: N#CCCCCn1ncc(N)n1
Reactant: CCN=C=S
Solvent: CC#N
Product: CCNC(=S)Nc1cnn(CCCCC#N)n1
Reaction time: 60 h

Procedure:
A solution of 5-(4-amino-1,2,3-triazol-2-yl)valeronitrile (1.65 g.) in acetonitrile (6 ml.) was treated with ethylisothiocyanate (0.87 g.) and the solution stirred for 2.5 days then heated under reflux for 4.5 hours. Evaporation of the solvent gave 5-[4-(3-ethylthioureido)-1,2,3-triazol-2-yl]valeronitrile.
Reaction SMILES: Cl.C[NH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[CH:6][CH:5]=1.N1C=CC=CC=1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O>[C:28]([NH:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]23[CH2:12][CH:13]4[CH2:19][CH:17]([CH2:16][CH:15]([CH2:14]4)[CH2:20]2)[CH2:18]3)=[CH:8][CH:9]=1)([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)Cl
Reactant: CNc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 18 h

Procedure:
A solution of the free base from 2.82 g. of the N-methyl-4-(1-adamantyloxy)aniline hydrochloride in 20 ml. pyridine was treated dropwise with 1.64 ml. ClCO2C2H5. Following 18 hours standing in the cold the mixture was poured into ice:H2O. This was extracted with Et2O and the organic layer washed in turn with H2O, cold 2.5 N HCl, H2O NaHCO3 and brine. The extract was then taken to dryness to leave behind N-methyl, N-carbethoxy-4-(1-adamantyloxy)aniline as an oil.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=1)=[CH2:16])[S:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])=[O:4].O.O.O.C([O-])(=[O:32])C.[Na+].C(OO)(=O)C>C(Cl)(Cl)Cl>[O:32]1[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[N:18]=2)([CH2:14][N:2]([CH3:1])[S:3]([CH:6]=[CH:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)(=[O:4])=[O:5])[CH2:16]1
Reactant: C=C(CN(C)S(=O)(=O)C=Cc1ccccc1)c1cccc(C(F)(F)F)n1
Reactant: CC(=O)[O-]
Agent: CC(=O)OO
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(CC1(c2cccc(C(F)(F)F)n2)CO1)S(=O)(=O)C=Cc1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 119.5 %

Procedure:
A mixture of 1.1 g of 3-(N-methyl-N-styrylsulfonylamino)-2-(6-trifluoromethylpyridin-2-yl)propene, 0.20 g of sodium acetate trihydrate, 2.19 g of 40% peracetic acid and 11 ml of chloroform was stirred at 60° C. for 5 hours. After the reaction mixture was cooled to room temperature, 10 ml of carbon tetrachrolide was added thereto, and the whole mixture was subsequently washed with water, an aqueous solution of 10% sodium bisulfite, a 2N aqueous solution of sodium hydroxide, water and saturated saline solution in that order and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluted with benzene-ethyl acetate 15:1) to obtain 0.70 g of Compound No. 4 in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[C:29]([OH:31])=O)(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:55][CH2:56][CH:57]([OH:64])[CH2:58][N:59]1[CH:63]=[CH:62][N:61]=[N:60]1>CN(C=O)C>[OH:64][CH:57]([CH2:58][N:59]1[CH:63]=[CH:62][N:61]=[N:60]1)[CH2:56][NH:55][C:29]([C:28]1[CH:27]=[C:26]([CH3:32])[NH:25][C:24]=1/[CH:23]=[C:16]1\[C:17](=[O:22])[NH:18][C:19]2[C:15]\1=[CH:14][C:13]([S:10]([CH2:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=2)=[O:31]
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1
Reactant: NCC(O)Cn1ccnn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NCC(O)Cn2ccnn2)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol), HOBt (33 mg, 1.2 eq.), EDAC.HCl (47 mg, 1.2 eq.) and 1-amino-3-[1,2,3]triazol-1-yl-propan-2-ol (30 mg, 1.1 eq.) in DMF (2 mL) was added TEA (0.071 mL, 2.5 eq.). After stirring at rt for 2 weeks, the reaction was concentrated, diluted with DCM and several drops of methanol. After standing at rt for one hour, the resulted precipitate was collected by vacuum filtration, washed and dried to give the titled compound as a yellow solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(CCN(C)C)C.[Li]C(CC)C.CN([CH:31]=[O:32])C>CCOCC>[C:1]([N:8]1[C@@H:13]([CH:31]=[O:32])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC1CCCCN1C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: C[C@H]1CCC[C@H](C=O)N1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of N-Boc-2-Methyl-Piperidine (9.4 g, 46.9 mmol) in 94 mL of ether was cooled to −60° C. and treated with TMEDA (7.1 mL, 46.9 mmol) followed by sec-BuLi (49.2 mL, 51.66 mmol) dropwise. The mixture was slowly warmed to −20° C. and stirred for 30 min and then cooled to −78° C. The mixture was treated with a solution of DMF (5.5 mL, 70.44 mmol) in 16 mL of ether via syringe, stirred for 10 min, and then quenched with 75 mL saturated ammonium chloride solution. The mixture was warmed to room temperature, and the organic layer was separated. The aqueous layer was extracted with ether, and the combined extracts were dried over K2CO3. The organic layer was concentrated to give a crude product as an oil which was chromatographed on silica with hexanes:EtOAc (4:1) to afford 6.5 g (66%) of the trans isomer and 2.1 g (21%) of the cis isomer. Both products were homogeneous by TLC analysis, with the cis isomer positiioned just above the trans isomer. 1H NMR (250 MHz) δ9.28-9.26 (d, 1 H), 4.25 (br. d, 1 H), 3.64-3.57 (m, 1H), 1.74-1.46 (m, 15 H), 1.09-1.04 (d, 3 H); 13C NMR (62.7 MHz) 196.3 (s), 155.1 (s), 77.4 (s), 59.2 (s), 47.3 (s), 29.3 (s), 28.2 (s), 25.4 (s), 16.3 (s) ppm.
Reaction SMILES: [CH2:1]([N:7]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:8]([CH:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[S:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].CI.[C:37](OCC)(=O)C>CN(C)C=O>[CH2:27]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]([CH:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:37])[C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[S:11]1)=[O:9])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCOC(C)=O
Reactant: CCCCCCN(CCCCCC)C(=O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCCCN(CCCCCC)C(=O)C1Sc2ccccc2-c2c1c1ccccc1n2C
Temperature: 25 °C

Procedure:
To a solution of 200 mg of N,N-dihexyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-6-carboxamide in 10 ml of N,N-dimethylformamide was added 21 mg of 60% sodium hydride/oil, followed by stirring at room temperature for an hour. To the solution was added 33 μl of methyl iodide, followed by stirring at room temperature for 5 hours. The reaction solution, after addition of ethyl acetate, was washed with water, 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane to give 155 mg of N,N-dihexyl-6,11-dihydro-11-methyl-5-thia-11-aza-benzo[a]fluoren-6-carboxamide.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40]([OH:42])=O)=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C@H:47]([CH2:50][CH2:51][CH2:52][CH2:53][NH:54]C(OCC1C=CC=CC=1)=O)[CH2:48][OH:49].Cl.NCC(N)=O>>[NH2:54][CH2:53][CH2:52][CH2:51][CH2:50][C@@H:47]([NH:46][C:40]([CH2:39][CH2:38][CH2:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:44])[CH3:45])=[CH:36][CH:35]=1)=[O:42])[CH2:48][OH:49]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: N[C@@H](CO)CCCCNC(=O)OCc1ccccc1
Agent: Cl
Agent: NCC(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)N[C@@H](CO)CCCCN)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and (R)-2-amino-6-benzyloxycarbonylamino-1-hexanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and glycinamide hydrochloride, respectively.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]([OH:20])=O)=[CH:15][C:14]=2[CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][C:42]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:41]2>C1COCC1.C(Cl)Cl.CN(C)C1C=CN=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]([NH:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[NH:43][C:42]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:41]4)=[O:20])=[CH:15][C:14]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: O=C(O)c1cc2cc(CSSc3ccccn3)ccc2o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc2cc(NC(=O)c3cc4cc(CSSc5ccccn5)ccc4o3)ccc2[nH]1
Reaction time: 8 h

Procedure:
A stirred solution of 15 (247 mg, 0.78 mmol) in 30 mL dry THF at room temperature under argon, was treated sequentially with solutions of dicyclohexylcarbodiimide (177 mg, 0.86 mmol) in 5 mL methylene chloride, 4-(dimethylamino)pyridine (29 mg, 0.23 mmol) in 2 mL methylene chloride, and 10 (200 mg, 0.86 mmol) in 5 mL methylene chloride. The reaction mixture was stirred overnight. Dicyclohexylurea was filtered from the reaction mixture, and the filtrate was washed with water, cold 0.1M HCl, saturated aqueous sodium bicarbonate, and water. The organic solution was dried over magnesium sulfate, filtered, and concentrated to give a dark oil. The crude product was further purified by chromatography on a silica gel column, eluting with ethyl acetate:hexanes to give 16 as an off-white solid: NMR (acetone-d6) δ 1.6 (s, 9H), δ 4.3 (s, 2H), δ 7.0-8.6 (m, 12H).