Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=1>C1COCC1>[CH3:28][O:27][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[N+:24]([O-:26])=[O:25])[CH2:17][N:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1
Reactant: COc1cc(CBr)ccc1[N+](=O)[O-]
Reactant: O=S1(=O)CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(CN2CCS(=O)(=O)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Thiomorpholine 1,1-dioxide (0.242 g, 1.788 mmol) and triethylamine (0.19 mL, 1.341 mmol) were added to a solution of 4-(bromomethyl)-2-methoxy-1-nitrobenzene (Preparation 74, 0.22 g, 0.894 mmol) in THF (2.2 mL). The reaction mixture was stirred overnight at room temperature before being concentrated under reduced pressure and purified via Biotage silica gel column chromatography eluting with (DCM/EtOAc 99/1 to 90/10) to afford the title product as a white solid (242 mg, 90%). 1H NMR (500 MHz, CDCl3): δ 3.00-3.04 (m, 4H), 3.09-3.12 (m, 4H), 3.71 (s, 2H), 3.98 (s, 3H), 7.01 (m, 1H), 7.09 (m, 1H), 7.84 (d, J=8.2 Hz, 1H). LC (Method C)-MS (ESI, m/z) tR 2.03 min, 301 [(M+H+), 100%].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:5]=[CH:4][C:3]=1[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19].[Cu][C:28]#[N:29]>CN(C)C=O.O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1/[CH:9]=[CH:8]/[C:6]1[CH:5]=[CH:4][C:3]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[C:2]([CH:7]=1)[C:28]#[N:29]
Reactant: O=S(=O)(c1ccccc1)c1ccc(/C=C/c2ccc(F)cc2F)cc1Br
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(/C=C/c2ccc(F)cc2F)ccc1S(=O)(=O)c1ccccc1
Temperature: 130 °C
Yield: 43.7 %

Procedure:
2-Bromo-4-[(E)-2-(2,4-difluorophenyl)vinyl]-1-(phenylsulfonyl)benzene (Example 55, 130 mg, 0.3 mmol) and copper(I) cyanide (40 mg, 0.45 mmol) were combined in N,N-dimethylformamide (20 mL) and heated to 130° C. for 3 hours. Further copper(I) cyanide (40 mg, 0.45 mmol) was added and heating continued overnight. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water (×3) and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 20-30% ethyl acetate/isohexane, followed by trituration with diethyl ether to give the title compound (50 mg, 44%). δH (360 MHz, d6 DMSO): 8.41 (1H, d, J=1.6 Hz), 8.28 (1H, d, J=8.4 Hz), 8.14 (1H, dd, J=1.7, 8.4 Hz), 8.01-7.98 (2H, m), 7.86-7.64 (4H, m), 7.58 (1H, d, J=16.6 Hz), 7.37 (1H, d, J=16.8 Hz), 7.32-7.28 (1H, m), 7.17 (1H, td, J=2.4, 8.5 Hz).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C(C)C)(C(C)C)[N:23]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][N:31]([S:34]([N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][C@@H:38]3[C:43]([O:45][CH3:46])=[O:44])(=[O:36])=[O:35])[CH2:30][CH2:29]2)=[CH:24]1)(C)C>O1CCCC1.C(OCC)(=O)C>[NH:23]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:29][CH2:30][N:31]([S:34]([N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][C@@H:38]3[C:43]([O:45][CH3:46])=[O:44])(=[O:36])=[O:35])[CH2:32][CH2:33]2)=[CH:24]1
Reactant: COC(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2ccn([Si](C(C)C)(C(C)C)C(C)C)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2cc[nH]c2)CC1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
Tetrabutylammonium fluoride (2.45 ml, 2.45 mmol) was added to a solution of methyl 1-[4-(1-triisopropylsilylpyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate (2.5 g, 4.89 mmol) [prepared as described in Step 2 above] in tetrahydrofuran (48 ml) at 0° C. After 30 min., the reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed (SiO2, 15-40% ethyl acetate/hexanes) to yield methyl 1-[4-(pyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate (31%) as a clear oil. This material was converted to 1-[4-(pyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (93%) by proceeding as described in Example 11, Step 1, but substituting methyl (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-3-methylbutyrate with methyl 1-[4-(pyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate.
Reaction SMILES: P([O-])([O-])([O-])=O.[Cl:6][C:7]1[C:8](=[O:30])[C:9](=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[C:28]=[O:29])OC)[C@H:10]([CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:11]=1.Cl.S([O-])([O-])(=O)=[O:33].[NH4+].[NH4+]>CC(C)=O>[Cl:6][C:7]1[C:8](=[O:30])[C:9](=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:28]([OH:29])=[O:33])[C@H:10]([CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:11]=1
Reactant: O=S(=O)([O-])[O-]
Reactant: CCCCCCC=C[C@@H]1C=C(Cl)C(=O)C1=CCCCCC(=C=O)OC
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: CCCCCCC=C[C@@H]1C=C(Cl)C(=O)C1=CCCCCCC(=O)O
Reaction time: 100 h
Yield: 68 %

Procedure:
450 ml of 0.1M phosphate buffer (pH8) was added to a solution of 734 mg (2.0 mmol) of (4R)-2-chloro-4-(1-octenyl)-5-(6-methoxy-carbonylhexylidene)-2-cyclopentenone in 45 ml of acetone, and then 45 ml of an aqueous solution of pig liver esterase was added. The mixture was stirred at 30°-35° C. for 100 hours. 0.1N hydrochloric acid was added to the reaction mixture to adjust its pH to 4, and then the mixture was saturated with ammonium sulfate. It was filtered, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried product was filtered, concentrated and subjected to silica gel column chromatography (silica gel, 50 mg; eluent, hexane:acetone:acetic acid=10:2:0.05→5:2:0.003) to give 480 mg (yield 68%) of (4R)-2-chloro-4-(1-octenyl)-5-(6-carboxyhexylidene)-2-cyclopentenone.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([CH3:70])=[CH:66][CH:65]=1>>[C:67]1([CH3:70])[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:65][CH:66]=1
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)C2NC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.2 g, 0.36 mmol), was reacted with diisopropylethylamine (0.18 g, 1.4 mmol), diphenylphosphinic chloride (0.25 g, 1.1 mmol), then reacted with p-toluidine (Aldrich) (0.057 g, 0.53 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid p-tolylamide as a white solid (Yield, 30 mg, 15%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23](OCC)=[O:24])=[CH:4][N:5]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH:23]=[O:24])=[CH:4][N:5]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cn(S(=O)(=O)c2cccc(C)c2)c(-c2ccccc2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(S(=O)(=O)n2cc(C=O)c(C)c2-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
Under a nitrogen atmosphere, a solution (60 mL) of ethyl 4-methyl-1-[(3-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate (2.48 g) in tetrahydrofuran was cooled to −78° C., and a 1.5 mol/L solution (13 mL) of diisobutylaluminum hydride in toluene was added dropwise over 15 min, and the mixture was further stirred at −78° C. for 30 min. 1 mol/L Hydrochloric acid (60 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile solution (100 mL), tetra-n-propylammonium perruthenate (0.21 g), N-methylmorpholine N-oxide hydrate (1.31 g) and molecular sieves 4A powder (6.0 g) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate (300 mL) was added to the residue, the suspension was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→3:1) to give the title compound as a yellow oil (yield 1.76 g, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5](=[CH:11][N:12]([CH3:25])[C:13]1[S:14][CH:15]=[CH:16][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl-].[CH2:28]=[N+:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH2:9]([O:8][C:6](=[O:7])[C:5](=[CH:11][N:12]([CH3:25])[C:13]1[S:14][C:15]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:16][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:4]([O:3][CH2:1][CH3:2])=[O:26])[CH3:10]
Reactant: C=[N+]1CCOCC1
Reactant: CCOC(=O)C(=CN(C)c1sccc1C(=O)OC(C)(C)C)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C(=CN(C)c1sc(CN2CCOCC2)cc1C(=O)OC(C)(C)C)C(=O)OCC
Yield: 96.2 %

Procedure:
A mixture of N-(3-tert-butoxycarbonyl-thien-2-yl)-methylaminomethylenemalonic acid diethyl ester (19.0 g) from Preparation No. 2 and 4-methylene morpholinium chloride (Dimmock, JR, et al Eur. J. Med. Chem. 1989, 24, 379-383) (13.4 g) in dry acetonitrile (50 ml) is heated at reflux for about 4 hr. The solution is then cooled in an ice bath and saturated aqueous sodium carbonate (98 ml) is slowly added. The solution is extracted three times with ethyl acetate (300 ml total) and the combined organic layers are then washed three times with water (600 ml total). The solvents are removed in vacuo to afford 23.0 g (96%) of the title compound as a brown oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH2:7].C(N(CC)CC)C.[F:15][C:16]([F:37])([F:36])[C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[CH:35]=[CH:34][C:27]([O:28][CH:29]([CH3:33])[C:30](Cl)=[O:31])=[CH:26][CH:25]=2)=[N:21][CH:22]=1>ClCCl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:30](=[O:31])[CH:29]([O:28][C:27]1[CH:26]=[CH:25][C:24]([O:23][C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:36])([F:37])[F:15])=[CH:22][N:21]=2)=[CH:35][CH:34]=1)[CH3:33]
Reactant: NCC1OCCO1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)NCC1OCCO1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
1,3-Dioxolan-2 ylmethylamine (4 grams; 0.04 mol), triethylamine (5 ml) and dichloromethane (150 ml) were placed in a 3-necked glass reaction flask equipped with stirrer, thermometer and reflux condenser and cooled to 5° C. 2[4-(5-Trifluoromethyl-2-pyridinyloxy)-phenoxy]propanoic acid chloride (9 grams; 0.027 mol) in dichloromethane (30 ml) was added in a five minute time period. The reaction mixture was stirred for 1 hour at 5° C.-20° C., washed with water, passed through phase separating paper and concentrated to a dark gum (10.5 grams). The product was chromatographed through Florisil clay (100 ml), using hexane-ethyl acetate solvent mixtures. The desired product was isolated as a yellow gum (3.0 grams) and had the following elemental analysis:
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:12](=O)[CH3:13].Cl>C(O)(C)C.C(OCC)(=O)C>[CH3:12][CH:13]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[S:8](=[O:10])(=[O:9])[NH:11]1
Reactant: CC=O
Reactant: Nc1cccnc1S(N)(=O)=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC1Nc2cccnc2S(=O)(=O)N1

Procedure:
A mixture of 1 g of 3-aminopyridine-2-sulfonamide (Preparation 1) and 0.28 g of acetaldehyde in 10 cm3 of isopropanol to which 10 drops of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 1 to 2 hours. After cooling, a crystalline precipitate of the title compound is collected on a filter and washed with isopropanol. The 3-methyl-2,3-dihydro-4H-pyrido[3,2- e] [1,2,4]thiadiazine 1,1-dioxide is recrystallized from a CH3OH/H2O (1/4) mixture.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[N:19]=1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][C:18]2[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]3[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=3[N:19]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: CC(C)n1c(CBr)nc2ccccc21
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2nc3ccccc3n2C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (746 mg, 5.2 mmol) was dissolved in anhydrous DMF (30 mL), then potassium carbonate (2.18 g, 15.8 mmol) and 2-(bromomethyl)-1-(propan-2-yl)-1H-benzimidazole (1.99 g, 7.9 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 12% DCM in MeOH to afford 6-methyl-2-({[1-(propane-2-yl)-1H-benzimidazol-2-yl]methyl}sulfanyl)pyrimidin-4-ol (1.01 g, 41% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.55 (s, 3H), 1.56 (s, 3H), 2.20 (s, 3H), 4.76 (s, 2H), 4.84-4.92 (m, 1H), 6.06 (bs, 1H), 7.13-7.20 (m, 2H), 7.54-7.57 (m, HA 7.68-7.71 (m, 1H); LRMS (ES) m/z 315 (100%, M+1).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[CH:6][CH:5]=1)[CH3:3].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]#[CH:11])=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)c1ccc(C#C[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude 1-(4-(2-propyl)phenyl)-2-trimethylsilylacetylene was dissolved in methanol (100 mL). Aqueous 1M potassium carbonate solution (25 mL) was added and the reaction stirred at room temperature for 2 hours. The reaction mixture was then diluted with water and extracted with pentane. The organic layers were combined, dried with magnesium sulfate, and evaporated under reduced pressure without heating to give crude 4-(2-propyl)phenylacetylene.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1)[CH:2]=C.[O:14]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl.CO>[OH:14][CH2:2][CH2:1][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1
Reactant: C=CCc1ccc2c(c1)COC2=O
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1OCc2cc(CCO)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(prop-2-en-1-yl)-2-benzofuran-1(3H)-one (13.5 g, 45.2 mmol) in 200 mL DCM/MeOH (V/V=1:1) was bubbled O3 at −78° C. for 30 min, and N2 was bubbled for another 15 min at −78° C. Then 20 mL of Me2S were added, and the mixture was stirred at r.t. overnight before concentrating to dryness. The residue was dissolved in MeOH (100 mL) and then cooled to 0° C. NaBH4 (5.90 g, 155 mmol) was added in portions. The resulting mixture was stirred at 0° C. for 1 hr, then quenched with citric acid (aq.) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with NaHCO3 (aq.) and brine, dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified via silica column chromatography (EtOAc/Petrol Ether=1:5) to give 5-(2-hydroxyethyl)-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+].[H][H]>C1COCC1.O>[C:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:13][OH:14])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCCCC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCC(CO)NC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
To a stirred solution of 2-benzyloxycarbonylamino-6-tert-butoxycarbonylamino-hexanoic acid (Cbz-Lys(Boc)-OH) (Chem-Impex International, 3.8 g, 10 mmol) in THF (25 mL) in a 100 mL round flask was added 1,1′-carbonyldiimidazole (CDI) (1.7 g, 10.5 mmol) at room temperature. After 20 minutes, the THF solution was transferred via a Teflon cannula (+=2 mm) to a stirred solution of sodium borohydride (0.75 g, 20 mmol) in water (10 mL) in a 1 L round flask immersed in a water bath at 5-10° C. The addition caused a strong evolution of hydrogen gas and the mixture was stirred for a couple of hours. The volatiles were then removed on a rotovap, and the residue was dissolved in ethyl acetate (150 mL). The ethyl acetate solution was extracted successively with cold 1 N HCl (2×50 mL), saturated sodium bicarbonate solution (2×50 mL), brine (100 mL), and was dried with anhydrous sodium sulfate. The dried ethyl acetate solution was then pass through a one inch flash pad of silica gel, and concentrated to provide a colorless solid (3.3 g, 91%), TLC Rf=0.24 (95:5:2 EtOAc:MeOH:H2O).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][N:7]=1)=[O:5].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Cl:12][C:11]1[C:6]([C:4](=[O:5])[CH2:3][NH:2][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[C:15]([F:14])([F:25])[F:26])=[N:7][CH:8]=[C:9]([Cl:13])[CH:10]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: NCC(=O)c1ncc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCC(=O)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Yield: 65.8 %

Procedure:
To a suspension of 3.7 g of 2-amino-1-(3,5-dichloropyridin-2-yl)ethanone hydrochloride in 50 ml of ethyl acetate, 30 ml of water and 3.5 g of 2-(trifluoromethyl)benzoyl chloride were added, and 6.1 g of potassium carbonate in 30 ml of water was added dropwise with stirring under cooling with ice, and the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction mixture was mixed with 20 ml of ethyl acetate, the resulting organic layer was collected, washed with water (20 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 2:8 to 6:4) as the eluent to obtain 3.8 g of the desired product as pale yellow crystals.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16].[C:30]1(=[O:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:30]2([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:20][C:21]=1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16]
Reactant: COC(=O)c1sccc1NC(=O)OC(C)(C)C
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)c1sc(C2(O)CCCCC2)cc1NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.75 h
Yield: 84253.7 %

Procedure:
Diisopropylamine (140 g, 1.39 mol) and 800 mL dry THF were added to a dry 12 L 4 neck flask with a mechanical stirrer under nitrogen. The solution was cooled to −40° C. and n-BuLi (1.29 mol) was added slowly while keeping the inside temperature around −40° C. The mixture was stirred for 45 min at −40° C. and then cooled to −78° C. To this solution, a solution of 3-tert-butoxycarbonylamino-thiophene-2-carboxylic acid methyl ester (99 g, 0.384 mmol) in 3.2 L THF was added drop wise. The mixture was stirred for 60 min at −78° C. and then cyclohexanone (118 g, 1.19 mmol) was added in 30 seconds. The mixture was stirred for 30 min at −78° C. The reaction mixture was quenched with 0.75 L of NH4Cl (sat). The aqueous phase was extract with 0.75 L of EtOAc. Combined the organic phase and washed them with 5 L of brine, Dried over Na2SO4, filtered and evaporated to a residue to afford 115 g (84%) of 3-tert-Butoxycarbonylamino-5-(1-hydroxy-cyclohexyl)-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH3:25])[C:10]([C@@H:12]1[CH2:16][C@H:15]([F:17])[CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11]>C(Cl)(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:17][C@@H:15]1[CH2:14][NH:13][C@H:12]([C:10]([N:9]([CH3:25])[CH3:8])=[O:11])[CH2:16]1
Reactant: CN(C)C(=O)[C@@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)[C@@H]1C[C@H](F)CN1
Reaction time: 2 h

Procedure:
18 mL of trifluoroacetic acid was added under ice cooling to a 60 mL chloroform solution of 5.98 g of the compound obtained in step 2-3, and the reaction mixture was stirred for 2 hours at the same temperature. After this, the solvent was distilled off under reduced pressure to obtain 12.1 g of residue (colorless oily substance). This compound was used in the following reaction without being purified.