Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:13]([S:16][CH2:17][CH2:18]O)([CH3:15])[CH3:14]>>[C:1]([O:12][CH2:18][CH2:17][S:16][CH:13]([CH3:15])[CH3:14])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(C)SCCO
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)OCCSC(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 2-(isopropylthio)ethanol as starting materials to give the aimed compound.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15].O>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:23]([C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=1)(=[O:24])=[O:25]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1cc(Br)c2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)n2ccc3c(Br)cc(F)cc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (299 mg, 7.48 mmol) was added to a stirred solution of 4-bromo-6-fluoro-1H-indole (800 mg, 3.74 mmol) in DMF (20 ml) that had been cooled in an ice bath to 0° C. and placed under nitrogen. The mixture was stirred for 5 mins before 4-nitrobenzenesulfonyl chloride (911 mg, 4.11 mmol) was added. The mixture was stirred at 0° C. for 1 hour. The resultant orange/brown solution was poured into stirring water (40 ml). The mixture was rapidly stirred for 30 mins. The resulting brown suspension was collected by filtration, washed with water and dried in a vacuum oven at 50° C. overnight to give a pale brown solid, which was purified by Flashmaster II, on a silica cartridge (100 g) using a gradient of ethylacetate and cyclohexane to afford the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:25](=[O:26])[CH2:24][Cl:23])[C@@H:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (R)-3-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester (795 mg, 3.68 mmol) in DCM (20 mL) was added triethylamine (1.53 mL, 11.04 mmol). The resulting mixture was cooled to 0° C. before the dropwise addition of chloroacetyl chloride (325 μL, 4.05 mmol). The mixture was warmed to RT and stirred for 5 h. The reaction mixture was partitioned between a saturated aqueous solution of NaHCO3 and DCM. The organic layer was separated and the aqueous layer extracted with DCM. The combined organic fractions were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography to give the title compound as a colourless oil which was a mixture of rotamers (710 mg, 66%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[I:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH2:22].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:22][C:21]1[CH:23]=[CH:24][C:25]([CH3:26])=[C:19]([I:18])[CH:20]=1)=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: Cc1ccc(N)cc1I
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(C)c(I)c2)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred suspension of 3-fluoro-4-methyl benzoic acid (1.15 g, 7.44 mmol) in CH2Cl2 (50 mL) and DMF (2 drops) was cooled to 0° C. under argon and treated with oxalyl chloride (0.71 mL, 8.18 mmol) dropwise. The mixture was warmed to r.t. and stirred for 1 h. In a separate flask, 3-iodo-4-methyl aniline (2.60 g, 11.16 mmol), K2CO3 (1.54 g, 8.93 mmol) and pyridine (4 drops) were suspended in CH2Cl2 (10 mL). The mixture was cooled to 0° C. under argon and the acid chloride reaction mixture was slowly added. Upon complete addition, the reaction mixture was allowed to warm to room temperature and stirred for 3 days. The resultant solid was filtered off and the reaction mixture was diluted with EtOAc. The organic phase was washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. Diethyl ether was added and the impurities were filtered off, affording the title compound as a brown solid. 1H-NMR (400 MHz, d6-DMSO) δ: 10.24 (1H, s), 8.32 (1H, d), 7.77 (3H, m), 7.46 (1H, t), 7.32 (1H, t), 2.35 (3H, s), 2.32 (3H, s).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[N+:8]([C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:18][CH:17]=[CH:16][CH:15]=2)([O-])=O.[H][H]>[Pt].C1(C)C=CC=CC=1>[NH2:8][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2ccccc12
Reactant: [H][H]
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCNc1c(N)cnc2ccccc12
Yield: 80.5 %

Procedure:
Platinum on carbon (1.0 g of 10%) and sodium sulfate (2 g) were added to a slurry of 1,1-dimethylethyl N-{2-[(3-nitroquinolin-4-yl)amino]ethyl}carbamate (100 g, 0.30 mol) in toluene (500 mL). The reaction vessel was placed on a Parr apparatus under 50 psi (3.5 Kg/cm2) hydrogen pressure overnight at ambient temperature. The reaction mixture was filtered through a layer of Celite® filter aid to remove the catalyst. The filtrate was concentrated under vacuum to provide 73 g of 1,1-dimethylethyl N-{2-[(3-aminoquinolin-4-yl)amino]ethyl}carbamate as a dark gold oil. Thin layer chromatography (silica gel; 10% methanol in dichloromethane) analysis indicated that the material was pure.
Reaction SMILES: C([S:4][C:5]1[C:6]([Cl:24])=[CH:7][C:8]([F:23])=[C:9]([C:11]2[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[CH:10]=1)(=O)C.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[Cl:24][C:6]1[C:5]([SH:4])=[CH:10][C:9]([C:11]2[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)=[C:8]([F:23])[CH:7]=1
Reactant: CC(=O)Sc1cc(-c2ccc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(C(F)(F)F)ccc(-c2cc(S)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
2.8 g (7.7 mmol) of 3-(5-acetylthio-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 30 ml of methanol, 8.5 ml (8.5 mmol) of a 1N sodium hydroxide aqueous solution was dropwise added thereto under cooling with ice After stirring at room temperature for 1 hour, the mixture was poured into water and acidified with citric acid and extracted with ethyl acetate. After washing with water and a saturated sodium chloride aqueous solution, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. Then, the obtained crude crystals were washed with n-hexane to obtain 2.4 g (yield: 93%) of the desired product. Melting point: 141-142° C.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH:5]=[C:6]([CH3:8])[CH3:7])[CH3:3].[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>C(Cl)Cl>[CH3:16][CH2:15][O:14][C:12]([CH:11]1[C:6]([CH3:8])([CH3:7])[CH:5]1[CH:4]=[C:2]([CH3:3])[CH3:1])=[O:13]
Reactant: CC(C)=CC=C(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClCCl
Product: CCOC(=O)C1C(C=C(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.6 %

Procedure:
A flask was charged with CH2Cl2 (25 mL), 2,5-dimethyl-2,4-hexadiene (25 mL) and 0.45 g of the Cu,K-PFIEP[SO3H] catalyst, prepared as described above. A solution of ethyl diazoacetate (2.5 g) in CH2Cl2 (25 mL) was added slowly dropwise and the resulting reaction mixture was stirred for 24 hours at ambient temperature. Gas chromatography analysis showed that the resulting product contained cis- and trans-ethyl chrysanthemumates in a 1:1.66 isomer ratio and a combined yield of 89.6%.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:8]([Cl:27])[N:7]=[C:6]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[CH2:2][CH2:3][CH3:4].C1C(=O)N([Cl:42])C(=O)C1>C(#N)C>[CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[C:21]3[Cl:42])[CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])=[C:8]([Cl:27])[N:7]=[C:6]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCn1c(-c2ccccc2C)nc(Cl)c1CN(CCC(C)C)Cc1ccc2[nH]ccc2c1
Solvent: CC#N
Product: CCCCn1c(-c2ccccc2C)nc(Cl)c1CN(CCC(C)C)Cc1ccc2[nH]cc(Cl)c2c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a solution of (3-Butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(1H-indol-5-ylmethyl)-(3-methyl-butyl)-amine (150 mg, 0.31 mmol) in 5 ml of anhydrous acetonitrile cooled to 0° C. is added NCS (44 mg, 0.33 mmol, 1.05 eq.), the resulting mixture is stirred at 40° C. overnight. The solvent is evaporated; the residue is purified through flash chromatography to give 112 mg of (3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-chloro-1H-indol-5-ylmethyl)-(3-methyl-butyl)-amine as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.39 (1H, S), 7.52 (1H, S), 7.11˜7.36 (6H, m), 6.98 (1H, d, J=2.4 Hz), 3.67 (2H, m), 3.65 (2H, s), 3.54 (2H, s), 2.52 (2H, t, J=7.2 Hz), 2.11 (3H, s), 1.62 (1H, m), 1.45 (2H, q, J=6.9 Hz), 1.10 (2H, m), 0.84 (6H, d, J=6.6 Hz), 0.73 (2H, m), 0.47 (3H, t, J=6.9 Hz); MS (+VE) m/z 511 (M+1).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[OH:16][C:17]1[CH:24]=[C:23](O)[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].N1C=CC=CC=1>ClCCl>[CH:19]([C:18]1[CH:21]=[CH:22][C:23]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])=[CH:24][C:17]=1[OH:16])=[O:20]
Reactant: O=Cc1ccc(O)cc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
A solution of triflic anhydride (1.77 ml, 10.5 mmol) in dichloromethane 10 ml) was added to a mixture of 2,4-dihydroxybenzaldehyde (1.38 g, 10 mmol) and pyridine (0.85 ml, 10.5 mmol) in dichloromethane (30 ml) at −70 C. Dry ice bath was removed and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with dichloromethane, washed with water, brine and evaporated in vacuo. The crude product was purified by column chromatography (silica gel, EA:Hex, 1:6) to give 1.55 g of trifluoro-methanesulfonic acid 4-formyl-3-hydroxy-phenyl ester (57%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.C(Cl)CCl.[CH2:22]([O:29][CH2:30][C:31](O)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:31](=[O:32])[CH2:30][O:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:6]=2[N:14]=1
Reactant: O=C(O)COCc1ccccc1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: NC(=O)c1cc2c3ccccc3n(C(=O)COCc3ccccc3)c2nc1N
Temperature: 25 °C
Reaction time: 23 h
Yield: 21.8 %

Procedure:
To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 150 mg, 0.663 mmol) in pyridine (7 mL) was added EDC (210 mg, 1.10 mmol), DMAP (85 mg, 0.693 mmol) and benzyloxyacetic acid (142 μL, 0.994 mmol) and the mixture was stirred at RT under an atmosphere of Ar. After 23 h, the reaction was quenched with water (20 mL), poured into a separatory funnel containing EtOAc (100 mL) and washed with water (75 mL). The organic layer washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by HPLC (Phenomenex Luna 15 μm C18, aqueous HCOOH/CH3CN) to yield 2-amino-9-[(benzyloxy)acetyl]-9H-pyrido[2,3-b]indole-3-carboxamide (28, 54 mg, 22%). NH4OAc standard conditions. DAD Retention time =7.6 min. M+H=375. 1H NMR (300 MHz, DMSO-d6): δ 8.76 (s, 1H), 8.52-8.49 (m, 1H), 8.04 (br s, 1H), 7.83-7.77 (m, 3H), 7.47-7.29 (m, 8H), 5.30 (s, 2H), 4.72 (s, 2H).
Reaction SMILES: C([O:5][C:6](=[O:37])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:17]=[CH:18][C:19]3[S:24](=[O:25])[CH2:23][CH2:22][N:21]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=4)(=[O:28])=[O:27])[C:20]=3[CH:36]=2)=[O:15])=[CH:9][CH:8]=1)(C)(C)C.O>C(O)=O>[Cl:35][C:31]1[CH:30]=[C:29]([S:26]([N:21]2[C:20]3[CH:36]=[C:16]([C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([C:6]([OH:37])=[O:5])=[CH:8][CH:9]=4)=[O:15])[CH:17]=[CH:18][C:19]=3[S:24](=[O:25])[CH2:23][CH2:22]2)(=[O:27])=[O:28])[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCS3=O)cc1
Solvent: O=CO
Solvent: O
Product: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCS3=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.4 %

Procedure:
A suspension of 4-{[4-(3-chloro-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoic acid tert-butyl ester (153 mg, 0.273 mmol) in formic acid (4 mL) was stirred for 16 h at room temperature, then the solution obtained was treated with water, and the suspension was stirred for another 90 min. The precipitate was collected by filtration and dried to produce the title compound (126 mg, 92%). White solid, 505.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=[O:13])[CH2:7][CH2:6]2.N1CC[CH2:16][CH2:15]1.CO.C(I)C>C1(C)C=CC=CC=1>[CH2:15]([CH:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:13])[CH3:16]
Reactant: C1CCNC1
Reactant: COc1ccc2c(c1)CCC(=O)C2
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCI
Product: CCC1C(=O)CCc2cc(OC)ccc21
Temperature: 25 °C

Procedure:
A solution of 6-methoxy-2-tetralone (120.55 grams, 0.684 mol) and pyrrolidine (61 mL, 0.685 mol) in toluene (1.7 L) was heated to reflux using a Dean-Stark trap apparatus for 3 hours. After removal of the azeotroped water, the reaction mixture was cooled to room temperature and concentrated to a solid. To this solid was added methanol (1.2 L) and ethyl iodide (121 mL, 1.51 mol). The resulting solution was heated at reflux overnight and then concentrated under vacuum to remove methanol. A solution of acetic acid (120 mL), sodium acetate (120 g) in water (240 mL) was added to the residue and the resultant mixture was heated at reflux for 2 hours. After cooling, the mixture was extracted several times with diethyl ether. The combined organic layers were washed twice with aqueous 1M HCl, twice with aqueous 1M NaOH and once with brine. After drying over magnesium sulfate, the solvent was evaporated to afford the title compound as an oil, 121.8 grams. Mass spectrum: m/e 204.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Cl[CH2:16][CH2:17][CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:29]1C=N[N:31]=[N:30]1>C(C(C)=O)C>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][CH2:17][CH2:18][C:19]2[NH:20][N:31]=[N:30][N:29]=2)=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: c1nnn[nH]1
Reactant: N#CCCCCl
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCc2nnn[nH]2)ccc(C(C)=O)c1O

Procedure:
The nitrile intermediate of the title compound was prepared following the procedure of Example 21 using 50.0 g. (257 mmoles) of 2,4-dihydroxy-3-propylacetophenone, 29.27 g. (282 mmoles) of 4-chlorobutyronitrile, 38.97 g. (282 mmoles) of potassium carbonate, and 4 g. of potassium iodide in 800 ml. of methyl ethyl ketone giving 57.58 g. of the nitrile intermediate as a rose-colored semi-crystalline solid. Twenty grams of the nitrile intermediate were then converted to the tetrazole in the usual manner giving 6.9 g. of the title compound, m.p. about 143°-145° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[O:3]1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:44][CH3:45])=[C:41]([Pb+3])[CH:42]=1>ClCCl.Cl>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:44][CH3:45])=[C:39]([CH:6]2[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[O:3][C:4]([CH3:11])([CH3:10])[C:5]2=[O:9])[CH:38]=1
Reactant: CCc1ccc(Br)cc1[Pb+3]
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Br)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To a mixture of 2,2,6,6-tetramethylpyran-3,5-dione (3.57 g, 21.00 mmol) and N,N-dimethylaminopyridine (13.50 g, 111.00 mmol) is added anhydrous chloroform (120 ml), followed by stirring at room temperature until dissolution. To this solution is added anhydrous toluene (37 ml), followed by 5-bromo-2-ethylphenyllead triacetate (10.69 g, 24.00 mmol) in one portion and the reaction mixture is heated at 80° C. for 2 hours, then allowed to stand overnight at room temperature. The mixture is diluted with dichloromethane (185 ml) and dilute aqueous hydrochloric acid (185 ml), followed by swirling for 5 minutes and filtration to remove inorganic residues (additional washing with dichloromethane). All organic fractions are combined, washed with brine, dried over anhydrous magnesium sulfate, then concentrated in vacuo to afford a crude oil which is further purified by flash column chromatography (hexane/ethyl acetate 5:1 ratio) to give the product as a yellow solid (4.47 g). Lead residues are removed by dissolving this solid in chloroform (50 ml) and stirring with 3-mercaptopropyl-functionalized silica gel (5.50 g, 1.20 mmol/g loading) overnight. After filtration and concentration 4-(5-bromo-2-ethylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (4.36 g) is afforded as a cream powder.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:37])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[C:28]([Cl:36])[CH:27]=2)[C@@H:20]([CH3:38])[C:19]1=[O:39])[CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1)=[O:8].[Li+].[BH4-].CO.CC(C)=O>C1COCC1>[Cl:36][C:28]1[CH:27]=[C:26]([NH:25][C:24]([N:21]2[CH2:22][CH2:23][N:18]([C@H:4]([CH2:3][OH:2])[CH2:5][CH2:6][C:7]([N:9]3[CH2:16][CH2:15][C:12]4([CH2:13][CH2:14]4)[C@H:11]([OH:17])[CH2:10]3)=[O:8])[C:19](=[O:39])[C@@H:20]2[CH3:38])=[O:37])[CH:31]=[CH:30][C:29]=1[C:32]([F:33])([F:34])[F:35]
Reactant: COC(=O)[C@H](CCC(=O)N1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)Nc2ccc(C(F)(F)F)c(Cl)c2)[C@@H](C)C1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(C)=O
Product: C[C@H]1C(=O)N([C@H](CO)CCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A cooled (−20° C.) solution of 0.29 g (0.50 mmol) of (S)-2-[(S)-4-(3-Chloro-4-trifluoromethyl-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-5-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-5-oxo-pentanoic acid methyl ester in 1.5 ml of THF was treated with 0.25 ml (0.50 mmol) of LiBH4 (2 M in THF) and 0.04 ml (1.00 mmol) of MeOH in 0.3 ml of THF. The reaction was warmed to +15° C. (during 3 h) and stirred for 1.5 h at RT, cooled to 0° C. and stopped with 0.17 ml (2.28 mmol) of acetone. The reaction was partitioned between aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried (Na2SO4) and evaporated to give after flash silica gel column (dichloromethane/MeOH 96:4 to 95:5) and precipitation (dichloromethane/ether) 0.19 g (68%) of the title compound as white amorphous powder. MS: 561.21 (MH+, Cl).
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]([F:19])([F:18])[C:6]1[CH:7]=[C:8]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1.[C:20]([O:24][C:25]([NH:27][C@@H:28]1[CH2:32][CH2:31][C@:30]([CH:36]([CH3:38])[CH3:37])([C:33](O)=[O:34])[CH2:29]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[CH:36]([C@:30]1([C:33]([N:15]2[CH2:16][CH2:17][N:12]([C:8]3[CH:9]=[N:10][CH:11]=[C:6]([C:5]([F:18])([F:4])[F:19])[CH:7]=3)[CH2:13][CH2:14]2)=[O:34])[CH2:31][CH2:32][C@@H:28]([NH:27][C:25](=[O:26])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:29]1)([CH3:38])[CH3:37]
Reactant: FC(F)(F)c1cncc(N2CCNCC2)c1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CCN(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 170.5 %

Procedure:
To a solution of 1-[5-(trifluoromethyl)pyridin-3-yl]piperazine trihydrochloride (0.22 g, 0.23 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (0.18 g, 0.66 mmol) in methylene chloride (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.338 g, 0.764 mmol) followed by triethylamine (0.22 mL, 1.6 mmol). The mixture was stirred at room temperature overnight and diluted with EtOAc. The solution was washed with saturated NaHCO3, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel (20% EtOAc/hexanes to 40% EtOAc/hexanes) to give 0.19 g (61%) of desired product. MS calculated for C24H35F3N4O3: (M+H) 485; found 485.2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[C:9]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:8]([CH3:26])[NH:7][C:6]=2[S:5][N:4]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>O1CCCC1>[CH3:34][S:35]([O:1][CH2:2][C:3]1[C:11]2[CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[C:9]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:8]([CH3:26])[NH:7][C:6]=2[S:5][N:4]=1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1=C(C)Nc2snc(CO)c2C1c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)Nc2snc(COS(C)(=O)=O)c2C1c1cccc([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
In an argon stream, 630 mg (1.68 mM) of ethyl 3-hydroxymethyl-6-methyl-4-(3-nitrophenyl)-4,7-dihydroisothiazolo[5,4-b]pyridine-5-carboxylate obtained in Example 2 was dissolved in 6 ml of anhydrous tetrahydrofuran, and under ice cooling, 0.62 ml (4.45 mM) of triethylamine was added. A solution of 0.26 ml (3.36 mM) of methanesulfonyl chloride in 2 ml of anhydrous tetrahydrofuran was added dropwise, and reacted at the above temperature for 45 minutes. Water (6 ml) was added to the reaction mixture, and the mixture was stirred for 10 minutes. The mixture was then poured into 10% HCl-ice, and extracted with methylene chloride. The methylene chloride layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 927 mg of crude ethyl 3-methanesulfonyloxymethyl-6-methyl-4-(3-nitrophenyl)-4,7-dihydroisothiazolo[5,4-b]pyridine-5-carboxylate as a pale yellow jelly-like product.