Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:24]=[N:23][C:11]2[O:12][CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[CH:24]=[N:23][C:11]2[O:12][CH2:13][CH2:14][NH:15][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cnc2c(c1)N(C(=O)OC(C)(C)C)CCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1cnc2c(c1)NCCO2
Temperature: 40 °C
Reaction time: 24 h
Yield: 20.3 %

Procedure:
To a suspension of tert-butyl 7-(tert-butylcarbamoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (1.425 g, 4.25 mmol) in DCM (5 mL) and DMF (5 mL) was added TFA (3 mL, 38.9 mmol). The reaction was stirred at 40° C. for 24 h. Additional TFA (2.2 mL, 28.5 mmol) was added to consume unreacted starting material. The reaction was allowed to stir at room temperature for 2 h. A further addition of TFA (4.4 mL, 57.0 mmol) was performed and the reaction was allowed to stir for 2 h. Upon consumption of the starting material the reaction mixture was concentrated in vacuo and purified by flash column chromatography using a gradient elution of DCM and 2-8% MeOH spiked with 1% TEA. The eluant was evaporated to yield an orange oil. The oil was treated with saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (2×50 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo to provide N-tert-butyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide (203 mg, 0.864 mmol, 20% yield 3 steps) as a white solid. LCMS (+ESI) m/z=236.1 [M+H]+;
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[CH2:17][N:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]([CH3:31])[C:3](=[O:4])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: CN(C)C(=O)c1cc(-c2ccccc2)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1cc(-c2ccccc2)ccc1CN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A 50 mL round-bottom flask was charged with tert-butyl 4-[[2-(dimethylcarbamoyl)-4-phenylphenyl]methyl]piperazine-1-carboxylate (300 mg, 0.710 mmol, 1.00 equiv), dichloromethane (5 mL), trifluoroacetic acid (1 mL). The resulting solution was stirred for 1 h at room temperature, concentrated under reduced pressure to yield 229 mg (crude) of N,N-dimethyl-5-phenyl-2-(piperazin-1-ylmethyl)benzamide as light yellow oil. LCMS (ESI, m/z): 324 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:33](=[N:35]O)[NH2:34])[CH:32]=1.CCN(C(C)C)C(C)C>>[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:33]2[N:34]=[C:17]([C:16]3[CH:20]=[CH:21][C:13]([N:7]4[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]4)=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:15]=3)[O:19][N:35]=2)[CH:32]=1
Reactant: COc1ccc(F)cc1C(N)=NO
Reactant: O=C(O)c1ccc(N2CCCCC2)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3)c(C(F)(F)F)c2)n1

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 42 (137 mg; 0.5 mmol; 1 eq.), Intermediate 23 (92 mg; 0.5 mmol, 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by crystallisation from n-pentane afforded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8](=O)[CH3:9])[CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+].[BH3-]C#[N:19].[Na+]>C1COCC1.CO>[F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([CH:8]([NH2:19])[CH3:9])[CH2:4][CH2:3]1
Reactant: CC(=O)C1CCC(F)(F)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)C1CCC(F)(F)CC1
Reaction time: 48 h
Yield: 54.1 %

Procedure:
To a solution of 1-(4,4-difluorocyclohexyl)ethanone (1 g, 6.17 mmol) in THF (5 mL) was added a solution of ammonium acetate (9.51 g, 123.4 mmol) and NaBH3CN (3.82 g, 61.7 mmol) in MeOH. The mixture was stirred for 48 hr. The reaction mixture was quenched with aqueous NaHCO3 and extracted with tert-Butyl-methyl ether (20 mL*3). The combined organic layers were washed with 1N HCl, and the organic and aqueous layer were separated. The aqueous layer was brought to above pH 8 with 2N NaOH and extracted with ethyl acetate (20 mL*3). The organic layer was washed with brine, dried over sodium sulfate. The organic layer was concentrated to give 1-(4,4-difluorocyclohexyl)ethanamine (545 mg, crude) for next step.
Reaction SMILES: C([O-])(O)=O.[Na+].[NH:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[CH2:11][OH:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:6]2[CH2:10][CH2:9][CH2:8][C@@H:7]2[CH2:11][OH:12])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: OC[C@H]1CCCN1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCC[C@@H]1CO
Temperature: 20 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a mixture of sat aq. NaHCO3 (44 g, 0.53 mol), CH2Cl2 (400 mL) and (R)-pyrolidin-2-yl-methanol (53 g, 0.53 mol) was added 4-bromo-benzenesulfonyl chloride (130 g, 0.50 mol) in CH2Cl2 (100 mL). The reaction was stirred at 20° C. overnight. The organic phase was separated and dried over Na2SO4. Evaporation of the solvent under reduced pressure provided (R)-[1-(4-bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (145 g, crude), which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ 7.66-7.73 (m, 4H), 3.59-3.71 (m, 3H), 3.43-3.51 (m, 1H), 3.18-3.26 (m, 1H), 1.680-1.88 (m, 3H), 1.45-1.53 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@H:16]1[C@@H:20]([CH3:21])[CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:17]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:9]([NH:15][C@H:16]3[C@@H:20]([CH3:21])[CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:17]3)=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)nc2c1Cl
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)nc12
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 2-bromo-8-chloroimidazo[1,2-b]pyridazine-7-carboxamide (2.198 g, 7.98 mmol), (3S,4S)-benzyl 3-amino-4-methylpyrrolidine-1-carboxylate (2.15 g, 9.18 mmol) and Hunig's Base (4.18 ml, 23.94 mmol) in DMF (7.9 ml) in a reaction vial was stirred at 90° C. for 2 h. After cooling to room temperature, the reaction solution was added slowly to a stirred ice-water resulting in a light tan precipitate. The suspension was stirred for 30 min. (3S,4S)-Benzyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-methylpyrrolidine-1-carboxylate (3.78 g, 7.98 mmol, 100% yield) was collected as a light tan solid via filtration. ESI-MS (analytical LCMS Method A): m/z 473, 475 ([M+H]+). HPLC (analytical HPLC Method A) Rt: 3.808 min.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].S(C1C=CC(C)=CC=1)(O[CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(=O)=O>>[CH:14]1([CH2:13][S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Oc1ccccc1S
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Product: Oc1ccccc1SCC1CCCC1
Yield: 83 %

Procedure:
This compound was prepared in 83% yield from 2-mercaptophenol and cyclopentylmethyl tosylate according to the procedure for 1p in Example VIII. Colorless oil; 1H NMR (CDCl3): δ 1.20-1.26 (m, 2H), 1.50-1.65 (m, 4H), 1.78-1.84 (m, 2H), 1.99 (s-7, J=7.45 Hz, 1H), 2.68 (J=7.40 Hz, 2H), 6.78 (s, 1H), 6.86 (dt, J=1.35 Hz, J=7.55 Hz, 1H), 7.24 (dt, J=1.65 Hz, J=7.85 Hz, 1H), 7.46 (dd, J=1.65, J=7.70 Hz, 1H); 13C NMR (CDCl3): δ 25.38, 32.32, 39.71, 43.33, 114.74, 119.64, 120.79, 130.94, 135.89, 156.90; HRMS (FAB): 208.09219 calcd for C12H16OS [M]+. found 208.09134 (−4.3 ppm, −0.9 mmu).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:16][CH2:17][CH:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH2:25][CH2:26][CH2:27][CH:28]([CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH3:29])[CH3:24])[CH3:19])(=O)=O>CN(C=O)C>[CH3:19][CH:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:24])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:29])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:17][CH2:16][O:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)CCCC(C)CCCC(C)CCCC(C)C)cc1
Reactant: OCC(CO)(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOCC(CO)(CO)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
Under a nitrogen gas stream, 36.09 g (265.1 mmol) of pentaerythritol was dissolved in 210 ml of dry DMF, and 5.3 g (132.5 mmol) of 60% NaH was added little by little under ice cooling. The resultant was heated to room temperature and agitated for 1 hour, and 30.0 g (66.26 mmol) of phytanyl tosylate was added dropwise thereto, followed by washing with 55 ml of DMF. The resultant was heated to 80° C. and agitated for 4 hours, the resulting reaction solution was concentrated under reduced pressure, 500 ml of ether was added to the residual solution to perform extractive dissolution twice, the product was washed twice with saturated saline, and then it was dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated, purified by silica gel column chromatography to obtain 6.3 g of mono-O-(3,7,11,15-tetramethylhexadecyl)pentaerythritol, which was in colorless, transparent, and somewhat viscous liquid form. The purity of the product determined by HPLC analysis was not lower than 99.5%. The results of NMR analysis are as shown below.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:28])[C@@H:8]([NH:20]C(OC(C)(C)C)=O)[C@H:9]([CH3:19])[CH2:10][CH2:11][NH:12][CH2:13][N:14]=[N:15][N+:16]([O-:18])=[O:17].[ClH:29]>C1COCC1.O1CCOCC1>[ClH:29].[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:28])[C@@H:8]([NH2:20])[C@H:9]([CH3:19])[CH2:10][CH2:11][NH:12][CH2:13][N:14]=[N:15][N+:16]([O-:18])=[O:17]
Reactant: C[C@H](CCNCN=N[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1nccs1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[C@H](CCNCN=N[N+](=O)[O-])[C@H](N)C(=O)Nc1nccs1
Reaction time: 2 h
Yield: 97 %

Procedure:
(2S,3R)-2-tert-Butoxycarbonylamino-3-methyl-5-(nitroimino-amino)methylaminopentanoic acid 1,3-thiazol-2-ylamide (101 mg, 0.243 mmol) is dissolved in 1 mL THF and 1.5 mL of 4 N HCl in dioxane is added. After 2 h, THF is added and the white precipitate is collected by filtration. The resulting oily solid is treated with methanol and concentrated in vacuo. THF is added and the mixture is concentrated in vacuo; this THF addition and concentration is repeated several times to give (2S,3R)-2-amino-3-methyl-5-(nitroimino-amino)methylaminopentanoic acid 1,3-thiazol-2-ylamide hydrochloride as a solid (83 mmol, 97%).
Reaction SMILES: C(OOC(C)(C)C)(C)(C)C.[CH3:11][C:12]([O:15][O:16][C:17]([C:20]#[C:21][C:22]([O:25][O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:24])[CH3:23])([CH3:19])[CH3:18])([CH3:14])[CH3:13]>>[CH3:24][C:22]([O:25][O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH2:21][CH2:20][C:17]([CH3:18])([O:16][O:15][C:12]([CH3:14])([CH3:13])[CH3:11])[CH3:19])[CH3:23]
Reactant: CC(C)(C)OOC(C)(C)C#CC(C)(C)OOC(C)(C)C
Agent: CC(C)(C)OOC(C)(C)C
Product: CC(C)(C)OOC(C)(C)CCC(C)(C)OOC(C)(C)C

Procedure:
di(t-butyl) peroxide, 2,5-dimethyl-2,5-di(t-butylperoxy)hexyne-3;
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH:7]1[C:13]([OH:15])=[O:14])=[O:5].[N+](=[CH:18][CH2:19][CH3:20])=[N-].[N+](NC(=N)N(N=O)CCC)([O-])=O>CCOCC>[SH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH:7]1[C:13]([O:15][CH2:18][CH2:19][CH3:20])=[O:14])=[O:5]
Reactant: CCC=[N+]=[N-]
Reactant: CN1CCN(C(=O)CCS)C(C(=O)O)C1
Agent: CCCN(N=O)C(=N)N[N+](=O)[O-]
Solvent: CCOCC
Product: CCCOC(=O)C1CN(C)CCN1C(=O)CCS
Reaction time: 3 h

Procedure:
To a stirred suspension of 11.6 gms. of DL-1-(3-mercapto-1-oxopropyl)-4-methylpiperazine-2-carboxylic acid in 150 ml. of ether there is added dropwise a solution of diazopropane in ether [prepared from 8.75 g. of N'-nitro-N-nitroso-N-propylguanidine by the procedure of McKay et al. Can. J. Res. 28 B, 683(1950)]. The mixture is stirred for an additional three hours, filtered and washed twice with 100 ml. of 5% aqueous sodium bicarbonate solution. The ether solution is dried over anhydrous magnesium sulfate, and then concentrated under atmospheric pressure, leaving as a residue the desired DL-1-(3-mercapto-1-oxopropyl)-4-methylpiperazine-2-carboxylic acid, n-propyl ester.
Reaction SMILES: C([NH:9][C:10]([NH:20][CH2:21][CH2:22][S:23][CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[N:11][CH2:12][CH2:13][CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)(=O)C1C=CC=CC=1>Cl>[N:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][S:23][CH2:22][CH2:21][NH:20][C:10]([NH:11][CH2:12][CH2:13][CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)=[NH:9]
Reactant: O=C(NC(=NCCCc1c[nH]cn1)NCCSCc1ccc2ccccc2n1)c1ccccc1
Agent: Cl
Product: N=C(NCCCc1c[nH]cn1)NCCSCc1ccc2ccccc2n1

Procedure:
0.95 g (2 mmol) of N-benzoyl-N'-[2-[(quinolin-2-yl) methylthio]ethyl]-N"-[3-(imidazol-4-yl)propyl]-guanidine are heated under reflux in 45 ml of 18% hydrochloric acid for 6 hours and the product is worked up by a method analogous to that of Example 109. 0.86 g (90%) of a hygroscopic, non-crystalline solid is obtained.
Reaction SMILES: [CH:1]1([C:6]2[C:15]3[C@@H:14]([OH:16])[CH2:13][C:12]([CH3:18])([CH3:17])[CH2:11][C:10]=3[N:9]=[C:8]([CH:19]([CH3:21])[CH3:20])[C:7]=2[C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])(=O)=O.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Si:48]([O:16][C@H:14]1[CH2:13][C:12]([CH3:17])([CH3:18])[CH2:11][C:10]2[N:9]=[C:8]([CH:19]([CH3:21])[CH3:20])[C:7]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=3)=[O:23])=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:15]1=2)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)c1nc2c(c(C3CCCC3)c1C(=O)c1ccc(C(F)(F)F)cc1)[C@@H](O)CC(C)(C)C2
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(c(C3CCCC3)c1C(=O)c1ccc(C(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: -18 °C
Reaction time: 0.33 h

Procedure:
Under argon, 3.65 g (7.95 mmol) of the compound from Example 3A are initially charged in 80 ml of dry toluene. At room temperature, 3.41 g (31.8 mmol, 4 eq.) of 2,6-lutidine are then added, and the mixture is cooled to −18° C. 3.65 ml (15.9 mmol, 2 eq.) of tert-butyldimethylsilyl trifluoromethanesulphonate are added dropwise to this solution. After 20 min, the reaction mixture is warmed to 0° C. and stirred at this temperature for a further 55 min. For work-up, saturated ammonium chloride solution (100 ml) is added and the mixture is, after warming to room temperature, extracted with ethyl acetate. The aqueous phase is extracted two more times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography (silica gel, mobile phase: isohexane/ethyl acetate 9:1).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([CH3:28])[O:21][C:20]3=[N:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][N:19]3[CH2:18]2)[CH2:12][CH2:11]1)[C:3](=[O:9])[O:4]C(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.C(Cl)(=O)O[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(Cl)Cl.O>[CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([CH3:28])[O:21][C:20]3=[N:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][N:19]3[CH2:18]2)[CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)OCc1ccccc1)C1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.4 %

Procedure:
Tert-butyl N-methyl-{1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl}carbamate prepared in Example 236 (207 mg, 0.52 mmol) was dissolved in methylene chloride (5 ml). To the solution, trifluoroacetic acid (5 ml) was added followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. To the residue, methylene chloride (5 ml), triethylamine (1 ml) and benzyl chlorocarbonate (0.15 ml, 1.05 mmol) were added followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into water, extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and crystallized from ethyl acetate-isopropyl ether to afford benzyl N-methyl-[1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]carbamate (184 mg, yield 82%) as a white powder.
Reaction SMILES: [F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1[CH:19]=[N:20][C:21]([S:25][CH3:26])=[CH:22][C:23]=1[CH3:24])[CH:12]=2)=[O:6].C(O)(=[O:29])C.OO>O>[F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1[CH:19]=[N:20][C:21]([S:25]([CH3:26])=[O:29])=[CH:22][C:23]=1[CH3:24])[CH:12]=2)=[O:6]
Reactant: CC(=O)O
Reactant: CSc1cc(C)c(-c2ccc3cc(NC(=O)[C@@H]4C[C@@H]4F)ncc3c2)cn1
Agent: OO
Solvent: O
Product: Cc1cc(S(C)=O)ncc1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Reaction time: 3 h
Yield: 45 %

Procedure:
A mixture of (1S,2S)-2-fluoro-N-(7-(4-methyl-6-(methylthio)pyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (150 mg, 0.3674 mmol) and acetic acid (4.0 mL) was treated with hydrogen peroxide (35 mass % in water, 0.16 mL, 1.8 mmol) at room temperature. After 3 hours, additional hydrogen peroxide was added (35 mass % in water, 0.03 mL; 0.3 mmol). After an additional 30 minutes, the reaction mixture was poured into water (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude product was purified via preparatory reverse-phase HPLC and lyophilized to yield 63.1 mg (45%) of the title compound. LCMS (ESI): RT (min)=4.013, M+H=384.2, method=E; 1H NMR (400 MHz, DMSO) δ 1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.22 (s, 1H), 8.61 (s, 1H), 8.54 (s, 1H), 8.15 (s, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.91 (s, 1H), 7.80 (d, J=8.5 Hz, 1H), 4.96 (m, 1H), 2.86 (s, 3H), 2.46 (s, 3H), 2.35-2.24 (m, 1H), 1.78-1.63 (m, 1H), 1.29-1.12 (m, 1H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:19][CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CI.CN(P(N(C)C)(N(C)C)=O)C>C1COCC1.[Cl-].[NH4+]>[CH:13]1([CH2:19][C:20]([CH3:1])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)C(C)CC1CCCCC1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(C)CC1CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a solution of diisopropylamine (8.9 ml, 63.3 mmol) in 100 ml of anhydrous THF was added dropwise n-butyl lithium (1.59N, 39.8 ml, 63.3 mmol) at -78° C. under argon atmosphere. After the mixture was stirred at -78° C. for 30 minutes, methyl 3-cyclohexyl-2-methylpropionate (7.7829 g, 42.2 mmol) was added dropwise. After the mixture was stirred at -78° C. for 30 minutes, a solution of methyl iodide (3.9 ml, 63.3 mmol) in HMPA (2.2 ml, 12.7 mmol) was added dropwise. After being stirred at -78° C. for 1 hour, the reaction mixture was diluted with an aqueous saturated solution of ammonium chloride. The aqueous mixture was extracted with ether (50 ml×4). Then, the combined ether layers were washed water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled to give a colorless liquid of methyl 3-cyclohexyl-2,2-dimethylpropionate (5.7294 g, yield 52.2%, b.p. 121.5°-123° C./22 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1)([OH:3])=[O:2].[CH2:16](O)[CH2:17][CH3:18]>S(=O)(=O)(O)O>[C:1]([C:4]1[O:5][C:6]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1)([O:3][CH2:16][CH2:17][CH3:18])=[O:2]
Reactant: O=C(O)c1cc(=O)c2cc(O)ccc2o1
Reactant: CCCO
Agent: O=S(=O)(O)O
Product: CCCOC(=O)c1cc(=O)c2cc(O)ccc2o1

Procedure:
14.14 g (49.2 mmoles) of 2-carboxy-6-hydroxy-4-oxo-4H-1-benzopyran is dissolved in 200 ml of n-propanol and 1 drop of concentrated sulfuric acid is added. The mixture is refluxed for 30 hours, concentrated. The resulting solid is suspended in water, neutralized with sodium bicarbonate and filtered, washing the solid with water, then drying. This gives 10.6 g of 2-carbopropoxy-6-hydroxy-4-oxo-4H-1-benzopyran as a solid which is purified by recrystallization from n-propanol/acetone or by HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[CH:3]=1.[CH3:13][C:14]1([CH3:27])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]1=2>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[CH:17]=[CH:16][C:15]4[C:14]([CH3:27])([CH3:13])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]=4[CH:19]=3)[CH:8]=2)[CH:3]=1
Reactant: Cc1ccc2cc(Br)ccc2c1
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Product: Cc1ccc2cc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)ccc2c1
Yield: 72.5 %

Procedure:
In accordance with the same procedures as in Example 1, part (b), starting with 2-methyl-6-bromonaphthalene (2.21 g, 10 mmoles) and 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-bromonaphthalene (3.20 g, 12 mmoles), there is obtained after column chromatography (9 hexane, 1 dichloromethane) 2-methyl-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)naphthalene (2.38 g, 72%) having a melting point of 173°-175° C.