Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].[Br:5][C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:12]([CH3:18])([CH3:17])[C@@H:11]([OH:19])[C@@H:10]([OH:20])[C:9]([CH3:22])([CH3:21])[C:8]=2[CH:7]=1.C([Li])CCC.C(N1CCCCC1)=[O:29]>O1CCCC1>[CH2-:1][C:2]([CH3:4])=[O:3].[Br:5][C:6]1[C:15]([CH:16]=[O:29])=[CH:14][C:13]2[C:12]([CH3:18])([CH3:17])[C@H:11]([OH:19])[C@H:10]([OH:20])[C:9]([CH3:22])([CH3:21])[C:8]=2[CH:7]=1
Reactant: O=CN1CCCCC1
Reactant: Cc1cc2c(cc1Br)C(C)(C)[C@H](O)[C@H](O)C2(C)C
Agent: [CH2-]C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)c2cc(C=O)c(Br)cc2C(C)(C)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a −78° C. solution of 9.04 g (25.6 mmol) 2-bromo-cis-6,7-dihydroxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene acetonide in 110 ml tetrahydrofuran was added 32.0 ml (51.1 mmol) of a 1.6M solution of n-butyllithium in hexanes. After 1 hour at −78° C., 5.79 g (51.1 mmol) of 1-formylpiperidine was added. After 20 minutes at −78° C., the resulting mixture was quenched with water. Upon warming to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude material was purified by flash chromatography with elution with 5% ethyl acetate/hexane to yield 5.65 g (73%) of 3-bromo-cis-6,7-dihydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde acetonide(MH+=303).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:11]([O:13][CH2:14][CH3:15])=[CH2:12].FC(F)(F)C(O)=O.[O:23]([CH2:41][C:42]([CH3:46])([CH3:45])[CH:43]=O)[Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[O:23]([CH2:41][C:42]([CH:46]1[CH2:12][CH:11]([O:13][CH2:14][CH3:15])[C:9]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=2)[NH:8]1)([CH3:45])[CH3:43])[Si:24]([C:37]([CH3:38])([CH3:39])[CH3:40])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: C=COCC
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOC1CC(C(C)(C)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Nc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Nitroaniline (200 mg), 0.15 ml of ethyl vinyl ether, and 0.1 ml of trifluoroacetic acid were dissolved in 5 ml of acetonitrile, and 500 mg of 3-(tert-butyldiphenylsilanoxy)-2,2-dimethylpropionaldehyde was added at 0° C. After 6 hours of stirring at room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=10:1-8:1) to obtain 34 mg of the title compound. Its physical properties are shown below.
Reaction SMILES: [CH2:1]([O:8][C:9](=O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)[C:13]([Cl:15])=[O:14]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][CH2:9][C:13]([Cl:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of carbonic acid monobenzyl ester (3.50 g, 21.0 mmol) in the 50 ml of DCM and 0.50 ml of DMF was cooled to −78° C. followed by addition of oxalyl chloride (11.79 ml, 105 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. After the completion of the reaction mixture (TLC monitoring), concentrated it to give 2-benzyloxyacetyl chloride (3.0 g, 96%). To an ice cold solution of 3-amino-4-chloro-benzoic acid methyl ester in 10 ml of DCM was added triethylamine (2.47 ml, 17.78 mmol) followed by addition of 2-benzyloxyacetyl chloride (3.0 g, 17.78 mmol) in 10 ml of DCM. The reaction mixture was stirred at 25° C. for 12 hr. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (5:95) as the eluent to provide the title compound (1.70 g, 31%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][S:12][CH2:13][CH2:14][OH:15])=[CH:4][N:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:16]([O:15][CH2:14][CH2:13][S:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][CH:4]=2)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc2ncn(CSCCO)c2n1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OCCSCn1cnc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 100 ml flask equipped with a magnetic stirring bar and a CaCl2 drying tube was charged with 1.0 g (4.4 mM) 2-amino-9-(2-hydroxyethylthiomethyl)-9H-purine, 0.054 g (0.44 mM) 4-dimethylaminopyridine, 0.9 ml (8.8 mM) acetic anhydride, and 200 ml of dry DMF. The solution was stirred for 24 hrs at room temperature and then quenched with 5 ml of MeOH. The solution was evaporated in vacuo (bath temp 40° C.) and the brown oil so obtained chromatographed using the "flash" method. Elution of the column with 1.5% methanol in ethyl acetate provided a yellow oil which crystallized on standing. The light yellow crystals were dissolved in a solution of 2% MeOH in toluene and treated with 0.05 g Darco G-60. The methanol was evaporated from the toluene solution resulting in the precipitation of light yellow crystals. The product was dried for 16 hrs at 78° C. to yield the title compound, mpt. 119°-120.5° C. Anal. Calcd. for C10H13N5O2S: C, 44.93; H, 4.9; N, 26.20. Found: C, 44.97, H, 4.96; N, 26.17. 1H NMR in DMSO 6 8.59 (1HS), 8.15 (1Hs), 6.52 (2H broad s) 5.26 (2Hs), 4.15 (2Ht J=6.36 Hz), 2.89 (2Ht J=6.36 Hz), 1.99 (3Hs).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].F[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>CN(C)C=O.O>[N:1]1([C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[C:15]#[N:16])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: N#Cc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-n1cnc2ccccc21
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Benzimidazole (2.00 grams, 16.9 mmol) was dissolved in 30 mL of anhydrous dimethylformamide. To this was added sodium hydride (0.68 grams 60%, 16.9 mmol). This was stirred at ambient temperature for 30 min. before addition of 1.80 mL (16.9 mmol) of 2-fluorobenzonitrile. The reaction was stirred at 50° C. for 18 hours after which time the mixture was cooled in an ice-water bath and diluted with 100 mL of water. The product was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and evaporated in vacuo giving the title compound. Mass spectral and NMR data agree with the structure. Also synthesized analogously was the 5,6-dimethyl benzimidazole analog.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4](/[CH:5]=[CH:6]\[C:7]([O:9]C)=[O:8])[CH:3]1[C:11]([OH:13])=[O:12].N1[C:24]2[C:19](=[CH:20]C=CC=2)[CH:18]=CC=1>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:11]([O:13][C:19]([CH3:24])([CH3:20])[CH3:18])=[O:12]
Reactant: c1ccc2ncccc2c1
Reactant: COC(=O)/C=C\C1C(C(=O)O)C1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C

Procedure:
A mixture of 2 g of tert.-butyl (1R, cis) 2,2-dimethyl-3-[Z-carboxyethynyl]-cyclopropane-carboxylic acid, 40 ml of ethyl acetate, 0.38 g of 10% palladium hydroxide on barium sulfate and 0.4 ml of quinoline was hydrogenated and was filtered. The filtrate was washed with 0.5 N hydrochloric acid and with water until the wash water was neutral, dried and evaporated to dryness under reduced pressure to obtain 2 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-[Z-2-carboxyethenyl]-cyclopropane-carboxylate melting at 94° C.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([N:14]1[CH2:19][CH2:18][C:17](O)([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH3:29])[CH3:28])[CH:21]=2)[CH2:16][CH2:15]1)[CH3:13].O.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH3:14].[CH2:12]([N:14]1[CH2:15][CH:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH3:28])[CH3:29])[CH:21]=2)[CH2:18][CH2:19]1)[CH3:13]
Reactant: CCN1CCC(O)(c2cccc(OC(C)C)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN1CC=C(c2cccc(OC(C)C)c2)CC1
Product: N
Temperature: 25 °C
Yield: 107 %

Procedure:
p-Toluenesulfonic acid (6.1 g, 31.9 mmoi) was added to a solution of N-ethyl-4-hydroxy-4-(3-(1-methylethoxy)phenyl)piperidine (Preparation 43, 4.2 g, 16.0 mmol) in toluene (50 ml), and the reaction mixture was heated under reflux for 3 h. The reaction mixture was allowed to cool to room temperature, water (20 ml) was added, and the resultant biphasic system was stirred vigorously for several minutes. The aqueous layer was basified with 2N aqueous sodium hydroxide solution (10 ml) and the two phases were separated. The aqueous layer was then further extracted with ether (3×10 ml) and the combined extracts were dried (MgSO4), filtered and concentrated to give a crude oil which was purified by silica column chromatography eluting with ethyl acetate:methanol: 0.880 ammonia (96:3:1) to give the title compound as an oil (2.1 g, 54%).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.C(N)=O.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=1[CH3:29])=O.[CH:30]([NH2:32])=[S:31].[OH-].[Na+]>O1CCOCC1>[CH3:29][C:23]1[CH:24]=[C:25]([OH:28])[CH:26]=[CH:27][C:22]=1[C:20]1[N:32]=[CH:30][S:31][CH:19]=1
Reactant: Cc1cc(O)ccc1C(=O)CBr
Reactant: NC=S
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: NC=O
Product: Cc1cc(O)ccc1-c1cscn1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a stirred solution of phosphorus pentasulfide (6.0 g, 13.5 mmol) in dioxane (60 ml) was added formamide (7.2 g, 160 mmol), and the mixture was heated at reflux temperature for 2 hours. The reaction mixture was cooled down to room temperature, and the solution was decanted away from solids. To a stirred solution of 2-bromo-1-(4-hydroxy-2-methylphenyl)-1-ethanone from step 1 (2.4 g, 10.5 mmol) in dioxane (20 ml) was added the thioformamide solution, and the mixture was heated at reflux temperature for 6 hours. The reaction mixture was cooled down to room temperature, and made basic by addition of 0.5M NaOH aqueous solution. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4) to give title compound (1.54 g, 77% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH:19]([O:22][CH3:23])[C:20]#[CH:21])[CH:16]=[C:15]([O:24][CH3:25])[C:14]=1[O:26][CH3:27]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:21]#[C:20][CH:19]([O:22][CH3:23])[C:17]2[CH:16]=[C:15]([O:24][CH3:25])[C:14]([O:26][CH3:27])=[C:13]([O:12][CH3:11])[CH:18]=2)=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1I
Reactant: C#CC(OC)c1cc(OC)c(OC)c(OC)c1
Product: COc1cc(C(C#Cc2c(C)nc(N)nc2N)OC)cc(OC)c1OC
Yield: 93.5 %

Procedure:
2,4-Diamino-5-iodo-6-methylpyrimidine (250 mg) was allowed to react with 1,2,3-Trimethoxy-5-(1-methoxyprop-2-ynyl)benzene (473 mg) as per the general procedure to afford 2,4-Diamino-5-(3-methoxy-3-(3,4,5-trimethoxyphenyl)prop-1-ynyl)-6-methylpyrimidine as a yellow powder (335 mg, 93%): Rf=0.29 (9:1, CHCl3:MeOH); mp=127-129° C.; 1H NMR (DMSO-d6) δ 6.84 (s, 2H), 6.37 (s, 2H), 5.34 (s, 1H), 3.78 (s, 6H), 3.66 (s, 3H), 3.35 (s, 3H), 2.23 (s, 3H); 13C NMR (DMSO-d6) δ 167.6, 164.3, 161.1, 152.8, 137.2, 134.8, 104.6, 95.7, 87.5, 81.8, 73.1, 60.0, 55.8, 55.3, 22.4; HRFAB [M+Li] 359.1701 (calculated C18H22N4O4Li: 359.1719). (R)-4-Isopropyl-3-(2-(3,4,5-trimethoxyphenyl)acetyl)oxazolidin-2-one. To a flame-dried 100 mL round-bottom flask was added 3,4,5-trimethoxyphenylacetic acid (2.10 g, 9.29 mmol). THF (25 mL) was added followed by Et3N (1.42 mL, 10.22 mmol). The solution was cooled to −78° C. Pivaloyl chloride (1.26 mL, 10.22 mmol) was added dropwise and the solution warmed to 0° C. and stirred for 1 h. In a separate flame-dried 50 mL round-bottom flask was added (R)-4-isopropyloxazolidin-2-one (1.0 g). THF (20 mL) was added and the solution cooled to −78° C. n-BuLi (6.83 mL, 9.29 mmol, 1.36 M) was added dropwise and the solution stirred at −78° C. for 15 min and then warmed to 25° C. where it was stirred for 15 min. The organolithium solution was transferred to the solution of the mixed anhydride via cannula at −78° C. The reaction was stirred at −78° C. for 15 min, warmed to 0° C., and stirred for 1 h. Water (10 mL) was added and the aqueous layer extracted with EtOAc (2×10 mL). The combined organics were washed with brine (10 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 30 g) using 25% EtOAc in hexanes as the eluent to afford trimethoxyphenyl)acetyl)oxazolidin-2-one as a colorless oil (2.30 g, 88%): Rf=0.28 (1:1, Hex:EtOAc); 1H NMR (CDCl3) δ 6.55 (s, 2H), 4.44-4.41 (m, 1H), 4.29-4.24 (m, 2H), 4.19 (dd, J) 9.0, 3.0 Hz, 1H), 4.12-4.07 (m, 1H), 3.82 (s, 6H), 3.80 (s, 3H), 2.36-2.30 (m, 1H), 0.87 (d, J) 6.8 Hz, 3H), 0.78 (d, J) 7.1 Hz, 3H); 13C NMR (CDCl3) δ 171.2, 154.1, 153.2, 129.4, 106.7, 63.4, 60.9, 58.6, 56.2, 41.6, 28.4, 18.0, 14.7, 14.3; HRFAB [M+Li] 344.1686 (calculated C17H23NO6Li: 344.1686).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[CH:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:24]2[CH2:25][CH2:26][CH:21]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:22][CH2:23]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1
Reactant: C1CCC(C2CCNCC2)CC1
Reactant: ClCCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)nnn2CCCCN1CCC(C2CCCCC2)CC1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(1-cyclohexyl)piperidine (5.1 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 6.5 g compound (I-121) with a yield of 63.7%. ESI-MS [M+H]+: m/z 341.3.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH:9]([CH2:14][CH:15]=[CH2:16])[CH:10]([OH:13])[CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[I:22]I.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)C.O>[I:22][CH2:16][C@H:15]1[O:13][C@H:10]([CH2:11][OH:12])[C@@H:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14]1
Reactant: C=CCC(OCc1ccccc1)C(O)CO
Reactant: II
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: OC[C@H]1O[C@H](CI)C[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A 0° C. solution of 4.5 g of product from Example 333 in 77.8 ml of diethyl ether and 25.5 ml of water is treated with 2.58 g of solid sodium bicarbonate followed by 7.6 g of iodine. The reaction is stirred for 3 hours at 0° C. then at room temperature overnight. The mixture is cooled to 0° C. and sodium sulfite is added until the reaction is colorless. The solution is extracted with diethyl ether, dried and concentrated in vacuo to give 7.0 g of an oil. The oil is purified by chromatography (Silica gel: 5% diethyl ether/hexane) to give 2.8 g of Isomer A and 1.86 g of Isomer B. Isomer A:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.[C:16]1([C@@H:22]2[CH2:24][C@H:23]2[C:25](O)=[O:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[C:11]([O:10][C:9](=[O:15])[NH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:25]([CH:23]2[CH2:24][CH:22]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:26])[CH2:2][CH2:3]1)([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CCN(C(=O)C2CC2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl piperidin-4-ylmethylcarbamate (Epsilon, 0.80 g, 3.73 mmol), (1R,2R)-2-phenylcyclopropanecarboxylic acid (T. Riley eta al, J. Med. Chem., 15, 1187, 1972) (0.61 g, 3.73 mmol), EDC (1.07 g, 5.60 mmol) and HOBt (0.76 g, 5.60 mmol) in DMF (10 mL) was stirred at RT for 2 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with aq. sat. NaHCO3 (50 mL), water (5×50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60 (90 g), eluting with 10:1-10:89-80 CH2Cl2:2-propanol:hexane to give the title compound. (1.22 g, 91.0%). M.S. (M+1): 359.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:21]([O:25][C:26]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])=[CH:35][CH:36]=2)[C:31]([CH:46](OS(C)(=O)=O)[CH3:47])=[CH:30][C:29]1([CH3:54])[CH3:53])=[O:27])([CH3:24])([CH3:23])[CH3:22]>CS(C)=O>[C:21]([O:25][C:26]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])=[CH:35][CH:36]=2)[C:31]([CH:46]([O:6][CH2:5][CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Br:1])[CH3:47])=[CH:30][C:29]1([CH3:53])[CH3:54])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: OCCc1ccccc1Br
Reactant: COc1ccccc1-c1ccc2c(c1)C(C(C)OS(C)(=O)=O)=CC(C)(C)N2C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccccc1-c1ccc2c(c1)C(C(C)OCCc1ccccc1Br)=CC(C)(C)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.037 mL of 2-bromophenethyl alcohol and 1 mL of DMSO was treated with 0.277 mL of 1.0 M sodium bis(trimethylsilyl)amide, then 86 mg of 4-(1-methanesulfonyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester in 1 mL DMSO was added at room temperature. The reaction mixture was allowed to stir at room temperature overnight. TLC showed starting material was consumed. The reaction was quenched with water and the product was extracted with EtOAc three times. The organic layers were combined, washed sequentially with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution, water, and brine, dried over magnesium sulfate, and the solvent evaporated in vacuo. The residue was purified by flash chromatography to yield 37 mg of 4-{1-[2-(2-bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: C([S:4][CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8])(=O)C.[Na].[OH-:12].[Na+:13]>O>[CH2:6]([S:7]([O-:9])(=[O:8])=[O:12])[CH2:5][S:4][S:4][CH2:5][CH2:6][S:7]([O-:10])(=[O:8])=[O:9].[Na+:13].[Na+:13]
Reactant: CC(=O)SCCS(=O)(=O)O
Reactant: [OH-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=S(=O)([O-])CCSSCCS(=O)(=O)[O-]

Procedure:
The ongoing S-acetyl-2-mercaptoethane sulfonic acid, sodium salt (20 g) is dissolved in water and added 1N sodium hydroxide to adjust the pH to 9.0. The reaction mixture is the then stirred while bubbling oxygen for 48 hours. The aqueous portion is then concentrated and crystallized out the product directly. Yield is found to be 80%. The product is characterized by NMR and corroborated the structure with the authentic sample.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]([NH2:13])([CH3:12])[CH3:11].[CH2:14]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26](Cl)=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[N:29]2)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[NH2:13][C:10]([CH3:12])([CH3:11])[CH2:9][NH:8][C:26]1[C:25]2[C:30](=[CH:31][C:22]([O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:23][CH:24]=2)[N:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33]
Reactant: CC(C)(N)CN
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Reaction time: 8 h
Yield: 73.6 %

Procedure:
Triethylamine (12.8 mL, 92.0 mmol) and 1,2-diamino-2-methylpropane (5.29 mL, 50.6 mmol) were added sequentially to a solution of 7-benzyloxy-4-chloro-3-nitroquinoline (14.5 g, 46.0 mmol) in dichloromethane (400 mL). The reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue was partitioned between water (200 mL) and dichloromethane (300 mL). The organic layer was washed with brine, dried over sodium sulfate, and then concentrated under reduced pressure to provide crude product as a brown solid. The crude product was passed through a layer of silica gel (eluting sequentially with chloroform and 96:4 chloroform:methanol) to provide 12.4 g of (2-amino-2-methylpropyl)(7-benzyloxy-3-nitroquinolin-4-yl)amine as a yellow solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[N:11]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]=[N:18][CH:19]=[CH:20][C:12]=12.[CH2:21]([Mg]Br)[CH3:22].O>O1CCCC1>[CH2:21]([CH:17]1[C:13]2=[N:14][CH:15]=[CH:16][N:11]=[C:12]2[CH:20]=[CH:19][N:18]1[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])[CH3:22]
Reactant: CC[Mg]Br
Reactant: c1cc2nccnc2cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCC1c2nccnc2C=CN1C(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of phenyl chloroformate (0.200 mL, 250 mg, 1.59 mmol) in tetrahydrofuran (3.5 mL) was added over 20 min to a solution of 200 mg (1.53 mmol) of pyrido[3,4-b]pyrazine (prepared according to the procedure of F. F. Duarte and F. D. Popp, J. Heterocyclic Chem., 31: 819-823 (1994)) in tetrahydrofuran (7.5 mL) cooled in a −25° C. bath. After 10 min, ethylmagnesium bromide (1.0M in tetrahydrofuran, 1.54 mL, 1.54 mmol) was added over 10 min. The mixture was allowed to warm to 0° C. over 1 h. After an additional 30 min at 0° C., water (20 mL) was added and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated sodium bicarbonate solution (10 mL) followed by saturated aqueous brine (10 mL). The aqueous layers were extracted in succession with ethyl acetate (25 mL) and the organic layers were dried over sodium sulfate, decanted, and evaporated. Purification by flash chromatography (silica gel, 4-5% ethyl acetate in 1:1 hexanes/dichloromethane) gave the title compound as a colorless syrup. LC/MS 282 (M+1).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH3:7].O1CCOCC1.[CH2:16]([O:18][C:19](=[O:22])[CH2:20]Br)[CH3:17]>O>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][CH:5]([C:4](=[O:9])[CH3:3])[C:6](=[O:8])[CH3:7])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CC(C(C)=O)C(C)=O
Reaction time: 0.33 h

Procedure:
28 g of potassium hydroxide dissolved in 28 ml of water was added to a mixture of 50 g of 2,4-pentandione, and 100 ml and 115 ml of dioxane at 0 to 10° C. After 20 minutes of stirring, 125 g of bromoacetic acid ethyl ester was added dropwise and the mixture was stirred for 19 hours. The layers were separated and washed with water and diethyl ether. The organic layer was dried and 3-acetyl-4-oxo-pentanoic acid ethyl ester was isolated by fractional distillation.