Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1O[C:11](=[O:27])[C@H:12]([CH3:26])[NH:13][C:14](=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1.Cl.[CH2:29]([O:31][C:32](=[O:36])[C@H:33]([CH3:35])[NH2:34])[CH3:30]>CCOC(C)=O>[CH2:29]([O:31][C:32](=[O:36])[C@H:33]([CH3:35])[NH:34][C:11](=[O:27])[C@H:12]([CH3:26])[NH:13][C:14](=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)[CH3:30]
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure Z and using N-(3-nitrophenylacetyl)-L-alanine 2,4,5-trichlorophenyl ester (from Example D8 above) and L-alanine ethyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp =193-195° C.). The reaction was monitored by tlc (Rf=0.4 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH2:19])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:20][C:21]([F:27])([F:26])[S:22](Cl)(=[O:24])=[O:23]>>[F:20][C:21]([F:27])([F:26])[S:22]([NH:19][CH2:18][C:14]1[CH:15]=[N:16][CH:17]=[C:12]([C:7]2[N:8]([CH3:11])[C:9]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH:13]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: Cn1c(-c2cncc(CN)c2)cc2ccc(Cl)cc21
Product: Cn1c(-c2cncc(CNS(=O)(=O)C(F)(F)F)c2)cc2ccc(Cl)cc21

Procedure:
C-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine (Example 205a) and trifluoromethanesulfonyl chloride are processed according to the method described in Example 186f to give C,C,C-trifluoro-N-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide. 1H NMR (400 MHz, MeOD) δ ppm 3.80 (s, 3H), 4.59 (s, 2H), 6.72 (s, 1H), 7.12 (dd, J=8.5, 1.9 Hz, 1H), 7.54 (s, 1H), 7.60 (d, J=8.6 Hz, 1H), 8.05 (t, J=2.1 Hz, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 404.0443 [(M+H)+ Calcd for C16H14ClF3N3O2S: 404.0447].
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]3[N:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:32]([S:36](Cl)(=[O:38])=[O:37])[CH2:33][CH2:34][CH3:35]>C(Cl)Cl>[C:15]([C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:36]([CH2:32][CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])=[CH:24][CH:23]=3)[N:17]([CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:10]=2[N:11]=1)#[N:16]
Reactant: CC(C)(C)Cn1c(Cc2ccc(N)cc2)cc2cnc(C#N)nc21
Reactant: CCCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)Nc1ccc(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 39 %

Procedure:
To a solution of 6-(4-amino-benzyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.3 mmol) in CH2Cl2 (5 ml) are slowly added triethylamine (0.36 mmol) and 1-butanesulfonyl chloride (0.36 mmol) at 0° C. The reaction mixture is stirred at room temperature for 15 h. The mixture is quenched with saturated ammonium chloride and extracted with two 50 ml portions of CH2Cl2. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum to give crude product. Purification of the residue by silica gel column chromatography affords title compound in 39% yield.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([NH:30][CH2:31][CH2:32][OH:33])[CH3:29]>>[CH2:28]([N:30]([CH2:20][CH2:19][CH2:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:27])([F:1])[F:26])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:31][CH2:32][OH:33])[CH3:29]
Reactant: CCNCCO
Reactant: CS(=O)(=O)OCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: CCN(CCO)CCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1; Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl ester and 2-ethylaminoethanol were converted to yield 2-(Ethyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl}-amino)-ethanol as light brown oil, MS: 409 (MH+).
Reaction SMILES: [I:1][CH3:2].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[C:20]([CH2:22][O:23][C:24](=[O:26])[NH2:25])[O:19][N:18]=2)=[CH:13][CH:12]=1>>[I-:1].[C:24]([O:23][CH2:22][C:20]1[O:19][N:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][N+:3]=3[CH3:2])=[CH:16][CH:15]=2)[CH:21]=1)(=[O:26])[NH2:25]
Reactant: CI
Reactant: NC(=O)OCc1cc(-c2ccc(OCc3ccccn3)cc2)no1
Product: C[n+]1ccccc1COc1ccc(-c2cc(COC(N)=O)on2)cc1
Product: [I-]
Temperature: 80 °C
Reaction time: 10 h

Procedure:
2 ml of iodomethane was added to 0.3 g of the compound carbamic acid 3-[4-(pyridin-2-ylmethoxy)-phenyl]-isoxazol-5-ylmethyl ester in Example 65 and stirred at 80° C. for 10 hours. A crude solid compound obtained after distillation of the solution under reduced pressure to remove an excess of MeI was recrystallized from ethyl acetate/hexane/methylene chloride to obtain 2-[4-(5-carbamoyloxymethyl-isoxazol-3-yl)-phenoxymethyl]-1-methyl-pyridinium iodide as a desired compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.[NH2:26][CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH2:33][CH3:34].[OH-].[Na+].O>O1CCOCC1.CC(C)=O>[OH-:23].[NH4+:3].[CH:10]1([CH2:9][NH:8][C:6]2[N:7]=[C:2]([NH:26][CH2:27][CH:28]3[CH2:32][CH2:31][CH2:30][N:29]3[CH2:33][CH3:34])[N:3]=[C:4]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([F:25])[CH:18]=3)[N:5]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCN1CCCC1CN
Reactant: COc1ccc(Nc2nc(Cl)nc(NCC3CCCCC3)n2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(C)=O
Solvent: O
Product: CCN1CCCC1CNc1nc(NCC2CCCCC2)nc(Nc2ccc(OC)c(F)c2)n1
Product: [NH4+]
Yield: 112.3 %

Procedure:
To a sample of 125 (10.02 g, 27.3 mmol) dissolved in 1,4-dioxane (150 mL) was added a solution of 2-(aminomethyl)-1-ethylpyrrolidine (4.0 mL, 27.3 mmol) in acetone (10 mL) followed by addition of NaOH (11 mL, 2.5 N, 27.3 mmol) and 27 mL of water. The reaction mixture was allowed to stir at reflux for about 2 hours. The reaction mixture was extracted 3 times with dichloromethane; the combined organic layers were washed with brine and dried over potassium carbonate. The sample was concentrated on the rotary evaporator and the resulting solid was dried overnight under vacuum. Column chromatography (silica gel, 93:6:1 dichloromethane:methanol:conc. ammonium hydroxide) yielded a light yellow solid, compound 126 (7.014 g, 56%), mp 72° C.; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 8.5 min, 93.4% purity; MS (ESI): m/z 458 (M+H, 37.3), 362 (4), 250 (100), 230 (15.3), 229 (44.1).
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.O.C(=O)([O-])O.[Na+].[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClC(Cl)Cl>[C:22]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:8][CH2:7]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cccc(N2CCNCC2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCN(c2cccc(O)c2)CC1
Temperature: 10 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a stirred solution of 80 parts of 3-(1-piperazinyl)phenol dihydrobromide in 360 parts of water and 180 parts of trichloromethane are added portionwise 42 parts of sodium hydrogen carbonate at 10° C. Then there are added dropwise, during a 15 minutes-period, 26 parts of acetic acid anhydride while cooling at 10° C. Upon completion, stirring is continued for 3 hours at room temperature. The precipitated product is filtered off, washed with water and crystallized from 2-propanol, yielding 37 parts (70%) of 1-acetyl-4-(3-hydroxyphenyl)piperazine; mp. 186.1° C.
Reaction SMILES: [O:1]([CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O1CCC[CH2:24]1.Cl>O.CO>[CH3:24][C:19]1[CH:18]=[C:13]([CH:12]=[CH:11][C:10]=1[CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1COc1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
A mixture of methyl 4-(1-phenoxyethyl)benzoate (0.32 g, 1.2 mmol), lithium hydroxide monohydrate (571 mg, 13.6 mmol), tetrahydrofuran (15 mL), methanol (5 mL) and water (5 mL) was stirred at 20° C. for 4 hours. The mixture was neutralized to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 3-methyl-4-(phenoxymethyl)benzoic acid (0.21 g, 72%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:5]=[CH:4][CH:3]=1.[C:17]([NH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)(=[O:19])[CH3:18].[OH-].[K+].Cl>C(O)C.O>[C:17]([NH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH:9][C:8]([C:7]2[C:2]([OH:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: COC(=O)COc1cccc(O)c1C(C)=O
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(C=CC(=O)c2c(O)cccc2OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a mixture of 6′-hydroxy-2′-(methoxycarbonylmethoxy)acetophenone (2.24 g) and 4-acetylaminobenzaldehyde (2.45 g) in ethanol (30 mL) were added water (10 mL) and potassium hydroxide (6.73 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (70 mL), and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give 4-acetylamino-2′-(carboxymethoxy)-6′-hydroxychalcone (3.35 g). A mixture of the obtained 4-acetylamino-2′-(carboxymethoxy)-6′-hydroxychalcone (3.3 g) and 10% palladium-carbon powder (1 g) in methanol (50 mL) was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration. The solvent of the filtrate was removed under reduced pressure, and the residue was dissolved in acetic acid (13.2 mL). To the solution were added sodium acetate (4.77 g) and acetic anhydride (4.8 mL), and the mixture was stirred at 115° C. for 20 hours. The reaction mixture was poured in to water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (10 mL). To the solution was added sodium methoxide (28% methanol solution, 5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue were added 1 mol/L hydrochloric acid (30 mL) and ethyl acetate, and the mixture was stirred for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was treated with dichloromethane-methanol. The precipitated crystals were collected by filtration. The crystals were washed with dichloromethane and dried under reduced pressure to give the title compound (0.86 g).
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CN(C=O)C.C(OCC)(=O)C>[CH2:14]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:10])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCBr
Reactant: OCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCOCCCCCCCCO
Temperature: 50 °C
Reaction time: 10 h
Yield: 33 %

Procedure:
At room temperature, a commercially available reagent of octane-1,8-diol (351.2 mg, 2.40 mmol) was dissolved in DMF (3.0 mL), and sodium hydride (60 wt %, 105.7 mg, 2.64 mmol) was added. The mixture was then warmed to 50° C., stirred for 10 hours while maintaining the temperature at 50° C., and cooled to room temperature. 1-Bromo-heptane (430.2 mg, 2.40 mmol) in DMF (1.5 mL) was then added, and the mixture was stirred at room temperature for 48 hours. The progress of reaction was stopped by adding water. Ethyl acetate was added, and the mixture was extracted. The organic layer was washed with water and a saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off. The resulting residue was then purified with SP1 (SiO2 cartridge, 50% ethyl acetate/n-hexane, Rf=0.8) to obtain 8-heptyloxy-octan-1-ol (No. 6804253; 193.8 mg, 33% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.CC(C)([O-])C.[K+]>CN(C)C=O.O>[NH:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[O:15][CH2:14][CH2:13]1
Reactant: OCCNc1c(Br)cnc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c3c(cnc2c1)OCCN3
Temperature: 25 °C
Yield: 23.3 %

Procedure:
A mixture of 8.0 g of 3-bromo-N-(2-hydroxyethyl)-4-quinolinamine and 4 g of potassium-tert-butoxide in 220 ml of dimethylformamide was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and diluted with 200 ml of water and the product was extracted with 4 portions of 50 ml of dichloromethane (DCM). The DCM solution was dried over sodium sulfate and concentrated. The oily residue was dissolved in 150 ml of ethanol. To this solution 5 ml of concentrated HCl was added, the HCl salt was separated by filtration and recrystallized from ethanol. This crystalline material was dissolved in 75 ml of water and the solution made alkaline (pH=8) with a sodium bicarbonate solution. The free base was filtered and dried in vacuo to yield 1.3 g of white solid, mp 175°-176° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.C(O)(C)C.O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: BrCCCc1ccccc1
Reactant: CC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(OCCCc2ccccc2)CC1
Reaction time: 4 h
Yield: 27.4 %

Procedure:
1-Acetylpiperidin-4-ol (Preparation 193, 8 g, 60 mmol) in N,N-dimethylformamide (50 ml) was added dropwise to a stirred suspension of sodium hydride (50% wt dispersion in oil, 3.68 g, 80 mmol) in N,N-dimethylformamide (50 ml) at room temperature under nitrogen. After stirring the reaction mixture for 4 hours, 1-bromo-3-phenylpropane (12.94 g, 65 mmol) in N,N-dimethylformamide (50 ml) was added dropwise to the solution at 0° C. and the reaction mixture was stirred for a further 4 h. The solution was diluted with isopropyl alcohol (20 ml) and water (100 ml) and then evaporated to give a semi solid. Water (100 ml) was added and the solution was extracted with petroleum ether (3×100 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give an orange oil (4.3 g, 27%).
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[C:16]2=[O:22])[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH:27]=[CH:28][C:29](O)=[O:30].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:23][C:24]1[CH:25]=[C:26](/[CH:27]=[CH:28]/[C:29]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[C:16](=[O:22])[CH:17]2[CH3:21])=[O:30])[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: CC1NCCN(CCCN2CCC3(CC3)[C@H](O)C2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)/C=C/c1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
To a suspension of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 25; 0.03 g, 0.2 mmol) in dichloromethane (1 ml) was added triethylamine (0.03 ml, 0.2 mmol) and acetic acid (0.02 ml, 0.4 mmol) followed by a solution of crude 2-methyl-3-oxo-4-(3-oxo-propyl)-piperazine-1-carboxylic acid tert-butyl ester (intermediate 14c; 0.06 g, 0.24 mmol) in dichloromethane (1 ml). Sodium triacetoxyborohydride (0.06 g, 0.26 mmol) was then added and the mixture stirred for 2 h, after which time the mixture was washed with saturated aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. The crude residue was then treated with HCl in dioxane (2 ml, 4 N) and stirred for 30 minutes after which time the reaction was concentrated to afford crude 1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride as a white powder (0.1 g). To a solution of crude 1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (0.03 g, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 3,4-dichlorocinnamic acid (0.2 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (4 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=480.1 (M+H)+.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:24][CH2:25][C:26](=O)[CH3:27])[N:18]([CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1.O>N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:26]([CH2:25][CH2:24][C:17]1[N:18]([CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:5])[C:15]=2[N:16]=1)[CH3:27]
Reactant: CON
Reactant: CC(=O)CCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CON=C(C)CCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 61.2 %

Procedure:
Methoxylamine hydrochloride (0.26 g, 3.1 mmol) was added to a stirred solution of 4-[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]butan-2-one (0.600 g, 1.84 mmol) in pyridine (9 mL), and the reaction was stirred at room temperature for 45 minutes. Water (50 mL) was added. The aqueous layer was separated, extracted with dichloromethane (2×50 mL), adjusted to pH 10 with the addition of saturated aqueous sodium carbonate, and extracted with dichloromethane (2×25 mL). The combined organic fractions were washed sequentially with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting white powder was stirred with diethyl ether for one hour, isolated by filtration, and washed with diethyl ether. The resulting solid (0.45 g) was recrystallized from acetonitrile (20 mL), and the crystals were isolated by filtration, washed with acetonitrile, and dried for 15 hours under vacuum at 60° C. to provide 0.40 g of 4-[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]butan-2-one O-methyloxime as white needles, mp 182-184° C.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>O>[CH3:13][N:12]([CH3:14])[S:11]([C:10]1[C:2]([O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:3]([N+:17]([O-:19])=[O:18])[CH:4]=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7])(=[O:16])=[O:15]
Reactant: Oc1ccccc1
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C)S(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1

Procedure:
A mixture of 4-chloro-5-dimethylsulphamyl-3-nitro-benzoic acid (3.08 g), a phenol (2g), sodium hydrogen carbonate (3.4 g), and water (20 ml) was heated at 90° C for 8 hours. Then water (40 ml) was added and, after cooling, the 5-dimethylsulphamyl-3-nitro-4-phenoxy-benzoic acid was precipitated by acidification with 4N hydrochloric acid. After isolation by filtration and several recrystallizations from ethanol, the said compound was obtained with a melting point of 224°-226° C.
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=O)C.Br[CH:21]([CH3:40])[C:22]([N:24]1[C:29]2([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[O:28][C:27]2[CH:35]=[CH:36][CH:37]=[CH:38][C:26]=2[C:25]1=[O:39])=[O:23].P([O-])([O-])([O-])=O>[Zn].O1CCCC1>[Si:13]([O:12][C@@H:10]([C@@H:6]1[C@@H:5]([C@@H:21]([CH3:40])[C:22]([N:24]2[C:29]3([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[O:28][C:27]3[CH:35]=[CH:36][CH:37]=[CH:38][C:26]=3[C:25]2=[O:39])=[O:23])[NH:8][C:7]1=[O:9])[CH3:11])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: CC(Br)C(=O)N1C(=O)c2ccccc2OC12CCCCC2
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1C(=O)c2ccccc2OC12CCCCC2
Yield: 74.6 %

Procedure:
1.0 g of (3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-azetidinone, 1.8 g of 3-(2-bromopropionyl)-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one and 0.68 g of zinc powders are added to 15 ml of tetrahydrofuran and the mixture is refluxed for 30 minutes. After cooling, the reaction mixture is poured into 0.2M phosphate buffer (pH 7.0) and the mixture is extracted with methylene chloride. The extract is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=3:1) to obtain 1.3 g of 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](N)[C:11]1C=[CH:15][CH:14]=[CH:13][CH:12]=1.ClCCl.C([OH:23])C>>[OH:23][C:5]1[CH:6]=[CH:7][C:2]([C:1]([O:9][CH:14]([CH3:15])[CH2:13][CH2:12][CH2:11][CH3:10])=[O:8])=[CH:3][CH:4]=1
Reactant: NCc1ccccc1
Reactant: CCO
Reactant: O=C([O-])c1ccccc1
Solvent: ClCCl
Product: CCCCC(C)OC(=O)c1ccc(O)cc1
Reaction time: 8 h
Yield: 100 %

Procedure:
Said benzoate (4.7 mmols) was dissolved in 20 ml of ethanol, and 9.7 mmols of benzylamine were added. The mixture was stirred overnight. To the reaction mixture was added 50 ml of dichloromethane. The organic layer was washed with a hydrochloric acid aqueous solution and water in this sequence. Subsequently, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained crude product was purified by silica gel column chromatography to afford 1-methylpentyl p-hydroxybenzoate in a yield of 100%.