Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=O)[NH:6][C:5]([CH3:9])=[N:4][S:3]1(=[O:11])=[O:10].P(Cl)(Cl)(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O>>[Cl:13][C:7]1[N:2]([CH3:1])[S:3](=[O:11])(=[O:10])[N:4]=[C:5]([CH3:9])[N:6]=1
Reactant: CC1=NS(=O)(=O)N(C)C(=O)N1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NS(=O)(=O)N(C)C(Cl)=N1
Temperature: 110 °C
Yield: 100 %

Procedure:
212 parts of 2,5-dimethyl-2H-1,2,4,6-thiatriazin-3-one-1,1-dioxide were introduced into a mixture of 292 parts of phosphorus pentachloride and 1,400 parts of phosphorus oxychloride at room temperature, while stirring. The reaction mixture was heated to 110° C. in the course of 30 minutes, stirred under reflux for 6 hours, and then concentrated under reduced pressure, giving 234 parts (100% of theory) of 3-chloro-2,5-dimethyl-2H-1,2,4,6-thiatriazine-1,1-dioxide of melting point 86°-90° C. (NMR (60 MHz, CDCl3): CH3 -C 2.4δ, CH3 -N 3.68δ).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[N:7]([CH:8]([CH3:11])[CH2:9]O)[C:6]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[C:14]([F:16])=[CH:15][C:5]=2[N:4]=1.N1C=CC=CC=1.S(Cl)([Cl:40])=O>C(OCC)C>[CH3:28][N:19]1[C:20]([C:24]([F:26])([F:27])[F:25])=[CH:21][C:22](=[O:23])[N:17]([C:13]2[C:14]([F:16])=[CH:15][C:5]3[N:4]=[C:3]([C:2]([F:31])([F:30])[F:1])[N:7]([CH:8]([CH3:11])[CH2:9][Cl:40])[C:6]=3[CH:12]=2)[C:18]1=[O:29]
Reactant: CC(CO)n1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(CCl)n1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 0.4 gram (0.0009 mole) of 2-[2-trifluoromethyl-5-fluoro-6-(1-methyl-6-trifluoromethyluracil-3-yl)benzimidazol-1-yl]propan-1-ol (Compound 7--prepared as in Step A of Example 8) in 10 mL of diethyl ether was cooled in an ice-water bath, and 0.07 mL (0.0009 mole) of pyridine was added at a rate to maintain the reaction mixture temperature below 5° C. Upon completion of the addition, 0.1 mL (0.0013 mole) of thionyl chloride was added dropwise from a syringe. Upon completion of the addition, the reaction mixture stirred at about 0° C. for 30 minutes. After this time, the reaction mixture was allowed to warm to ambient temperature, where it stirred for about 18 hours. Analysis of the reaction mixture by thin layer chromatography (TLC) indicated the reaction was not complete. The reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride, and 0.1 mL of thionyl chloride and 0.07 mL of pyridine were added. The mixture was warmed to reflux, where it stirred for about 24 hours. Analysis of the reaction mixture using TLC indicated the reaction was still not complete. Additional equivalents of thionyl chloride and pyridine were were added to the reaction mixture each day for a period of five days, as the reaction mixture stirred at reflux. At the end of five days the reaction mixture was allowed to cool to ambient temperature, where it stirred for two days. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was washed with an aqueous solution saturated with sodium chloride and dried with sodium sulfate. The mixture was filtered, and the filtrate concentrated under reduced pressure, yielding about 0.3 gram of 1-methyl-3-[1-(1-methyl-2-chloroethyl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil, mp 93°-95° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[O:23]([CH2:30][CH2:31][CH2:32]Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:32][CH2:31][CH2:30][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: ClCCCOc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCOc2ccccc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride and 3-phenoxypropyl chloride were reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-2-methoxy-N-((1-(3-(phenoxy)propyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[C:7]3[C:13](=[C:14]([OH:15])[C:4]=2[O:3][CH2:2]1)[O:12][C:10](=[O:11])[CH:9]=[CH:8]3.S(OC)(O[CH3:20])(=O)=O>>[CH3:20][O:15][C:14]1[C:4]2[O:3][CH2:2][CH2:1][C:5]=2[CH:6]=[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]=12)=[O:11]
Reactant: O=c1ccc2cc3c(c(O)c2o1)OCC3
Reactant: COS(=O)(=O)OC
Product: COc1c2c(cc3ccc(=O)oc13)CCO2

Procedure:
The process of claim 1, in which the 2,3-dihydroxanthotoxol of step 4 is methylated with dimethyl sulfate to form 2,3-dihydroxanthotoxin.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].[CH2:33](O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:7])[CH3:2]
Reactant: OCc1ccccc1
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1
Solvent: C1CCOC1
Product: CCCC(NC(=O)Cc1ccc(C(=O)OCc2ccccc2)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
0.35 g (0.8 mmol) of 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoic acid was refluxed together with 0.15 g (0.9 mmol) of N,N'-carbonyldiimidazole in 15 ml of absolute tetrahydrofuran for 2 hours. Then, 1.03 ml (10 mmols) of benzyl alcohol were added, and the mixture was refluxed for 3.5 hours. The reaction mixture was then evaporated in vacuo, and the residue was purified by column chromatography on silica gel (chloroform/acetone=9/1).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].C([N:11](CC)CC)C.[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20](N)=[C:19]([Cl:25])[CH:18]=1.O>C(#N)C>[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([CH:3]([C:2]([CH3:8])([CH3:7])[CH3:1])[C:4]([NH2:11])=[O:5])=[C:19]([Cl:25])[CH:18]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCN(CC)CC
Reactant: Cc1cc(Br)cc(Cl)c1N
Solvent: O
Solvent: CC#N
Product: Cc1cc(Br)cc(Cl)c1C(C(N)=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) and triethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution. of 4-Bromo-2-chloro-6-methylphenylamine (5.0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (7.46 g, 100% yield).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH3:19])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[N:16][NH:17][CH:18]=3)[CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.C(=O)([O-])O.[Na+].I[CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31]>CN(C)C=O>[NH3:4].[CH3:31][O:30][CH2:29][CH2:28][CH2:27][CH2:26][N:4]1[CH2:5][CH2:6][C:7]([CH3:19])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[N:16][NH:17][CH:18]=3)[CH:9]=2)[CH:2]([CH3:1])[CH2:3]1
Reactant: COCCCCI
Reactant: CC1CNCCC1(C)c1cccc(-c2c[nH]nn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCCN1CCC(C)(c2cccc(-c3c[nH]nn3)c2)C(C)C1
Product: N
Temperature: 25 °C
Yield: 46.1 %

Procedure:
To a solution of 3,4-dimethyl-4-(3-(1H-1,2,3-triazol-4-yl)phenyl)piperidine (Preparation 44, 50 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydrogencarbonate (25 mg, 0.29 mmol) and 1-iodo-4-methoxybutane (Preparation 15, 50 mg, 0.23 mmol). The resultant mixture was heated at 60° C. overnight and then cooled to room temperature. The residue given was partitioned between saturated aqueous sodium hydrogencarbonate solution (25 mL) and ether (15 mL). The phases were separated and the aqueous layer was further extracted with ether (2×15 mL). The combined extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography eluting with a gradient of CH2Cl2:MeOH:0.88 ammonia (100:8:1) to give the title compound as a colourless oil (15 mg, 22%).
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[C:9]2=[N:10][CH:11]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:13]=[C:8]2[CH:7]=[CH:6]1)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>C(#N)C>[C:14]([C:12]1[CH:13]=[C:8]2[CH:7]=[CH:6][NH:5][C:9]2=[N:10][CH:11]=1)([CH3:16])=[CH2:15]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(C)(C)O)cnc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: C=C(C)c1cnc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
To 2-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-propan-2-ol (97, 0.500 g, 1.5 mmol) in acetonitrile (10.0 mL) were added triethylsilane (1.00 mL, 6.3 mmol) and trifluoroacetic acid (0.50 mL, 6.5 mmol) under an atmosphere of nitrogen. The reaction was refluxed for 3 hours, then cooled down to room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 50% ethyl acetate in hexane to give the compound (98, 0.200 g, 84%). MS (ESI) [M+H+]+=159.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5](CS([O-])(=O)=O)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:2].[N-:20]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C1COCC1.O>[CH2:1]([O:3][CH2:4][CH:5]([NH2:20])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOCC(COc1ccc(F)cc1)CS(=O)(=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOCC(N)COc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
Dissolve [1-(ethoxymethyl)-2-(4-fluorophenoxy)ethyl]methanesulfonate (2.3 g, 7.87 mmol) in DMF (3 mL) and add sodium azide (1 g, 15.38 mmol) to the mixture. Stir the mixture at 70° C. for 3 hours. Add Et2O (150 mL) and wash with water (3×10 mL). Separate the phases; dry the organic phase over Na2SO4; filter; and concentrate the filtrate under reduced pressure to give a clear oil. Dissolve the oil in a mixture of THF (50 mL) and H2O (12.5 mL). Add triphenylphosphine (3.0 g, 11.44 mmol) and stir at 30° C. for 2 hours. Purify the reaction mixture via SCX-ion exchange chromatography with 1N NH3/MeOH to provide the product fractions. Concentrate the select fractions under reduced pressure and then purify via flash column chromatography using a gradient of 1% to 10% of MeOH in DCM collecting fractions at wavelength of 214 nm. Concentrate under reduced pressure to give the title compound as a colorless oil (880 mg, 33.5%). MS (m/z): 214 (M+1).
Reaction SMILES: C1(NC(N)=S)C=CC=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[F:29])=[S:20])=[C:14]([OH:30])[C:13]=1[S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32].[Si:37](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].N1C=CN=C1>>[F:29][C:23]1[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[C:14]=1[O:30][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])=[S:20]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(F)c2F)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: NC(=S)Nc1ccccc1
Agent: c1c[nH]cn1
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(F)c2F)c1O[Si](C)(C)C(C)(C)C
Yield: 64.7 %

Procedure:
Following the general procedure for protected phenyl thiourea formation outlined in example 12, N-[4-chloro-2-hydroxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2,3-difluorophenyl)thiourea (418 mg, 1.0 mmol), tert-butyldimethylsilyl chloride (745 mg, 5.0 mmol) and imidazole (136 mg, 2.0 mmol) were reacted to form the desired product (347 mg, 65%). EI-MS m/z 536.2 (M+).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[NH2:25][CH:26]([CH2:29][OH:30])[CH2:27][OH:28]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH:26]([CH2:29][OH:30])[CH2:27][OH:28])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: NC(CO)CO
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Product: O=C(NC(CO)CO)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 49 %

Procedure:
As described for example 325, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.61 mmol) was converted, using 2-amino-1,3-propandiol instead of rac-2-amino-1-propanol, to the title compound (117 mg, 49%) which was obtained as a white solid MS: m/e=388.2 [M+H]+.
Reaction SMILES: C1CCC=CC=1.O.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][N:23]2C(OCC2C=CC=CC=2)=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CCO.[Pd]>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][N:18]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][NH:23]2)[CH2:19][CH2:20]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCN(CC2CCCCN2C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1=CCCC=C1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CC2CCCCN2)CC1
Reaction time: 48 h
Yield: 83.2 %

Procedure:
14.5 ml of cyclohexadiene followed by 3.3 g of 10% Pd/C having a 50% water content are added, under an inert atmosphere, to a solution of 6.43 g of the compound obtained in step 6.1, in 50 ml of EtOH. The medium is stirred at AT for 48 hours and then filtered. The filtrate is evaporated, to give 3.63 g of the desired compound.
Reaction SMILES: O[Li].O.[C:4]([O:8][C:9]([N:11]([CH3:46])[C@@H:12]([CH3:45])[C:13]([NH:15][C@H:16]1[CH2:22][O:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][C:32]([C:40]([O:42]C)=[O:41])=[CH:33]3)[C:17]1=[O:44])=[O:14])=[O:10])([CH3:7])([CH3:6])[CH3:5].OS([O-])(=O)=O.[K+]>O.CO>[C:4]([O:8][C:9]([N:11]([CH3:46])[C@@H:12]([CH3:45])[C:13]([NH:15][C@H:16]1[CH2:22][O:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][C:32]([C:40]([OH:42])=[O:41])=[CH:33]3)[C:17]1=[O:44])=[O:14])=[O:10])([CH3:6])([CH3:7])[CH3:5]
Reactant: COC(=O)c1ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc4ccccc43)c(OC)ccc2c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]O
Solvent: O
Solvent: CO
Product: COc1ccc2cc(C(=O)O)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2ccccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
LiOH.H2O (24.0 mg, 573 μmol, Eq: 3) was dissolved in water and the solution was added to a solution of methyl 5-(((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-6-methoxy-2-naphthoate (113 mg, 191 μmol, Eq: 1.00) in MeOH (3 mL) and the mixture was heated to 50° C. for 1 h and then to 60° C. for 1 h. The mixture was cooled, KHSO4 solution was added and the mixture extracted with EtOAc. The combined extracts were concentrated and the residue purified by silica gel chromatography to afford 5-(((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-6-methoxy-2-naphthoic acid (103 mg, 93%) as a white powder.
Reaction SMILES: C(C1CCCN([CH2:14][C:15]([C:17]2[CH:26]=[CH:25][C:20]3[NH:21][C:22](=[O:24])[O:23][C:19]=3[CH:18]=2)=[O:16])C1)C1C=CC=CC=1.O1C2C=CC=CC=2NC1=O.[Cl:37]CC(Cl)=O>>[Cl:37][CH2:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]2[NH:21][C:22](=[O:24])[O:23][C:19]=2[CH:18]=1)=[O:16]
Reactant: O=C(CN1CCCC(Cc2ccccc2)C1)c1ccc2[nH]c(=O)oc2c1
Reactant: O=C(Cl)CCl
Agent: O=c1[nH]c2ccccc2o1
Product: O=C(CCl)c1ccc2[nH]c(=O)oc2c1

Procedure:
from 6-(2-(3-benzylpiperidino)-1-oxoethyl)-2,3-dihydrobenzoxazol-2-one ("P"; obtainable by reaction of 2,3-dihydrobenzoxazol-2-one with chloroacetyl chloride to give 6-chloroacetyl-2,3-dihydrobenzoxazol-2-one ("Q"), then reaction with 3-benzylpiperidine):
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].Cl.[CH3:16][NH:17][O:18][CH3:19].C(N(CC)CC)C.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(Cl)Cl>[CH3:19][O:18][N:17]([CH3:16])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:4]=1
Reactant: CNOC
Reactant: Cc1ccc(C(=O)O)cc1S(N)(=O)=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(C)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3.63 g of 4-methyl-3-sulfamoyl-benzoic acid, 1.92 g of N,O-dimethylhydroxylamine hydrochloride, and 5.02 mL of triethylamine in methylene chloride (120 mL) is treated with 8.32 g of benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate. The reaction mixture is stirred overnight at room temperature, washed sequentially with saturated aqueous sodium bicarbonate, water and a saturated sodium chloride solution, dried (magnesium sulfate) and concentrated in vacuo. The crude material is purified by silica gel chromatography (1:2 hexanes/ethyl acetate) to give N-methoxy-4,N-dimethyl-3-sulfamoyl-benzamide as a white powder. MS (m/z): 257 (M−1); Rf 0.25 (1:2 hexanes/ethyl acetate).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([F:11])[CH:3]=1.[Mg].[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O1CCCC1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([F:11])[CH:3]=1)=[O:19])[CH3:18]
Reactant: Fc1cc(Br)c2occc2c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cc(F)cc2ccoc12
Temperature: 20 °C
Yield: 79 %

Procedure:
Dissolve 7-bromo-5-fluorobenzofuran (2 g, 9.3 mmol) in 5 ml tetrahydrofuran under nitrogen. Add magnesium turnings (0.25 g, 1.1 equivalents) and heat to reflux to facilitate Grignard formation. In a separate flask place diethyl oxalate (1.3 mL, 2 equivalents) in 3 mL tetrahydrofuran, and cool to 0° C. under nitrogen. When Grignard formulation is complete, add via canula to the diethyl oxalate solution. Stir the reaction for 2-4 hours while slowly warming to 20° C. Extract with diethyl ether. Wash organic layer with brine. Dry over magnesium sulfate, filter and concentrate to a light yellow oil. Purifacation by column chromatography (4:1 hexanes:ethyl acetate) affords 1.74 g (79%) of an oil which solidifies upon standing. MS (ES, m/z): 237.0 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH:3]1[O:5][CH2:4]1.CO.C(N(CC)CC)C.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>C(OCC)C>[Br:1][CH2:2][CH:3]([OH:5])[CH2:4][S:25][C:22]1[CH:23]=[CH:24][C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:21]=1
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: BrCC1CO1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)c1ccc(SCC(O)CBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a stirred solution of 75.3 g [46.7 ml (0.55 mole)] 1-bromo-2,3-epoxypropane (epibromohydrin) in 14 ml 1:1 methanol/triethylamine cooled to 0°-5° C. in an ice-water bath, 83 g (0.5 mole) p-tert-butyl-thiophenol was added dropwise. After the addition was complete, the reaction mixture was allowed to come to room temperature and was stirred at room temperature for about 2 hours. The reaction mixture was dissolved in ethyl ether; washed with 1N sodium hydroxide, with 2N hydrochloric acid, with water until neutral and then with brine (twice). The organic phase was dried, filtered and concentrated to give 140.6 g of the above-identified product as an orange-red oil.
Reaction SMILES: C1(C([NH:20][CH:21]2[C:41](=[O:42])[N:23]3[CH:24]([C:29]4[N:33]([CH2:34][C:35]5[O:39][C:38]([CH3:40])=[CH:37][CH:36]=5)[N:32]=[N:31][N:30]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[NH2:20][CH:21]1[C:41](=[O:42])[N:23]2[CH:24]([C:29]3[N:33]([CH2:34][C:35]4[O:39][C:38]([CH3:40])=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]12
Reactant: Cc1ccc(Cn2nnnc2C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(C)C)o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(Cn2nnnc2C2N3C(=O)C(N)[C@H]3SC2(C)C)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a stirred solution of 1.827 g. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[5-methylfurfuryl]tetrazol-5-yl)penam in 3 ml. of acetone is added a solution of 0.59 g. of p-toluenesulfonic acid monohydrate in 2 ml. of acetone. The mixture is stirred at ambient temperature for 30 minutes, and then the precipitate which has formed is filtered off. This affords 0.87 g. (54% yield) of the title compound as its p-toluenesulfonate salt. The NMR spectrum of the product (CDCl3) shows absorptions at 7.28 ppm (q, 4H), 6.50 ppm (d, 1H), 6.01 ppm (s, 1H), 5.86 ppm (s, 2H), 5.71 ppm (s, 1H), 5.68 ppm (d, 1H), 5.09 ppm (d, 1H), 2.00 ppm (2s, 6H), 1.66 ppm (s, 3H) and 0.88 ppm (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[C:15](Cl)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O>[CH3:1][C:2]1([CH3:14])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=2)[O:3]1
Reactant: CC1(C)CC(C)(C)c2ccccc2O1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice bath cooled solution of 2 g (10.53 mmol) of 2,2,4,4-tetramethylchroman (Compound 40) in 25 ml of nitromethane was added, under nitrogen, 941 mg (11.99 mmol) of acetyl chloride followed by 1.59 g (11.92) mmol) of aluminum chloride. The cooling bath was then removed and the mixture stirred at room temperature for 16 h. The mixture was then cooled again in an ice bath and treated with 25 ml of conc. HCl. The mixture was then filtered and the residue washed with methylene chloride. The filtrate was concentrated in vacuo and the resultant residue was purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give the title compound as a yellow oil. PMR (CDCl3): & 1.38 (6H, s), 1.39 (6H, s), 1.87 (2H, s), 2.56 (3H, s), 6.83 (1H, d, J-8.7 Hz), 7.71 (1H, dd, J-8.7 Hz, 2.1 Hz), 7.98 (1H, d, J-2.1 Hz). MS exact mass, m/e 232.1468 (calcd. for C13H20O2, 232.1464).