Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[C:12]([O:16][C:17]([N:19]1[C@@H:23]([CH3:24])[CH2:22]OS1(=O)=O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:18])[NH:19][C@@H:23]([CH3:22])[CH2:24][N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: C[C@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Reactant: N#Cc1ccc2[nH]ccc2c1
Product: C[C@@H](Cn1ccc2cc(C#N)ccc21)NC(=O)OC(C)(C)C

Procedure:
This compound was obtained according to example 4, step A] from 5-cyanoindole (500 mg) and (S)-4-methyl-2,2-dioxo-[1,2,3] oxathiazolidine-3-carboxylic acid tert-butyl ester IV (1.0 g). Yield: 1.09 g, yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C[O:11][C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17]C)=[O:16].CC(C)([O-])C.[K+].[OH-].[Na+]>C(O)(C)(C)C.CO>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:13](\[CH2:14][C:15]([OH:17])=[O:16])/[C:12]([OH:19])=[O:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)CCC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CO
Product: O=C(O)C/C(=C\c1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Yield: 41 %

Procedure:
A solution of 4-fluorobenzaldehyde (1.0 g, 8.05 mmol) and dimethylsuccinate (1.41 g, 9.66 mmol) in tert-butanol (2 mL) was added drop-wise within 30 minutes to a refluxing mixture of potassium tert-butoxide (0.994 g, 8.86 mmol) in tert-butanol (8 mL). Refluxing was continued until all the starting material was consumed as demonstrated by TLC analysis. The reaction temperature was warmed to room temperature, and tert-butanol was removed in vacuo. The residue was dissolved in 1.0 N aqueous HCl (10 mL) and was extracted with ethyl acetate (2×5 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an oil. This crude product was dissolved in methanol (10 mL). An aqueous solution of 2.0 N NaOH (10 mL) was added into the solution at room temperature and the mixture was refluxed overnight. The resulting suspension was concentrated, and the obtained residue was dissolved in water (10 mL). The resulting solution was washed with ethyl acetate (2×10 mL). The aqueous layer was acidified (pH˜2) with the drop wise addition of concentrated HCl. The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude residue. Crystallization from ether/hexane gave 2-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-succinic acid (0.74 g, 41%) as a white solid. MS cald. for C11H8FO4 [(M−H)−]: 223, obsd. 223.1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.[CH3:12][S:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>C1COCC1>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:18]([C:17]1[CH:20]=[CH:21][C:14]([S:13][CH3:12])=[CH:15][CH:16]=1)[OH:19]
Reactant: CSc1ccc(C=O)cc1
Reactant: Cn1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(C(O)c2nccn2C)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-methylimidazole (10.0 g, 122 mmol) in 500 mL THF at −78° C. was added n-butyllithium (2.5M in hexanes, 48.7 ml, 118 mmol) dropwise and the resulting solution was stirred at −78° C. for 30min. 4-(Methylthio)benzaldehyde (14.73 ml, 110 mmol) was then added at −78° C. and the mixture was stirred until completion by TLC, and quenched with NH4Cl (sat). The mixture was then diluted with EtOAc, extracted and washed (NaHCO3 (sat.), brine). The organic phase was dried over MgSO4, filtered and concentrated. Crystalisation (EtOAc/Hexanes) yielded (1-Methyl-1H-imidazol-2-yl)[4-(methylthio)phenyl]methanol.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:30]([O:31][CH2:32][CH:33]3[CH2:37][CH2:36][O:35][CH2:34]3)=[CH:29][CH:28]=[CH:27][C:26]=2[F:38])[C:21]([Cl:39])=[CH:20][N:19]=1>>[Cl:39][C:21]1[C:22]([NH:24][C:25]2[C:30]([O:31][CH2:32][CH:33]3[CH2:37][CH2:36][O:35][CH2:34]3)=[CH:29][CH:28]=[CH:27][C:26]=2[F:38])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: Fc1cccc(OCC2CCOC2)c1Nc1nc(Cl)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OCC4CCOC4)n3)cc2CC1

Procedure:
5-Chloro-N(4)-[2-fluoro-6-(tetrahydro-furan-3-ylmethoxy)-phenyl]-N(2)-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-pyrimidine-2,4-diamine was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(tetrahydro-furan-3-ylmethoxy)-phenyl]-amine in an analogous manner to Example 1221d. Title compound was isolated as a white solid (90 mg, 62%) HPLC purity=99%, LCMS=542.21 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.63 (bs, 1H), 9.28 (s, 1H), 8.49 (s, 1H), 8.09 (s, 1H), 7.40-7.34 (m, 1H0, 7.26 (s, 1H), 7.13 (d, J=7.7 Hz, 1H), 7.02-6.93 (m, 2H), 6.85 (d, J=8.5 Hz, 1H), 3.92-3.85 (m, 2H), 3.71-3.69 (m, 1H), 3.63-3.52 (m, 6H), 3.41-3.23 (m, 7H), 3.12-2.82 (m, 6H), 1.82-1.77 (m, 1H), 1.50-1.46 (m, 1H).
Reaction SMILES: C([Al](CC)CC)C.[Cl-].C([Al+]CC)C.[NH:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.CC1C=CC(O)=C(C)C=1.C[C:29]1[NH:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2>>[NH:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:29]1.[NH:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1
Reactant: Cc1cc2ccccc2[nH]1
Agent: CC[Al+]CC
Agent: CC[Al](CC)CC
Agent: Cc1ccc(O)c(C)c1
Solvent: c1cc[nH]c1
Product: c1ccc2[nH]ccc2c1
Reaction time: 0.25 h

Procedure:
A catalyst solution was prepared using the standard procedure described here, in which the molar ratios of TEA (triethylaluminum) to DEAC (diethylaluminum chloride) to pyrrole compound to Cr were standardized to TEA:DEAC:pyrrole:Cr=11:8:3:1. Anhydrous, degassed ethylbenzene was added to a dry vial in a drybox. To this vial was added neat triethylaluminum (TEA) and neat diethylaluminum chloride (DEAC). The contents were mixed and allowed to stand for 15 minutes. The selected pyrrole was then slowly added, as gas evolution was observed in most cases. Chromium(III) 2-ethylhexanoate (7.25 wt % Cr in ethylbenzene) was used as the transition metal compound and was added slowly to the alkylaluminum/pyrrole solution with stirring. The catalyst solution was diluted to a concentration of 5.6 mg Cr/mL by adding an appropriate amount of ethylbenzene to constitute the active catalyst what was used as prepared. Orange colored solutions were observed for 2,4-DMP, 2-methylindole, and 2,5-DEP based catalyst, which are typical. 2,5-DBP initially produced an orange solution, but gradually precipitated a noticeable amount of grey solid over the course of 24 h. Both indole and pyrrole produced an orange solution with a white, fluffy solid which was removed by filtration. 2,5-DIP produced copious amounts of black precipitate suggesting that the catalyst solution was fairly unstable
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]3[N:22]([CH2:23][Si](C)(C)C)[N:21]=[N:20][CH:19]=3)[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[N:21]=[N:20][CH:19]=3)[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2cnnn2C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2cnnn2C)c1
Reaction time: 16 h
Yield: 85.9 %

Procedure:
To a solution of methyl 3-(5-methylpyridin-2-yl)-5-{1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-5-yl}benzoate (122 mg, 0.321 mmol) in THF (5 mL) was added 2 M tetrabutylammonium fluoride in THF (1.60 mL, 3.20 mmol). After 16 h, the mixture was distributed between 100 ml of dichloromethane and 100 ml of 1 M ammonium chloride solution. The organic layer was washed with 50 mL of brine and concentrated to give title compound (85 mg). MS 309.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[NH:17]1[CH2:21][CH2:20][C@@H:19]([CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18]1.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:21][CH2:20][C@@H:19]([CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:18]2)=[N:5][CH:4]=1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Reactant: O=C(NC[C@@H]1CCNC1)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CC[C@@H](CNC(=O)OCc4ccccc4)C3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (0.500 g, 2.29 mmol) 1:4 (MeOH/CH2Cl2) (40 mL) were added phenylmethyl [(3R)-3-pyrrolidinyl-methyl]carbamate (for a synthesis see WO2006002047 Preparation 23(b)) (0.536 g, 2.29 mmol) and triethylamine (0.351 mL, 2.52 mmol) and the resulting solution stirred at ambient temperature for 1 h. Na(OAc)3BH (1.46 g, 6.87 mmol) was added and the solution stirred an additional 18 hours. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column [0-100% CHCl3/(90:10:1) CHCl3/MeOH/NH4OH)] to yield a colorless oil, (0.333 g, 33%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.[N:17]1([CH2:23][CH2:24]O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:24][CH2:23][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:11][CH:10]=2)[O:5]1
Reactant: OCCN1CCOCC1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(OCCN3CCOCC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a stirring solution of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenol (2.55 g, 11.58 mmol), 2-morpholin-4-ylethanol (1.60 mL, 1.73 g, 13.2 mmol) and triphenyl phosphine (3.64 g, 13.9 mmol) in methylene chloride (60 mL) at 0° C. was added dropwise DIAD (2.82 g, 13.9 mmol). The reaction was allowed to warm to room temperature and stir overnight. After 18 hours, additional portions of triphenyl phosphine (1.51 g, 5.8 mmol), 2-morpholin-4-ylethanol (0.70 mL, 5.8 mmol), and DIAD (1.17 g, 5.8 mmol) were added. After stirring an additional 2 hours at room temperature the reaction was concentrated and the residue purified by flash chromatography (5% to 25% EtOAc in CHCl3) to provide the product as a white solid (2.855 g, 74%).
Reaction SMILES: [NH3:1].[F:2][C:3]1([F:34])[C:32](=S)[NH:31][C:5]2([C:18]3[CH:17]=[C:16]([O:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:14][C:13]=3[O:12][C:11]3[C:6]2=[CH:7][C:8]([C:25]2[CH:26]=[N:27][CH:28]=[N:29][CH:30]=2)=[CH:9][CH:10]=3)[CH2:4]1>C1COCC1.[Hg](Cl)Cl>[F:2][C:3]1([F:34])[C:32]([NH2:1])=[N:31][C:5]2([C:18]3[CH:17]=[C:16]([O:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:14][C:13]=3[O:12][C:11]3[C:6]2=[CH:7][C:8]([C:25]2[CH:26]=[N:27][CH:28]=[N:29][CH:30]=2)=[CH:9][CH:10]=3)[CH2:4]1
Reactant: CC(C)(C)COc1ccc2c(c1)C1(CC(F)(F)C(=S)N1)c1cc(-c3cncnc3)ccc1O2
Reactant: N
Agent: Cl[Hg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)COc1ccc2c(c1)C1(CC(F)(F)C(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 55 °C
Reaction time: 14 h

Procedure:
Ammonia gas was bubbled through a solution of 4,4-difluoro-2′-(neopentyloxy)-7′-(pyrimidin-5-yl)spiro[pyrrolidine-2,9′-xanthene]-5-thione (0.013 g, 0.028 mmol) in THF (0.350 mL) at 55° C. for 2 minutes. Mercury(II) chloride (0.011 g, 0.042 mmol) was added in one portion and ammonia gas was bubbled through for 3 more minutes while heating at 55° C. (THF solution replenished as necessary to maintain a volume of ˜0.2-0.3 mL). The resulting reaction was stirred at 55° C. under nitrogen atmosphere for 14 hours. After cooling, the reaction was partitioned between CH2Cl2 (25 mL) and water (10 mL). The reaction mixture was diluted with a 10:1 mixture of saturated aqueous ammonium chloride/ammonium hydroxide, the layers were separated and the aqueous layer was extracted with CH2Cl2 (3×25 mL). The combined organic extracts were washed with a 10:1 mixture of saturated aqueous ammonium chloride/ammonium hydroxide, water, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to provide a residue that was purified by filtering through a pad of silica gel by eluting with 1:10 MeOH 2 M ammonia solution in CH2Cl2 followed by further purification by preparative thin layer chromatography (20:1 CHCl3/MeOH) to provide 4,4-difluoro-2′-(neopentyloxy)-7′-(pyrimidin-5-yl)-3,4-dihydrospiro[pyrrole-2,9′-xanthen]-5-amine as a white solid after triturating with pentane. MS m/z=451.2 [M+H]. This procedure is analogous to that described in Foloppe et al, Tetrahedron Letters, 33, 20, pp. 2803-2804, 1992.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[CH:11][CH:12]=2)[NH:7][C:6](=[O:30])[CH:5]=1>C(O)C.[Pd]>[ClH:1].[ClH:1].[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][N:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:22][CH2:23]3)=[CH:11][CH:12]=2)[NH:7][C:6](=[O:30])[CH2:5]1
Reactant: Cc1cc(=O)[nH]c2cc(OCCCN3CCN(c4ccccc4)CC3)ccc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1CC(=O)Nc2cc(OCCCN3CCN(c4ccccc4)CC3)ccc21
Reaction time: 8 h
Yield: 119.5 %

Procedure:
1.0 gram of 4-methyl-7-[3-(4-phenylpiperazinyl)-propoxy]carbostyril dihydrochloride and 0.3 g of palladium black are dispersed in 200 ml of ethanol under hydrogen at a pressure of 2 atmospheres at room temperature and catalytic reduction is carried out at 70°-80° C. for 8 hours. After cooling the reaction mixture, the palladium black is removed by filtration and the mother liquor is concentrated to dryness. The residue is recrystallized from a mixture of methanol-ether to obtain 0.6 g (yield: 60%) of 4-methyl-7-[3-(4-phenylpiperazinyl)-propoxy]-3,4-dihydrocarbostyril.dihydrochloride.dihydrate in the form of colorless crystals with a melting point of 260°-265° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:17][S:18](Cl)(=[O:20])=[O:19].[Na+].[Cl-]>O.C1(C)C=CC=CC=1>[CH3:17][S:18]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)OC1CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-piperidinol (23.98 g), 168.66 g of toluene and 83.56 g of a 30% aqueous solution of NaOH were respectively weighed and placed in a 500-mL four-necked flask. While the mixture was stirred, the flask inside temperature was lowered to 6.7° C. Then, 31.73 g of methanesulfonyl chloride was added dropwise over 4 hours and 30 minutes at a flask inside temperature of 5 to 10° C. Water (33 mL) was added to dissolve the NaCl which had precipitated out in the aqueous phase, and the mixture was separated into the toluene phase and aqueous phase. A toluene solution of 1-benzyl-4-piperidinol methanesulfonate was thus obtained in a yield of 40.3 mole percent.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: NS(=O)(=O)c1cc2ccccc2o1
Product: Cc1ccc(NC(=O)NS(=O)(=O)c2cc3ccccc3o2)cc1
Yield: 63.7 %

Procedure:
2-Benzofuransulfonamide (7.6 mmol), prepared as described in Example 1, was reacted with 4-methylphenylisocyanate (7.6 mmol) as described in Method A to obtain 1.6 g of the title product as a solid. 1H NMR (CD3SOCD3): δ8.91 (s, 1 H), 7.87 (d, J =8 Hz, 1 H), 7.81 (s, 1 H), 7.76 (d, J =8 Hz, 1 H), 7.57 (dd, J =8, 8 Hz, 1 H), 7.42 (dd, J =8, 8 Hz, 1 H), 7.28 (d, J =9 Hz, 2 H), 7.07 (d, J =9 Hz, 2 H), 2.23 (s, 3 H). Analysis for C16H14N2O4S:
Reaction SMILES: C(OC(N1CCN([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)CC1)=O)(C)(C)C.Cl.[C@H:32]12[CH2:38][C@H:35]([NH:36][CH2:37]1)[CH2:34][N:33]2[C:39]([NH2:41])=[O:40]>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:36]3[CH2:37][C@@H:32]4[CH2:38][C@H:35]3[CH2:34][N:33]4[C:39]([NH2:41])=[O:40])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: NC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Agent: Cl
Product: NC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc([C@H]2COc3cccnc3O2)cc1

Procedure:
Compound 268 is synthesized from Intermediate C and Intermediate P according to General Method J. (LC/MS method 16: ES+ m/z 367.3 [M+H]+, Rt=0.27 min)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[N:12][O:13][CH3:14])[C:9]([OH:11])=O)[N:3]=1.P(Cl)(Cl)(Cl)=O.[NH2:20][CH:21]1[C:41](=[O:42])[N:23]2[C:24]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])=[CH:25][CH2:26][S:27][C@H:22]12.C[Si](CC(N)=O)(C)C>C(Cl)Cl.CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[N:12][O:13][CH3:14])[C:9]([NH:20][CH:21]2[C:41](=[O:42])[N:23]3[C:24]([C:28]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=4)=[O:29])=[CH:25][CH2:26][S:27][C@H:22]23)=[O:11])[N:3]=1
Reactant: CON=C(C(=O)O)c1nccc(N)n1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1nccc(N)n1
Temperature: 3 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
A mixture of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (2.32 g) and phosphoryl chloride (4.6 g) in methylene chloride (15 ml) was stirred for 30 minutes at 3° C. To the mixture was added dropwise a solution of N,N-dimethylformamide (3.0 ml) in methylene chloride (15 ml) and stirred for 40 minutes at 3° C. A solution of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (3.20 g) and trimethylsilyl acetamide (15 g) in methylene chloride (60 ml) was cooled to -5° C. and added to the activated acid solution obtained above. The mixture was stirred for 30 minutes at 3° to 5° C. and for additional 30 minutes at ambient temperature. The solvent was evaporated to dryness and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with an aqueous solution of sodium bicarbonate and water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was washed with diethyl ether to give 4-nitrobenzyl 7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) (3.1 g) as a powder, mp 125°-131° C. (dec.).
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[I:8][CH:9]([I:20])[S:10]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]>C(O)(=O)C>[I:20][CH:9]([I:8])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([N:17]2[C:4](=[O:5])[CH:3]=[CH:2][C:1]2=[O:7])=[CH:18][CH:19]=1)(=[O:12])=[O:11]
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(S(=O)(=O)C(I)I)cc1
Solvent: CC(=O)O
Product: O=C1C=CC(=O)N1c1ccc(S(=O)(=O)C(I)I)cc1

Procedure:
A mixture of 8.1 g. of maleic anhydride and 31.7 g. of p-(diiodomethylsulfonyl)aniline in 160 ml. of glacial acetic acid is treated in the fashion of Example 2 to produce crude N-[p-(diiodomethylsulfonyl)phenyl]maleimide. This material is washed with water, air-dried, and recrystallized from acetone to a pale, crystalline powder, m.p. 217° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)=[O:12])[CH2:6]1.[O:23]=[C:24]1[NH:28][CH:27]=[C:26]([C:29](O)=[O:30])[O:25]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]([CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([Cl:22])[CH:18]=[C:19]([Cl:21])[CH:20]=2)=[O:12])[CH2:6]1)[C:29]([C:26]1[O:25][C:24](=[O:23])[NH:28][CH:27]=1)=[O:30]
Reactant: O=C(O)c1c[nH]c(=O)o1
Reactant: CNCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1)C(=O)c1c[nH]c(=O)o1

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 2-(2-(methylamino)ethyl)morpholine-4-carboxylate (step 2)(169 mg, 0.487 mmol), 2-oxo-2,3-dihydrooxazole-5-carboxylic acid ((Example 21, step 1)) (161 mg, 0.487 mmol), T3P® (50% in DMF) (426 μl, 0.730 mmol) and Huenig's base (425 μl, 2.433 mmol) in DMF (1622 μl) was stirred at room temperature for 20 hours. The resulting mixture was diluted with EtOAc and washed with water. The organic portion was dried with MgSO4, filtered and concentrated under reduced pressure. The crude material was dry loaded with silica onto an ISCO 4 g column eluting with 0-100% EtOAc (1% acetic acid) in iso-hexane. The product fractions were concentrated under reduced pressure to afford the title compound;
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH:35][CH3:36])[CH:32]([CH3:34])[CH3:33]>>[CH2:31]([N:35]([CH3:36])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH:32]([CH3:34])[CH3:33]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Reactant: CNCC(C)C
Product: CC(C)CN(C)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1

Procedure:
The product from Example 23D and isobutyl(methyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.82 (m, 1H), 7.74 (d, J=8.1, 2H), 7.58 (m, 2H), 7.51 (d, J=8.1 Hz, 2H), 6.81 (s, 1H), 3.3-3.8 (m, 14H), 2.96 (s, 3H), 2.2 (m, 1H), 1.09 (d, J=6.6 Hz, 6H); MS (DCI) m/z 421 (M+H)+;
Reaction SMILES: [OH:1][CH:2]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:33])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:32])[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>ClCCl>[OH:1][CH:2]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:33])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:32])[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][S:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:42]
Reactant: O=C(CCCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)CSc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(CCCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)CS(=O)c1ccccc1

Procedure:
(2S)-2-[1-Hydroxy-2-(phenylthio)ethyl]-1-[N-(4-phenyl-butyryl)-L-prolyl]pyrrolidine (1.25 g) was subjected to oxidation in the same manner as in Example 2-A) in dichloromethane (9 ml) using 1.1 equivalent of m-chloroperbenzoic acid to give 1.18 g of (2S)-2-[1-hydroxy-2-(phenylsulfinyl)ethyl]-1-[N-(4-phenylbutyryl)-L-prolyl]-pyrrolidine.