Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[OH:19])#[N:11].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:19][C:13]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=1[C:10]#[N:11]
Reactant: N#Cc1cc(Cl)ccc1O
Reactant: BrCc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccc1OCc1ccccc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
To a stirred mixture of 2-bromo-benzyl bromide (5.00 g, 20.0 mmol) and 2-cyano-4-chloro-phenol (13.2 g, 21.0 mmol) in anhydrous DMF under argon was added 95% NaH (0.56 g, 22.0 mmol) portionwise. This reaction mixture was stirred at room temperature for 1.5 hours and then quenched with water. The resulting mixture was diluted with ether (400 mL), and washed sequentially with water (3×100 mL), 1N NaOH solution (2×30 mL), saturated NaHCO3 solution (1×60 mL) and brine (1×60 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 5.30 g of 2-(2-Bromo-benzyloxy)-5-chloro-benzonitrile Example 348A in 82% yield. HPLC Rt=3.89 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H=322
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19]O)[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Br)(Br)[Br:22].O.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][Br:22])[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: BrP(Br)Br
Reactant: COc1ccc(CCN2CCCC(CO)C2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CCN2CCCC(CBr)C2)cc1OC
Temperature: 0 °C
Reaction time: 15 h

Procedure:
4.4 g (0.0157 mol) of N-[2-(3,4-dimethoxy-phenyl)-ethyl]-3(hydroxymethyl)-piperidine are dissolved in 70 ml of carbon tetrachloride and cooled to 0° C. Then 1.63 ml (0.0173 mol) of phosphorus tribromide is added, whereupon a bulky precipitate is immediately formed. The mixture is stirred for 15 hours at ambient temperature, water is added and the mixture is neutralized with 2 molar sodium hydroxide solution. The organic phase is separated off, washed with water, dried over magnesium sulphate, concentrated by evaporation in vacuo and purified over 310 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to 5%). Yield: 2.0 g (37.2% of theory), Rf value: 0.5 (aluminium oxide neutral, eluant: 2% ethanol in methylene chloride).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:21])[N:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)CC)C>O1CCOCC1>[Br:21][C:4]1[N:3]=[C:2]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)(=[O:10])=[O:9])[CH:5]=1
Reactant: C1CNCCN1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)c1cc(Br)nc(Br)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)c1cc(Br)nc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.2 %

Procedure:
0.222 g (0.0005 mol) of 2,6-dibromo-4-(3-trifluoromethylbenzenesulphonyl)-pyridine was dissolved in 10 ml of dioxan and treated with 0.047 g (0.00055 mol) of piperazine and 0.7 ml of triethylamine. The mixture was stirred at room temperature for 20 hrs. and subsequently at 40° C. for 3 hrs., the solvent was then removed and the residue was chromatographed on silica gel with 5% methanol in dichloromethane. There was obtained 0.14 g (62%) of 1-[6-bromo-4-(3-trifluoromethylbenzenesulphonyl)-pyridin-2-yl]-piperazine as yellow crystals; m.p.: 160-162° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3([C:23]([OH:25])=O)[CH2:22][CH2:21]3)=[O:19])=[C:13]([F:26])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>O1CCCC1>[F:26][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[NH:17][C:18]([C:20]1([C:23](=[O:25])[NH:32][C:31]2[CH:33]=[CH:34][C:28]([F:27])=[CH:29][CH:30]=2)[CH2:22][CH2:21]1)=[O:19])[O:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([C:1]([NH2:2])=[O:3])[CH:9]=1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)O)CC3)c(F)c2)ccn1
Reactant: Nc1ccc(F)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 87.1 %

Procedure:
To a suspension of 1-[4-(2-carbamoylpyridin-4-yl)oxy-2-fluorophenylaminocarbonyl]cyclopropanecarboxylic acid (743 mg) and 4-fluoroaniline (459 mg) in tetrahydrofuran (30 ml) was added 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (1.22 g), followed by stirring at room temperature for 7.5 hr. The reaction mixture was partitioned between ethyl acetate and an aqueous solution of sodium hydrogencarbonate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the resultant residue was suspended by addition of tert-butyl methyl ether—ethyl acetate (1:1, 20 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as a white solid (815 mg, 87%).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([C:23]([F:26])([F:25])[F:24])[N:8]=2)[CH:6]=1.[C:27]([NH:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[CH:12]=[C:11]([C:13]4[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:17][CH:18]=4)[CH:10]=[C:9]([C:23]([F:26])([F:25])[F:24])[N:8]=3)[CH:6]=2)[CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(-c2cc(-n3cnc(I)c3)nc(C(F)(F)F)c2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)c1

Procedure:
The title compound was prepared from 2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.93) (0.200 g, 0.41 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.117 g, 0.46 mmol) according to the general procedure VI. Obtained as a white solid (0.120 g, 51%). MS (ISP) 569.2 [(M+H)+].
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[O:15]=[C:16]1[C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:31][CH3:32])[CH:23]=2)[CH2:18][CH2:17]1.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].CO>C(OCC)(=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:28]3[CH2:29][CH2:30][C:25]4([C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:31][CH3:32])[CH:23]=5)[CH2:18][CH2:17][C:16]4=[O:15])[CH2:26][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: COc1ccc2c(c1)C1(CCNCC1)C(=O)CC2
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(c1)C1(CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC1)C(=O)CC2

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 3,4-dihydro-2-oxo-7-methoxyspiro[naphthalene-1(2H),4'-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 55% overall yield. FDMS m/e=434 (M+ of free base). α[D]589 =-5.55(c=0.54, methanol).
Reaction SMILES: C1([C@@H](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)N2CC[C@](CC(O)(C)C)(C3C=CC=CC=3)OC2=O)CC1.Br[C:39]1[CH:44]=[CH:43][C:42]([C@H:45]([CH:64]2[CH2:66][CH2:65]2)[N:46]2[CH2:51][CH2:50][C@:49]([CH2:58][C:59]([OH:62])([CH3:61])[CH3:60])([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48][C:47]2=[O:63])=[CH:41][CH:40]=1.Br[C:68]1[CH:69]=[N:70][C:71]([CH3:74])=[N:72][CH:73]=1>>[CH:64]1([C@@H:45]([C:42]2[CH:43]=[CH:44][C:39]([C:68]3[CH:69]=[N:70][C:71]([CH3:74])=[N:72][CH:73]=3)=[CH:40][CH:41]=2)[N:46]2[CH2:51][CH2:50][C@:49]([CH2:58][C:59]([OH:62])([CH3:61])[CH3:60])([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48][C:47]2=[O:63])[CH2:66][CH2:65]1
Reactant: Cc1ncc(Br)cn1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H](c2ccc(Br)cc2)C2CC2)C(=O)O1
Agent: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C2CC2)C(=O)O1
Product: Cc1ncc(-c2ccc([C@H](C3CC3)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from 3-{(S)-cyclopropyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one {prepared in analogy to the intermediate in Example 3 from 3-[(S)-(4-bromo-phenyl)-cyclopropyl-methyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one} and 5-bromo-2-methyl-pyrimidine following a procedure analogous to that described in Example 3. LC-MS (Method 1): tR=3.28 min; Mass spectrum (ESI+): m/z=472 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[Br:18]N1C(=O)CCC1=O.Cl(O)(=O)(=O)=O>ClCCl>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][C:8]([Br:18])=[C:3]([O:2][CH3:1])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: COc1cccc(OC)c1-c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: COc1ccc(Br)c(OC)c1-c1ccccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
1,3-Dimethoxy-2-(tol-2-yl)-benzene 1, (10 g, 43.86 mmol), N-bromosuccinimide (8.26 g, 46.4 mmol), and perchloric acid (70%, 0.5 ml) were mixed in dichloromethane (200 ml) and stirred for 4 hrs at room temperature. The reaction mixture was quenched with sodium bicarbonate solution (5%, 100 ml), the dichloromethane layer was washed with water (100 ml), brine (100 ml), and the solvent was removed. The crude product was purified by silica-gel chromatography eluting with hexane and ethyl acetate (0% to 10% ethyl acetate) yielding 10.8 g (80%) of 2.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>C1COCC1>[CH2:3]([O:9][C:11]1[C:15]([C:16]2[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCO
Reactant: Cc1ccc(-c2nsnc2Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCOc1nsnc1-c1ccc(C)nc1
Reaction time: 2 h

Procedure:
Sodium hydride (0.72 g, 15 mmol) was dissolved in dry THF (20 ml) and 1-hexanol (1.53 g, 15 mmol) and a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)-6-methylpyridine (1.06 g, 5 mmol) in dry THF (15 ml) was added. The reaction mixture was stirred for 2 h. After addition of water the mixture was extracted with ether, and the ether phase was dried and evaporated. The residue consisted of the crude title compound, which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[OH:25])=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].[CH2:26](O)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[O:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2O)c1
Reactant: OCCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A mixture of 5-chloro-2-hydroxy-[1,1′;2′,1″]terphenyl-3″-carboxylic acid ethyl ester (100 mg, 0.28 mmol), phenethyl alcohol (31 mg, 0.25 mmol), triphenyl phosphine (74 mg, 0.28 mmol), diisopropyl azodicarboxylate (57 mg, 0.28 mmol) in THF (6 ml) was stirred at room temperature overnight. The mixture was then poured into water and extracted with ether, the organic layers were dried over MgSO4 and evaporated. The residue was chromatographed through an SPE column using iso-hexane to yield the title compound (95 mg, 80%) as an oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:15]1[C:25]2=[C:26]3[C:21](=[CH:22][CH:23]=[CH:24]2)[CH2:20][CH2:19][C:18](=[O:27])[N:17]3[CH2:16]1.N.C1(C)C(CC#N)=CC=CC=1>O>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH2:11][C:12]([C:23]2[CH:22]=[C:21]3[C:26]4=[C:25]([CH2:15][CH2:16][N:17]4[C:18](=[O:27])[CH2:19][CH2:20]3)[CH:24]=2)=[O:14])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CCC(=O)O)CC1
Reactant: O=C1CCc2cccc3c2N1CC3
Agent: Cc1ccccc1CC#N
Agent: N
Solvent: O
Product: CC(=O)N1CCC(CCC(=O)c2cc3c4c(c2)CCN4C(=O)CC3)CC1
Temperature: 105 °C
Reaction time: 7 h
Yield: 98 %

Procedure:
A mixture of 1-acetyl-4-piperidinepropionic acid (1.99 g, 9.99 mmol), 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one (1.73 g, 9.99 mmol) and polyphosphoric acid (24 g) was stirred at about 105° C. for 7 hours under nitrogen. Cold water (16 mL) at about 5° C. was slowly added dropwise thereto at −40 to 70° C. and 25% aqueous ammonia was added dropwise thereto at 40 to 50° C. to adjust pH to 8.5. A mixture of toluene-acetonitrile (1:1) (20 mL) was added. The layers were separated, a mixture of toluene-acetonitrile (1:1) (10 mL) was added to the aqueous layer, and the layers were separated. The organic layers were combined, and concentrated to a volume of the solution of ⅕. Diisoporpyl ether (7 mL) was added to the residue to precipitate crystals. The mixture was stirred at about 25° C. for about 1 hour and then at 0 to 5° C. for about 1 hour. Precipitated crystals were separated, washed with diisopropyl ether (3 mL) and dried to obtain 3.47 g (yield 98.6%) of the desired compound as crystals.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[C:43]([NH2:51])(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[N:46][CH:45]=1.C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:46]4[CH:47]=[CH:48][CH:49]=[C:44]([C:43](=[O:50])[NH2:51])[CH:45]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Reactant: NC(=O)c1cccnc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3cccc(C(N)=O)c3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 3.9 %

Procedure:
To a solution of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole) in DMSO (2 ml) was added nicotinamide (244 mg, 2 mmoles), and the mixture was stirred at ambient temperature for 1.5 hours and poured into ethyl acetate (200 ml) with stirring. The resulting precipitate was collected by filtration. The quaternized salt (500 mg) was dissolved in HCOOH (5 ml) in the presence of sodium bisulfite (50 mg), and the mixture was heated at 40°-50° C. for 40 minutes, with stirring, and evaporated to dryness. The residue was dissolved in water (40 ml) and an insoluble solid was filtered off and washed with a small amount of water. The filtrate and wash were combined and chromatographed on a reverse phase column, PrepPAK-500/C18 (100 ml). After elution with water and 5%, 10% and 20% aqueous CH3OH, successively, the fractions containing the desired material were combined, concentrated in vacuo and freeze-dried to yield 21 mg (3.8%) of the title compound (I-1G) (E) as a yellow powder. Mp. >175° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12])[CH3:2].[Br:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([NH2:24])=[CH:17][C:16]=1[CH3:25]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:24][C:18]1[CH:19]=[C:20]([N+:21]([O-:23])=[O:22])[C:15]([Br:14])=[C:16]([CH3:25])[CH:17]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)CCCCCN=C=O
Reactant: Cc1cc(N)cc([N+](=O)[O-])c1Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(Br)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 36 %

Procedure:
6-Isocyanato-hexanoic acid ethyl ester (370 μL, 2.16 mmol) was added to a solution of 4-bromo-3-methyl-5-nitro-phenylamine (250 mg, 1.08 mmol, Example 135: step a) in CH2Cl2 (5 mL, anhydrous) at rt. The reaction mixture was stirred overnight, then diluted in EtOAc and washed with saturated NH4Cl solution, water, and brine. The organic layer was dried over magnesium sulfate. Removal of solvents in vacuo was followed by flash chromatography (50–75% EtOAc/hexanes) to afford the title compound as a brown oil (162 mg, 36%). 1H-NMR (CDCl3): δ 7.59 (d, 1H, J=2.56 Hz), 7.42–7.48 (m, 1H), 4.10–4.17 (m, 2H), 3.20–3.28 (m, 2H), 2.39 (s, 3H), 2.29–2.35 (m, 2H), 1.47–1.68 (m, 4H), 1.23–1.41 (m, 5H).
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[N+](=[CH2:17])=[N-].Cl>CO>[C:1]([O:14][CH3:17])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: C=[N+]=[N-]
Agent: Cl
Solvent: CO
Product: COC(=O)/C=C/c1ccc(O)c(OC)c1

Procedure:
Methyl ferulate was prepared by methylating commercial ferulic acid (made by Tokyo Kasei Kogyo Co. LTD., Japan) with diazomethane or methyl alcohol acidified with hydrochloric acid (Fisher Method).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[CH:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>[OH-].[Na+]>[CH:13]1([C:18]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCC1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)NCCC[C@H](NC(=O)C1CCCC1)C(=O)O
Temperature: 25 °C
Yield: 131.2 %

Procedure:
(L)-Arginine (32.8 g., 0.19 moles) was dissolved in 188 mL of 2 N sodium hydroxide. Cyclopentanoyl chloride (22.9 mL, 0.19 moles) was added dropwise to the mixture. The reaction mixture was maintained at about 25° C. for 2 hours. The mixture was then acidified to pH 1.5 with aqueous (4:1) hydrochloric acid. The precipitate which formed was separated by decantation. The solids were dissolved in 2 N sodium hydroxide to pH 7.5 and dried by lyophilization to furnish 67.4 g of N-cyclopentanoyl-(L)-arginine. The product was a white solid.
Reaction SMILES: C1(N(C(=O)C2C=CC([N+]([O-])=O)=CC=2)N)C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.C1(O)C=CC=CC=1.ClP([N:38]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[N:39]=[C:40]([Cl:50])[C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=1)(Cl)=O>C(Cl)(Cl)(Cl)Cl>[C:51]1([NH:38][N:39]=[C:40]([Cl:50])[C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: O=[N+]([O-])c1ccc(C(Cl)=NN(c2ccccc2)P(=O)(Cl)Cl)cc1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: NN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: Oc1ccccc1
Product: O=[N+]([O-])c1ccc(C(Cl)=NNc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A quantity (12.86 g., 0.05 mole) of p-nitrobenzoic acid phenylhydrazide, prepared according to the method described by J. Hausknecht, Chem. Ber. 22, p. 324 (1889), was added to a suspension of 10.41 g. (0.05 mole) phosphorus pentachloride in 75 ml. carbon tetrachloride, and the resulting suspension was heated to the reflux temperature. Heating at the reflux temperature was continued until evolution of hydrogen chloride gas ceased. After cooling the reaction mixture to about 25° C., it was poured into an ice-cold suspension of 15.5 g. (0.17 mole) of phenol in 50 ml. carbon tetrachloride. When the reaction between the phenol and the p-nitrobenzoyl chloride (dichlorophosphinyl)phenylhydrazone intermediate was completed, the carbon tetrachloride solvent and other volatile components were removed by evaporation under reduced pressure at 30° C. The resulting suspension of p-nitrobenzoyl chloride phenylhydrazone in triphenyl phosphate was filtered and the filter cake comprising the p-nitrobenzoyl chloride phenylhydrazone was washed with 100 ml. carbon tetrachloride, 50 ml. methanol, and 50 ml. ether. The solid on the filter was recrystallized from a solvent mixture consisting of 100 ml. benzene and 300 ml. naphtha (boiling range 203° to 212° F.). There was thus obtained 4.10 g. of p-nitrobenzoyl chloride phenylhydrazone having a melting point of 156° to 157.5° C. A second recrystallization from a mixture of benzene and Skellysolve C gave the compound melting at 157° to 158.5°C.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[CH:5]=[C:6]([N:36]([CH3:40])[C:37]([NH2:39])=[O:38])[CH:7]=[C:8]([CH3:35])[C:9]=1/[CH:10]=[CH:11]/[S:12]([N:15]1[CH2:34][CH2:33][C:18]2([N:22]=[C:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28][CH2:29][CH2:30][CH3:31])[NH:20][C:19]2=[O:32])[CH2:17][CH2:16]1)(=[O:14])=[O:13].O>CC(C)=O>[CH3:35][C:8]1[CH:7]=[C:6]([N:36]([CH3:40])[C:37]([NH2:39])=[O:38])[CH:5]=[C:4]([CH3:3])[C:9]=1/[CH:10]=[CH:11]/[S:12]([N:15]1[CH2:16][CH2:17][C:18]2([N:22]=[C:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28]([CH2:29][CH2:30][CH3:31])=[O:1])[NH:20][C:19]2=[O:32])[CH2:33][CH2:34]1)(=[O:13])=[O:14]
Reactant: CCCSCCCCCC1=NC2(CCN(S(=O)(=O)/C=C/c3c(C)cc(N(C)C(N)=O)cc3C)CC2)C(=O)N1
Reactant: OO
Solvent: CC(C)=O
Solvent: O
Product: CCCS(=O)CCCCCC1=NC2(CCN(S(=O)(=O)/C=C/c3c(C)cc(N(C)C(N)=O)cc3C)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
30% aqueous hydrogen peroxide (0.013 ml) was added to a mixed solution of (E)-1-(3,5-dimethyl-4-(2-((4-oxo-2-(5-(propylthio)pentyl)-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)vinyl)phenyl)-1-methyl-urea (55 mg) and molybdenum(IV) dichloride dioxide (3 mg) in acetone (1.5 ml)-water (0.5 ml), and the mixture was stirred at room temperature for five minutes in a nitrogen stream. The reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, CH2Cl2-MeOH) to give 1-[3,5-dimethyl-4-((E)-2-{4-oxo-2-[5-(propane-1-sulfinyl)-pentyl]-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl}-vinyl)-phenyl]-1-methyl-urea (64 mg).