Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[NH:20]3)=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].Br[CH2:30][CH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44]>CC#N>[Br:1][C:2]1[S:3][C:4]([C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:20]3[CH2:30][CH2:31][CH2:32][CH2:33][N:34]3[C:38](=[O:39])[C:37]4[C:36](=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:35]3=[O:44])=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: COC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)[nH]c3c2)sc1Br
Solvent: CC#N
Product: COC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Temperature: 25 °C
Yield: 42.7 %

Procedure:
To a stirred solution of 4 (45 mg, 0.10 mmol) in anhydrous CH3CN (5 mL) was added CsF-Celite (125 mg) under N2, followed by addition of N-(4-bromobutyl)-phthalimide (28 mg, 0.10 mmol). The resulting mixture was refluxed for five hours, cooled to room temperature, and filtered. The filtrate was evaporated in vacuo. MPLC purification (Hex:EtOAc/4:1) of the residue gave 5 as a yellow solid (28 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.74 (m, 6H), 7.59 (s, 1H), 7.47 (m, 5H), 6.60 (s, 1H), 4.32 (t, J=7.2 Hz, 2H), 3.73 (s, 3H), 3.71 (s, 2H), 3.52 (t, J=6.8 Hz, 2H), 1.72 (m, 2H), and 1.51 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 187.3, 170.4, 168.5, 145.2, 144.3, 136.8, 135.6, 134.9, 134.2, 134.1, 132.5, 132.1, 130.7, 129.5, 129.0, 128.8, 123.5, 123.4, 121.5, 120.6, 112.5, 103.1, 52.5, 43.7, 37.3, 35.1, 27.4, and 25.8.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]2[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(O)(C)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:9]=3)[N:14]=[C:13]([CH3:18])[C:12]=2[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:24][CH:25]=1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1S(C)(=O)=O
Reactant: C1COCCN1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCCCCCC
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccc(F)cc2)c1S(C)(=O)=O
Temperature: 110 °C
Yield: 408.2 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (79 mg, 0.076 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (73 mg, 0.152 mmol) and cesium carbonate (1.86 g, 5.7 mmol). 6-Bromo-4-(4-fluoro-phenyl)-3-methanesulfonyl-2-methyl-quinoline (compound of example 14) (200 mg, 0.52 mmol) in tert.-butanol (20 ml) was added, followed by morpholine (0.40 g, 4.56 mmol). The tube was sealed and heated at 110° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate with a gradient from 100:0 to 40:60 to give a yellow solid (850 mg, 56%). MS: m/z=401 (M+H).
Reaction SMILES: [C:1]([CH2:7][C:8]([O:10]CC)=O)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].O.[NH2:14][NH2:15].O>C(O)C>[C:2]([CH:1]1[CH2:7][C:8](=[O:10])[NH:15][NH:14]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: NN
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Solvent: O
Solvent: CCO
Product: CC(C)(C)C1CC(=O)NN1
Reaction time: 8 h

Procedure:
1.0 kg of ethyl pivaloylacetate was dissolved in 1.0 liter of ethanol, and 320 g of hydrazine hydrate was dropwise added thereto while cooled with water. After completion of the addition, the reaction was carried out overnight at room temperature, and then 5.0 liter of water was added thereto and stirred. The crystal as precipitated was filtered out under reduced pressure and fully washed with water, and then this was further washed with a little amount of methanol and dried with air. Yield: 812 g.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:18])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[I-].[CH3:26][CH2:27][CH2:28][CH3:29].[CH3:30][C:31]([CH2:33][CH3:34])=O>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:26][CH2:27][CH2:28][CH3:29])=[C:13]([O:18][CH2:30][CH2:31][CH2:33][CH3:34])[CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCCC
Reactant: CCC(C)=O
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)c(O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCCCOc1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1OCCCC
Temperature: 40 °C
Yield: 90 %

Procedure:
4′-methanesulfonyl-biphenyl-3,4-diol (30 mg) and potassium carbonate (38 mg) were dissolved in methylethylketone. Afterward, butane iodide (0.038 ml) was added and heated for 24 hours at 40° C. After filtering just potassium carbonate, the residue was separated through a silica gel attributed chromatography (an eluting agent: ethylacetate/n-hexane=1/1, v/v). As a result, the present compound (35 mg, productive yield 90%) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19](O)[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].C(C1C=CC(NC(C2C=C(OS(C(F)(F)F)(=O)=O)C=C(OCC)C=2)C(OC)=O)=CC=1)#N.[S:56]1[CH:60]=[CH:59][CH:58]=[C:57]1B(O)O>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([C:57]3[S:56][CH:60]=[CH:59][CH:58]=3)[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOc1cc(O)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Reactant: OB(O)c1cccs1
Agent: CCOc1cc(OS(=O)(=O)C(F)(F)F)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Product: CCOc1cc(-c2cccs2)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1

Procedure:
Analogously to Example 145, from methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-hydroxy-phenyl)-acetate via methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-trifluoromethanesulphonyloxy-phenyl)-acetate by reaction with thiophene-2-boronic acid there was obtained the compound methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-thiophen-2-yl-phenyl)-acetate, which was converted into methyl (RS)-(4-carbamimidoyl-phenylamino)-(3-ethoxy-5-thiophen-2-yl-phenyl)-acetate hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[F:13][C:14]1[C:24]([NH2:25])=[CH:23][C:17]2[NH:18][C:19](=[O:22])[CH2:20][O:21][C:16]=2[CH:15]=1.C(N(CC)CC)C.O>C(Cl)Cl>[F:13][C:14]1[C:24]([NH:25][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:23][C:17]2[NH:18][C:19](=[O:22])[CH2:20][O:21][C:16]=2[CH:15]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1cc2c(cc1F)OCC(=O)N2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1COc2cc(F)c(NC(=O)c3ccccc3[N+](=O)[O-])cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 2-nitro-benzoyl chloride (2.04 g, 90% purity, 10 mmol) in CH2Cl2 (20 mL) was added dropwise into a mixture of 7-fluoro-6-amino-2H-1,4-benzoxazin-3-(4H)-one (1.78 g, 10 mmol) and triethylamine (1.1 g, 11 mmol) in CH2Cl2 (20 mL) over 10 min with ice-water bath cooling. The reaction mixture was then stirred at room temperature overnight. The mixture was poured into water and the resulting precipitate was collected by suction-filtration and washed with hexane and then water to give 7-fluoro-6-(2-nitrobenzoyl)amino-2H-1,4-benzoxazin-3-(4H)-one, 2.9 g (yield: 92%) as a solid: mp >248° C.
Reaction SMILES: CS(C)=O.[Cl-].[OH:6][CH:7]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:8][N:9]1[C:14]2=[N:15][C:16]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1.CCN(CC)CC>C(Cl)Cl>[O:6]=[C:7]([CH2:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:8][N:9]1[C:14]2=[N:15][C:16]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: O=c1c(-c2cccc(C(F)(F)F)c2)c(-c2ccncc2)nc2n1CCCN2CC(O)CCc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(CCc1ccccc1)CN1CCCn2c1nc(-c1ccncc1)c(-c1cccc(C(F)(F)F)c1)c2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
A solution of DMSO (0.25 mL, 3.5 mmol) in CH2Cl2 (10 mL) at −78 C was treated with a solution of oxallyl chloride (2N in CH2Cl2, 0.8 mL, 1.6 mmol) dropwise. After stirring for 15 min, a solution of 9-(2-hydroxy-4-phenyl-butyl)-2-pyridin-4-yl-3-(3-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (227 mg, 0.43 mmol) in CH2Cl2 (15 mL) was added. The mixture was stirred at −60 C for 15 min before a solution of Et3N (0.5 mL, 3.6 mmol) in CH2Cl2 (3 mL) was added. The reaction mixture was allowed to warm to room temperature overnight and was washed with NaHCO3 (aq). The organic layer was dired (Na2SO4), and concentrated. The residue was eluted on silica gel with 0-5% (2N NH3-MeOH in CH2Cl2) to afford the product as a light yellow solid (148 mg, 63%). M+1 519.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:16][CH2:15][C:14]([C:17](O)=[O:18])=[CH:13][C:12]=3[CH:20]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.Cl.[CH3:33][N:34]([CH2:41][C@H:42]1[CH2:47][CH2:46][C@H:45]([NH2:48])[CH2:44][CH2:43]1)[CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:16][CH2:15][C:14]([C:17]([NH:48][C@H:45]4[CH2:44][CH2:43][C@H:42]([CH2:41][N:34]([CH3:33])[CH:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)[CH2:47][CH2:46]4)=[O:18])=[CH:13][C:12]=3[CH:20]=2)=[CH:6][CH:7]=1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CO3)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)N[C@H]2CC[C@H](CN(C)C4CCOCC4)CC2)CO3)cc1
Reaction time: 2 h

Procedure:
Into a suspension of 6-(4-methylphenyl)-2H-1-benzopyran-3-carboxylic acid (150 mg) and 1-hydroxybenzotriazole (114 mg) in acetonitrile (15 ml) was added at room temperature 1-ethyl-3-(340 -dimethylaminopropyl)carbodiimide hydrochloride (162 mg), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (253 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (257 mg) and triethylamine (0.16 ml) in acetonitrile (20 ml), and the resulting mixture was stirred for 5 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure to remove the solvent, the residue was subjected to purification using column chromatography (ethanol/ethyl acetate 1:1) and to recrystallization (ethyl acetate/hexane) to obtain trans-6-(4-methylphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]-2H-1-benzopyran-3-carboxamide (compound 67) (144 mg) as colorless crystals.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:26])[CH2:11][N:12]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:8].[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32]([Cl:34])=[O:33].Cl>C1COCC1>[ClH:34].[NH2:12][CH:11]([C:32](=[O:33])[C:28]1[S:27][CH:31]=[CH:30][CH:29]=1)[C:10]([O:9][CH2:7][CH3:8])=[O:26]
Reactant: O=C(Cl)c1cccs1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(N)C(=O)c1cccs1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a stirred solution of potassium tert-butoxide (0.84 g, 7.5 mmol) in dry THF (5.25 mL) under an N2 atmosphere at −78° C. was added a cooled (−78° C.) solution of N-(diphenylmethylene)glycine ethyl ester (2.00 g, 7.5 mmol) in dry THF (3 mL), dropwise. The resulting solution was stirred at −78° C. for 30 minutes when it was added via canula to a stirred solution of 2-thiophene carbonyl chloride (0.80 mL, 7.5 mmol) in dry THF (3 mL) under an N2 atmosphere at −78° C. The resulting mixture was stirred at −78° C. for 1 hour. The reaction was warmed to room temperature, 3N aqueous HCl (7.5 mL) was then added and the mixture stirred for 15 minutes. The resulting mixture was then concentrated in vacuo, diluted with water and washed with Et2O. The aqueous phase was evaporated to dryness to afford ethyl 2-amino-3-oxo-3-(thiophen-2-yl)propanoate hydrochloride (1.345 g) as a pale solid which was used without further purification. LCMS (2) Rt: 1.44 min; m/z (ES+) 214.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)=[O:4].[CH3:15][O:16][CH2:17][CH2:18][NH2:19].C(N(C(C)C)CC)(C)C.[C:29](OC=O)(=[O:31])C>>[CH:29]([N:19]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)=[O:4])[CH2:18][CH2:17][O:16][CH3:15])=[O:31]
Reactant: CCCOc1ccc(C(=O)CBr)cc1
Reactant: COCCN
Reactant: CC(=O)OC=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1ccc(C(=O)CN(C=O)CCOC)cc1

Procedure:
By substantially following the procedure of Example 585c using 37 g (≤140 mmole) of 2-bromo-4'-propoxyacetophenone (Example 585b), 16 g (210 mmole) of 2-methoxyethylamine, 22 g (170 mmole) of diisopropylethylamine, and 50 g of formic acetic anhydride mixture (≤350 mmole) 18.5 g of the desired compound, an oil, was obtained.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][NH:2]2.F[C:9](F)(F)[C:10]([OH:12])=O.[OH-].[Na+].[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:24][O:23][C:17]1[CH:22]=[C:21]([CH:20]=[CH:19][CH:18]=1)[O:12][C:10]1[CH:9]=[C:6]([N:2]2[CH2:3][CH:4]3[CH2:7][CH:1]2[CH2:6][NH:5]3)[CH:1]=[N:2][CH:3]=1
Reactant: COc1ccccc1
Reactant: C1NC2CNC1C2
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(Oc2cncc(N3CC4CC3CN4)c2)c1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a stirred solution of (1S,4S)-5-(5-(3-methoxyphenoxy)-3-pyridyl)-2-tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane (0.62 g, 1.5 mmol) in anisole (3.5 mL) at 0-5° C. and under a nitrogen atmosphere, trifluoroacetic acid (2.5 mL) was added drop-wise over a 10 min period. After 0.5 h at 25° C., the solution was adjusted to pH 5 using 10% NaOH, followed by extraction with diethyl ether (1×15 mL) to remove the anisole. The aqueous portion was adjusted to pH 11 using 10% NaOH, followed by extraction with diethyl ether (3×25 mL). The combined diethyl ether extracts were dried (Na2SO4), filtered, and concentrated under vacuum to give a colorless oil (0.41 g, 82%).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](=[O:12])([OH:11])[OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([C:19]([CH2:24][CH3:25])([CH2:22]O)[CH2:20]O)[CH2:16][CH2:17][CH3:18]>>[CH2:15]([C:19]1([CH2:24][CH3:25])[CH2:22][O:11][P:9](=[O:10])([CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:12][CH2:20]1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC(CC)(CO)CO
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Product: CCCCC1(CC)COP(=O)(Cc2ccc([N+](=O)[O-])cc2)OC1

Procedure:
With 4-nitrobenzylphosphonic acid and 2-butyl-2-ethyl-1,3-propanediol, the same procedure as in Reference Example 11 was followed, to yield 5-butyl-5-ethyl-2-(4-nitrobenzyl)- 1,3,2-dioxaphosphorinane-2-oxide, which was then recrystallized from ethanol-hexane to yield colorless prisms having a melting point of 111° to 112° C.
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][C@H:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1.[CH:41]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH2:42].CCO>CC(O)C>[CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][C@H:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:42][CH2:41][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:33][CH2:34]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Reactant: C=CS(C)(=O)=O
Solvent: CC(C)O
Solvent: CCO
Product: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(CCS(C)(=O)=O)CC2)C4)c(C)c1
Temperature: 100 °C
Yield: 77.6 %

Procedure:
A mixture of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (3.04 g, 5.6 mmol) and methyl vinyl sulfone (5.94 g, 56 mmol) in a mixed solvent of EtOH (70.0 mL) and 2-propanol (70.0 mL) was heated at 100° C. for 22 h and then evaporated. Chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (190:10:1) afforded title compound (2.82 g, 78%). 1H NMR (DMSO-d6) δ 1.68-1.85 (4H), 2.15 (m, 2H), 2.18 (s, 311, CH3), 2.21 (s, 3H, CH3), 2.75 (m, 2H), 3.05 (m, 2H), 3.08 (s, 3H, CH3), 3.54 (m, 1H), 3.70 (m, 1H), 3.93-4.19 (4H), 4.43 (s, 1H), 4.47 (s, 1H), 5.48 (d, J=6 Hz, 0.5H, NH), 5.53 (d, J=6 Hz, 0.5H, NH), 6.20 (m, 1H), 6.81 (m, 1H), 6.90-6.99 (2H), 7.31-7.37 (1.5H), 7.67 (s, 0.5H), 7.80 (s, 0.5H), 7.94 (s, 0.5H), 11.14 (br d, J=6 Hz, 1H, NH), 11.22 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 649.5 (MH+); Anal. Calcd for C33H40N6O6S: C, 61.09; H, 6.21; N, 12.95, S 4.94. Found: C, 60.85; H, 6.17; N, 12.87, S 4.85.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]([C:8]2[NH:12][N:11]=[CH:10][CH:9]=2)=[N:6][N:7]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C>[N:13]([CH2:2][C:3]1[S:4][C:5]([C:8]2[NH:12][N:11]=[CH:10][CH:9]=2)=[N:6][N:7]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1nnc(-c2ccn[nH]2)s1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1nnc(-c2ccn[nH]2)s1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a 1 mL DMF solution of 2-(chloromethyl)-5-(1H-pyrazol-5-yl)-1,3,4-thiadiazole (58 mg, 0.29 mmol) was added sodium azide (20 mg, 0.30 mmol). Stirring continued at rt for 3 hr. The reaction mixture was concentrated and diluted with AcOEt and water. The organic layer was separated. The aqueous layer was extracted with AcOEt twice and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (60 mg).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:6]=[C:7]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:8][C:9]1(C(OCC)=O)[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:28][C:27]([CH3:29])=[N:26][CH:25]=4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[N:16][N:17]=[C:10]12.[Cl-].[NH4+].O.[CH2:44]1[CH2:48][O:47]CC1>>[F:4][C:5]1[CH:6]=[C:7]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:8][C:9]1([C:48]([OH:47])([CH3:44])[CH3:1])[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:28][C:27]([CH3:29])=[N:26][CH:25]=4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[N:16][N:17]=[C:10]12
Reactant: C1CCOC1
Reactant: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COc1cc(-c2nnc3n2CCCC3(Cc2ccc(F)c(F)c2)C(C)(C)O)ccc1-c1cnc(C)o1

Procedure:
Methylmagnesium bromide (12% THF solution, 13 mL) was added to a mixture of ethyl 8-(3,4-difluorobenzyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1.60 g) in THF (16 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, and methylmagnesium bromide (12% THF solution, 13 mL) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (740 mg).
Reaction SMILES: O.[C:2]([O:6][CH2:7][C:8]([Cl:11])([Cl:10])[Cl:9])(=[O:5])[CH:3]=O.C1(P(=[CH:31][C:32]2[CH2:33][S:34][C@@H:35]3[C@H:55]([NH:56][C:57](=[O:64])[CH2:58][C:59]4[S:60][CH:61]=[CH:62][CH:63]=4)[C:54](=[O:65])[N:36]3[C:37]=2[C:38]([O:40][CH:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:11][C:8]([Cl:9])([Cl:10])[CH2:7][O:6][C:2]([CH:3]=[CH:31][C:32]1[CH2:33][S:34][C@@H:35]2[C@H:55]([NH:56][C:57](=[O:64])[CH2:58][C:59]3[S:60][CH:61]=[CH:62][CH:63]=3)[C:54](=[O:65])[N:36]2[C:37]=1[C:38]([O:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])=[O:5]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: O=CC(=O)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CC(=O)OCC(Cl)(Cl)Cl)CS[C@H]12
Yield: 47 %

Procedure:
A suspension of 2,2,2-trichloroethyl glyoxylate monohydrate (435 mg., 1.86 mmole) in dry methylene chloride (25 ml.) was stirred at 23° and treated, over 10 minutes, with diphenylmethyl 3-(triphenylphosphoranylidenemethyl)-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (765 mg., 1 mmole). After stirring for 45 minutes, the solvent was removed in vacuo and the residue was extracted with ethyl acetate (50 ml.); the insoluble material was filtered off and the filtrate was washed well with water (2 × 50 ml.) and brine (50 ml.), dried, and evaporated to an oil (1.07 g.). This material was purified by chromatography on 0.05-0.2mm. Kieselgel, with benzene; ethyl acetate = 10:1 as eluent. Combination of similar fractions (as judged by t.l.c.) gave the title compound (325 mg., 47%), as an amorphous white solid, m.p. 70° to 81° (decomp.), [α] - 72.2° (CHCl3), λmax. 313 nm (ε 9,300) with an inflexion at 237 nm. (ε 14,900), νmax. (CHBr3) 3415 (NH), 1789 (β-lactam), 1728 (--CO2R), and 1682 and 1510 cm.-1 (CONH); the p.m.r. spectrum (CDCl3) indicated that this compound was mainly the cis-isomer, with signals at τ 3.50 (NH, d, J 9 Hz.); 4.08 and ca. 2.60 (CH=CH, two d, JAB 12 Hz.); 4.09 (C(7) -H, dd, J 5, 9 Hz.); 4.93 (C(6) -H, d, J 5 Hz.); 5.33 (--CH2CCl3, s); 6.16 (--CH2CONH--, s); and 6.29 and 6.61 (C(2) --CH2, AB-q J 18 Hz.), together with the trans-isomer (10 to 15%) with signals at τ 3.88 and 1.96 (CH=CH, two d, J 16 Hz.) [Found: C, 53.4; H, 3.6; N, 3.8; S, 9.1; Cl, 15.25; C31H25Cl3N2O6S2 (692.0) requires C, 53.8; H, 3.6; N, 4.05; S, 9.3; Cl, 15.4%]. Rf 0.54 (Merck GF254 + 266 plates, with benzene: ethyl acetate = 5:1 for development).