Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=O)[NH:12][N:11]=2)[CH:2]=1.P(Cl)(Cl)([Cl:23])=O.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O1CCOCC1.O>[Cl:23][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([CH2:9][CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:11][N:12]=1
Reactant: O=c1[nH]nc(CCCc2cccnc2)c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: Clc1nnc(CCCc2cccnc2)c2ccccc12
Temperature: 45 °C
Reaction time: 36 h

Procedure:
Under exclusion of air, 771 mg (2.9 mmol) 4-[3-(pyridin-3-yl)propyl]phthalazin-1(2H)-one in 14 ml acetonitrile is mixed with 1.11 g (7.25 mmol) phosphoryl chloride and 1.45 ml 4 N HCl in dioxane and stirred for 36 h at 45° C. Then 50 ml water is added, the reaction mixture adjusted to alkaline pH with sat. Na2CO3 solution and immediately extracted 3 times with EtOAc. Drying (Na2SO4) of the organic phases and evaporation yield the title compound; FAB-MS (M+H)+=284.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[CH3:22][C:23]1(C)COC2=CC3OCC4(C=3C=[C:24]12)C1C(=CC=CC=1)NC4=O.BrCCC.BrCC1OC(C(F)(F)F)=CC=1>>[CH2:22]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21])[CH2:23][CH3:24]
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: FC(F)(F)c1ccc(CBr)o1
Solvent: CCCBr
Product: CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 1-bromopropane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (64%) as a white solid: mp 158-160° C.; MS (ES+) m/z 324.4 (M+1).
Reaction SMILES: [NH:1]1[C:10]2C(=CC=CC=2)N=CC1=O.[N+:12]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=O)[CH:19]=[N:18]2)([O-:14])=[O:13].[N+:26]([O-])([O-])=O.[K+]>OS(O)(=O)=O>[N+:12]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]1[CH:10]=[N:1][N:26]=[C:20]1[CH:19]=[N:18]2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1cnc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: O=c1cnc2ccccc2[nH]1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc2c(c1)ncc1nncn12

Procedure:
The procedure of Example I.D. was followed except the quinoxalin-2-one was converted to the 6-nitroquinoxalin-2-one by first dissolving in conc. H2SO4 and cooling in an ice bath, and adding KNO3 in 3 portions. The product was collected by conventional technique and subsequently converted to 2-hydrazino-6-nitroquinoxaline. This compound was reacted with triethylorthoformate as per Example I.D., yielding 7-nitro-1,2,4-triazolo[4,3-a]quinoxaline (16).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1)=[O:4].[C:15](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[F:14][C:2]([F:1])([F:13])[C:3]([N:5]([C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1)[CH3:15])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ccc(I)cc1)C(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(C(=O)C(F)(F)F)c1ccc(I)cc1

Procedure:
Part B: The above-obtained amide was dissolved in acetone (80 mL), to which potassium carbonate (15.75 g, 114.1 mmol) and iodomethane (9.6 mL, 114.1 mmol) were added. The reaction was heated to reflux for 2 hours and cooled, and the resulting solid was filtered. The solvent was removed from the filtrate. The residue was dissolved in dichloromethane, washed with water and brine, and dried over sodium sulfate. After filtration and removal of solvent, the solid was further dried in vacuo to give the desired 2,2,2-trifluoro-N-(4-iodo-phenyl)-N-methyl-acetamide as a white solid. MS found: (M+1)+=330.05.
Reaction SMILES: [N-]=[N+]=[N-].[Na+].[N:5]([C@@H:8]1[CH2:13][O:12][C@H:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[OH:27])=[N+:6]=[N-:7]>CO>[N:5]([C@H:8]1[CH2:13][O:12][C@@H:11]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C@@H:9]1[OH:27])=[N+:6]=[N-:7]
Reactant: [N-]=[N+]=N[C@@H]1CO[C@H](C(c2ccccc2)c2ccccc2)C[C@H]1O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=N[C@H]1CO[C@@H](C(c2ccccc2)c2ccccc2)C[C@@H]1O

Procedure:
(1R, 4R, 7S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 8c (0.04 g, 0.15 mmol) was treated with NaN3 (0.05 g, 0.75 mmol) and NH4Cl (0.018 g, 0.33 mmol) (Procedure F) yielded (2R, 4S, 5S)-5-Azido-2-benzhydryl-tetrahydro-pyran-4-ol 30b, 0.04 g (95%, [α]D=(+)108, c=1, MeOH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[CH3:2].Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)=[O:22])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)=[O:22])[CH2:19][CH2:20]1)=[O:11])[CH3:2]
Reactant: CCOC(=O)CCCCC(=O)O
Reactant: NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of adipic acid mono ethyl ester (154 mg, 0.883 mmol) and 3,5-dichlorobenzyl 4-aminopiperidine-1-carboxylate HCl salt (Example 9, step 2)(300 mg, 0.883 mmol) in DMF (2 mL) was added Huenig's base (0.771 mL, 4.42 mmol) and T3P® (50% in DMF) (1.031 mL, 1.767 mmol) and the mixture was stirred at RT for 4 hrs. The resulting mixture was diluted with EtOAc and washed with a saturated solution of sodium bicarbonate.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:15][C:16]2[C:17](=[O:35])[N:18]([C:22]3[CH:23]=[C:24]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:25]([NH:27][CH:28]3[CH2:30][CH2:29]3)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13][CH2:12]1.[CH2:36]([CH2:38][NH2:39])[OH:37]>>[CH:28]1([NH:27][C:25](=[O:26])[C:24]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:39][CH2:38][CH2:36][OH:37])[CH2:14][CH2:13][CH2:12]4)[C:17]3=[O:35])[CH:23]=2)[CH2:30][CH2:29]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CCC2)c1=O
Reactant: NCCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCNCCO)CCC2)c1=O

Procedure:
The title product was prepared from 3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 268g) and ethanolamine using a similar method to that described for example 167f.
Reaction SMILES: [N:1]1([C:21]([CH3:23])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:2]1[C:3]([NH:5][C@H:6]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].[SH:24][NH:25][C@H:26]([C:31]([NH:33][C@H:34]([C:39]([NH:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29].C(Cl)CCl>CN(C)C=O>[N:1]1([C:21]([CH3:23])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:2]1[C:3]([NH:5][C@H:6]([C:11]([NH:13][CH2:14][C:15]([S:24][NH:25][C@H:26]([C:31]([NH:33][C@H:34]([C:39]([NH:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:17])=[O:12])[CH2:7][CH:8]([CH3:9])[CH3:10])=[O:4]
Reactant: CC(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O
Reactant: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NS
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NSC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of Ac-Pro-Leu-Gly-OH (0.7 g, 2.1 mmol), HS-Leu-Leu-Gly-OC2H5 (0.6 g, 1.7 mmol) and HBT (0.26 g, 1.7 mmol) in 15 ml dimethylformamide was added EDC (0.4 g, 2.1 mmol). The solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue partitioned between salt water and ethyl acetate. The ethyl acetate layer was washed consecutively with dilute sodium bicarbonate in salt (NaCl) water, dilute hydrochloric acid in salt water, salt water, 1.0 mM cupric sulfate in salt water (to remove any mercapto products) and finally salt water. The ethyl acetate was dried over magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate concentrated in vacuo, yielding 0.8 g (73%) glassy residue of crude thiopeptolide product. A 100 mg sample of this crude product was purified by low pressure C18 column chromatography. The purified thiopeptolide, had an acceptable amino acid analysis, a consistent mass spectrum and a single peak on HPLC analysis. Anal. Calcd. for
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][P:12]([CH2:19][O:20]S(C1C=CC(Cl)=CC=1)(=O)=O)(=[O:18])[O:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C@H:39]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH3:40])=[CH:34][CH:33]=1>>[C:44]([O:43][C:42]([NH:41][CH:39]([CH3:40])[CH2:38][C:35]1[CH:34]=[CH:33][C:32]([O:20][CH2:19][P@:12]([CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:18])[O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:37][CH:36]=1)=[O:48])([CH3:47])([CH3:45])[CH3:46]
Reactant: C[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CCCCOP(=O)(CCCOCc1ccccc1)COS(=O)(=O)c1ccc(Cl)cc1
Product: CCCCO[P@](=O)(CCCOCc1ccccc1)COc1ccc(CC(C)NC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared from 3-benzyloxypropyl-(4-chlorobenzenesulfonyloxymethyl)phosphinic acid, n-butyl ester and (R)-2-(4-hydroxyphenyl)-1-methylethylcarbamic acid, t-butyl ester according to the method described in Procedure 24. The crude product was purified by chromatography, eluting with dichloromethane containing 3% methanol, to give an oil.
Reaction SMILES: [Na].[C:2]([SH:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:22][NH:23][C:24](=[O:27])[CH2:25]Cl>C(O)C>[C:2]([S:21][CH2:25][C:24]([NH:23][CH3:22])=[O:27])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CNC(=O)CCl
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: CCO
Product: CNC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.75 h

Procedure:
To a solution of 26.55 g of sodium in 1800 ml of ethanol is added 288.8 g of tritylmercaptan. Then with ice-cooling a solution of 111.8 g of N-methylchloracetamide in 1000 ml of ethanol is added dropwise whereupon a grey-white precipitate is formed. After completion of the addition stirring is continued at room temperature for 45 minutes and the mixture then concentrated to half its volume. The precipitate is filtered, washed with isopropanol, water and again isopropanol and dried to give the title product. m.p. 200°-210°.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13](S(C)=O)=[N:14][CH:15]=[C:10]3[CH2:9][NH:8][C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.CS(C)=O>C(OCC)(=O)C>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:28][C:25]4[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)=[N:14][CH:15]=[C:10]3[CH2:9][NH:8][C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)c1ncc2c(n1)N(C1CCCC1)C(=O)NC2
Reactant: COc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(Nc2ncc3c(n2)N(C2CCCC2)C(=O)NC3)cc1
Reaction time: 3 h
Yield: 24.2 %

Procedure:
A solution of 300 mg (1.07 mmol) of 1-cyclopentyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, 527 mg (4.28 mmol) of p-anisidine, and 1.5 mL of dimethyl sulfoxide is heated at 130° C. for 30 hours, then cooled and diluted with ethyl acetate. The mixture is washed three times with aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The residual solids are washed with 9:1:0.1:0.1 chloroform/ethyl acetate/ethanol/triethylamine then with chloroform, and suspended in 150 mL of 7:3 chloroform/methanol. The suspension is diluted with 20 mL of hexane, stirred for 3 hours, and filtered to afford 88 mg (24%) of the title compound as an off-white powder: mp 247-249° C. (dec).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([O:33][CH3:34])[CH:28]=2)=[CH:21][N:20]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([O:33][CH3:34])[CH:28]=3)=[CH:21][N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: COc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)ccn1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CCO
Product: COc1cc(Cc2cnc(NCCSCc3ccc(CN(C)C)o3)[nH]c2=O)ccn1

Procedure:
A mixture of 2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamine (2.50 g), 2-nitroamino-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone (2.77 g) and ethanol (15 ml) was boiled under reflux for 19 hours and evaporated. The residue was triturated with hot water to leave 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone. A mixture of this pyrimidine (3.04 g), 2N hydrogen chloride in ethanol (20 ml) and ethanol (80 ml) was boiled under reflux for 48 hours and evaporated to dryness. The residue was recrystallised from methanol/ethanol to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone trihydrochloride m.p. 181°-185°.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[OH:15]O>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[N+:5]([O-:15])[CH:6]=[CH:7][N:8]=2)[N:3]=1
Reactant: OO
Reactant: CCOc1nc(N)nc2nccnc12
Solvent: O=C(O)C(F)(F)F
Product: CCOc1nc(N)nc2c1ncc[n+]2[O-]
Reaction time: 48 h
Yield: 32 %

Procedure:
To a cooled (0° C.) solution of the compound of example 7 (2.47 g, 12.9 mmoles) in trifluoroacetic acid (53 ml) was added dropwise 2.53 ml of a 35% aqueous H2O2 solution. The reaction mixture was kept at 4° C. for two days in the refrigerator, whereby another 1.25 ml of the same H2O2 solution was added after 1 day. The solution was concentrated in vacuo. The residue was suspended in water and neutralized by the addition of a concentrated ammonia solution. Evaporation of the solvent in vacuo and purification of the residue by flash chromatography (silica, using a CH3OH/CH2Cl2 mixture (6:94) as the eluent) provided the title compound as a yellow powder (861 mg, yield: 32%). Mass spectrum data are as follows: m/z (%): 230 ([M+Na]+, 30), 208 ([M+H]+, 100), 180 [(M+H-ethene)+, 10].
Reaction SMILES: Br[C:2]1[C:7]([CH:8]2[N:13]3[C:14](=[O:20])[NH:15][C:16]4=[CH:17][CH:18]=[CH:19][C:11](=[C:12]34)[O:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:21][N:22](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:20]=[C:14]1[N:13]2[CH:8]([C:7]3[C:2]([C:21]#[N:22])=[N:3][CH:4]=[CH:5][CH:6]=3)[CH2:9][O:10][C:11]3=[C:12]2[C:16](=[CH:17][CH:18]=[CH:19]3)[NH:15]1
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2cccc3c2n1C(c1cccnc1Br)CO3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ncccc1C1COc2cccc3[nH]c(=O)n1c23
Temperature: 160 °C

Procedure:
A suspension of 4-(2-bromopyridin-3-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (964 mg, 2.90 mmol), zinc cyanide (1.00 g, 8.70 mmol) and tetrakis(triphenylphosphine)palladium(0) (335 mg, 0.290 mmol) in N,N-dimethylformamide (20.4 mL) was degassed and heated in a microwave at 160° C. for 20 min. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. The crude product was suspended in hot ethyl acetate and diluted with hexanes to twice the volume, which resulted in the precipitation of a solid. The solid was collected by filtration and washed with ethyl acetate to give the desired product (656 mg). The filtrate was concentrated to a residue which was purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product that was combined with the precipitated material (0.709 g total, 88% combined yield) as a racemic mixture. LCMS calculated for C15H11N4O2 (M+H)+: m/z=279.1. found: 278.9.
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][C@H:19]([O:24]C(=O)C(C)(C)C)[CH2:18][CH2:17]2)C.Cl[CH2:41][C:42]([N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])=O>>[CH2:45]([N:44]([CH2:47][CH3:48])[CH2:42][CH2:41][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1)[CH3:46]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1-c1ccc2c(c1)CC[C@@H](OC(=O)C(C)(C)C)C2
Product: CCN(CC)CCOc1ccc(CCCNc2cc(OC)c(OC)cc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 89.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N,N-diethylacetamide (8.1 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.2 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5](N)[CH2:4][CH2:3]1.[S:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:9][CH2:8][C:7]2=[C:6]3[C:13](=[CH:12][CH:11]=[CH:10]2)[C:17]2[CH2:16][S:15][CH2:20][CH2:19][C:18]=2[N:5]3[CH2:4][CH2:3]1
Reactant: CN1CCc2ccccc2N(N)CC1
Reactant: O=C1CCSCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCc2cccc3c4c(n(c23)CC1)CCSC4
Temperature: 25 °C
Yield: 23.6 %

Procedure:
To a solution of 4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (1.50 g, 8.1 mmole) in 1-propanol (100 mL) was added tetrahydro-thiopyran-4-one (5.0 g, 43 mmole), followed by p-toluenesulfonic acid monohydrate (3.2 g, 16.8 mmole), and the resulting reaction mixture was refluxed for 40 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with ethyl acetate (300 mL) and washed with saturated aqueous sodium bicarbonate (150 mL), saturated aqueous sodium chloride (150 mL), dried (sodium sulfate) and concentrated in vacuo. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 0.52 g of the title compound as an off-white solid, mp 123-125° C., with a trace of ethyl acetate. MS (ESI) m/z 273 ([M+H]+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)O)[CH:18]=[CH:19][CH:20]=1.C1(P([N:43]=[N+:44]=[N-:45])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:43]([CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)=[N+:44]=[N-:45]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OC(c1ccccc1)c1cccc(OCCCCCCCCC2OCCO2)c1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NC(c1ccccc1)c1cccc(OCCCCCCCCC2OCCO2)c1
Temperature: 45 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a stirred solution of (3-(8-(1,3-dioxolan-2-yl)octyloxy)phenyl)-(phenyl)methanol (1.63 g, 4.24 mmol) in toluene (10 mL) under an atmosphere of nitrogen, diphenylphosphoryl azide (1.10 mL, 5.10 mmol) and DBU (0.77 mL, 5.11 mmol) was added. The reaction mixture was stirred at 45° C. for 3 hours and then at RT for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford impure title compound (1.11 g, 64%). This material was used directly in the next step.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:33](=[O:34])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)=[O:21])=[C:15]([Cl:19])[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:37]I>CN(C)C=O.O.C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:33](=[O:34])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]4[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=4)=[O:21])=[C:15]([Cl:19])[CH:16]([CH3:37])[S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS(=O)[C@H]12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC1C(Cl)=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Reaction time: 0.67 h

Procedure:
To a solution of p-nitrobenzyl 7-phenylacetamido-3-chloro-3-cephem-4-carboxylate-1-oxide (504 mg) in dimethylformamide (20 ml) one adds a 50% suspension of sodium hydride (48 mg) in mineral oil under nitrogen atmosphere, stirs for 40 minutes, adds methyl iodide (0.5 ml), stirs for 15 minutes at room temperature, dilutes with water, extracts with ethyl acetate, washes with water, dries, concentrates under reduced pressure, and purifies by chromatography to give p-nitrobenzyl 7-phenylacetamido-2-methyl-3-chloro-3-cephem-4-carboxylate-1-oxide (38 mg).
Reaction SMILES: [Br-].[F:2][C:3]([F:8])([F:7])[C:4]([Zn+])=[CH2:5].Br[C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH:18]([F:20])[F:19])=[C:12]([Cl:21])[CH:11]=1>O1CCCC1.CN(C)C=O>[Cl:21][C:12]1[CH:11]=[C:10]([C:4]([C:3]([F:8])([F:7])[F:2])=[CH2:5])[CH:15]=[C:14]([Cl:16])[C:13]=1[O:17][CH:18]([F:20])[F:19]
Reactant: FC(F)Oc1c(Cl)cc(Br)cc1Cl
Reactant: C=C([Zn+])C(F)(F)F
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(OC(F)F)c(Cl)c1)C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To 1M solution of 1-(trifluoromethyl)ethenyl zinc bromide in tetrahydrofuran (see J. Org. Chem. 1991, 56, 7336 for preparation) (21 mL) was added a solution of 4-bromo-2,6-dichloro-1-(difluoromethoxy)benzene (2.4 g) in N,N-dimethylformamide (12 mL), then the bulk of the tetrahydrofuran was removed in vacuo. Dichlorobis(triphenylphosphine)palladium(II) (0.23 g) was added to the residual N,N-dimethylformamide solution, which was stirred at 100° C. for 3 hours under nitrogen atmosphere and then cooled to room temperature. The resulting mixture was poured into water (100 mL) and extracted with diethyl ether (100 mL×1). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel eluted with hexane to afford the title compound as a brown oil (1.8 g).