Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:16])[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C)C=O.O>[N:17]([CH2:2][C:3]1([CH3:16])[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1)=[N+:18]=[N-:19]
Reactant: CC1(CCl)CN(c2ccc(Cl)cn2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(CN=[N+]=[N-])CN(c2ccc(Cl)cn2)C(=O)O1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A mixture of 5-(chloromethyl)-3-(5-chloropyridin-2-yl)-5-methyl-1,3-oxazolidin-2-one (1.01 g, INTERMEDIATE 17) and sodium azide (503 mg) was heated to 140° C. in 40 ml of dimethylformamide for 40 h. The mixture was then cooled to room temperature, and diluted with 150 ml of water and extracted with 150 ml of ethyl acetate (3×). The combined organic layers were washed with water (100 ml) and brine (100 ml). Then they were dried over sodium sulfate and concentrated in vacuo (overnight to remove dimethylformamide) to provide 570 mg (55%) of the title compound. Mass spectrum (ESI) 268.1 (M+1).
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]([CH3:21])([O-])[CH3:19].[K+]>CN(C=O)C>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=[CH:17][C:18]2[CH:21]=[CH:21][C:18]([CH:17]=[CH:9][CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:19][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[O-]
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: C(=Cc1ccc(C=CC=C(c2ccccc2)c2ccccc2)cc1)C=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 15.5 %

Procedure:
In 100 ml of DMF were dissolved 5.53 g of 3,3-diphenylacrolein and 5.0 g of p-xylene-α,α'-diylbis(diethyl phosphonate), and 3.87 g of potassium tert-butoxide was added to the solution at room temperature. Thereafter, the reaction was carried out for 4 hours at room temperature with stirring and the reaction mixture was poured into 100 ml of ice-water with stirring. Then, precipitates thus deposited were collected by filtration, dissolved in benzene, and separated and purified by silica gel column chromatography (eluent: benzene). After distilling off benzene from the effluent, the residue was recrystallized from ethyl acetate to provide 1.00 g (yield 15.6%) of yellow crystals having a melting point of from 237.0° C. to 249.5° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:20][CH:21]([C:24]1([CH3:28])[CH2:27][O:26][CH2:25]1)[C:22]#[N:23]>>[C:22]([CH:21]([C:24]1([CH3:28])[CH2:27][O:26][CH2:25]1)[NH:20][C:10]([C:7]1[CH:6]=[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])#[N:23]
Reactant: CC1(C(N)C#N)COC1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Product: C[C@H](Oc1cc(C(=O)NC(C#N)C2(C)COC2)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (example 68a) and 2-amino-2-(3-methyloxetan-3-yl)acetonitrile (example 251b) as starting materials and isolated (180 mg, 83%); MS (ESI, m/z): 384.6 (M+H+).
Reaction SMILES: Br[CH2:2][N:3]1[C:7](=[O:8])[CH2:6][S:5][C:4]1=[O:9].[SH:10][C:11]1[N:16]2[CH:17]=[CH:18][N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)C>[N:19]1[CH:18]=[CH:17][N:16]2[C:11]([S:10][CH2:2][N:3]3[C:7](=[O:8])[CH2:6][S:5][C:4]3=[O:9])=[CH:12][CH:13]=[CH:14][C:15]=12
Reactant: Sc1cccc2nccn12
Reactant: O=C1CSC(=O)N1CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1CSC(=O)N1CSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a nitrogen atmosphere, 2.10 g (10 mmol) of 3-bromomethylthiazolidine-2,4-dione was added to a solution of 1.50 g (10 mmol) of 5-mercaptoimidazo[1,2-a]pyridine and 1.67 ml (10 mmol) of triethylamine in 50 ml of ethanol, followed by stirring at room temperature for 16 hours. After the solvent was distilled off, the residue was dissolved in dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate) to yield 1.41 g (50.5%, light brown solid) of the desired product.
Reaction SMILES: [CH:1]1([C:7]2[CH:25]=[CH:24][C:10]([O:11][CH2:12][C@H:13]3[O:23][C:16]4=[N:17][C:18](=[O:22])[C@@H:19]([CH3:21])[CH2:20][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[CH:1]1([C:7]2[CH:25]=[CH:24][C:10]([O:11][CH2:12][C@H:13]3[O:23][C:16]4=[N:17][C:18](=[O:22])[C:19]([CH3:21])=[CH:20][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H]1CN2C[C@@H](COc3ccc(C4CCCCC4)cc3)OC2=NC1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: Cc1cn2c(nc1=O)O[C@H](COc1ccc(C3CCCCC3)cc1)C2
Temperature: 110 °C
Yield: 21.2 %

Procedure:
To a solution of (2S,6S)-2-(4-cyclohexyl-phenoxymethyl)-6-methyl-2,3,5,6-tetrahydro-oxazolo[3,2-a]pyrimidin-7-one (38 mg, 0.111 mmol) in toluene (3 ml) was added 96 mg (1.11 mmol) of manganese(IV) oxide. The reaction mixture was heated at 110° C. overnight. The reaction mixture was filtered and the filtrate concentrated and loaded onto a silica gel column, and eluted with 2-7% isopropanol/methylene chloride to afford 8 mg of (S)-2-(4-cyclohexyl-phenoxymethyl)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([C:8]1[CH:9]=[C:10]([NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21]C=2O)=[O:16])[CH:11]=[CH:12][CH:13]=1)#[N:7].Cl>O1CCCC1.N1C=CC=CC=1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][C:5]2[O:4][C:2](=[O:3])[N:14]([C:10]3[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=3)[C:6]#[N:7])[C:15](=[O:16])[C:17]=2[CH:18]=1
Reactant: COC(=O)Cl
Reactant: N#Cc1cccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1cccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 49 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 9 (1.4 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 21.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11]([O:15][C:16](=[O:23])[NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:20]2[CH2:21][CH2:22][C@@H:18]([NH:17][C:16](=[O:23])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:19]2)=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(Br)cc2C=O)C1
Temperature: 120 °C
Yield: 83.3 %

Procedure:
5-Bromo-2-fluorobenzaldehyde (1.55 mL, 13.0 mmol) and tert-butyl-(3R)-pyrrolidin-3-ylcarbamate (2.90 g, 15.6 mmol) in DMF (70 mL) were treated with potassium carbonate (2.25 g, 16.3 mmol). The solution was heated to 120° C. for 18 h under nitrogen. The solution was allowed to cool to ambient temperature and was diluted with ethyl acetate (150 mL) and washed with water (100 mL). The organic phase was separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (30% ethyl acetate/hexanes) to afford product 22-A as a yellow solid (4.00 g, 83%). 1H NMR (500 MHz, CD3OD): δ 10.02 (s, 1H), 7.81 (d, J=2.9 Hz, 1H), 7.51 (dd, J=11.2, 2.4 Hz, 1H), 6.88 (d, J=9.27 Hz, 1H), 4.20 (m, 1H), 3.60–3.51 (m, 2H), 3.42 (m, 1H), 3.21 (m, 1H), 2.22 (m, 1H), 2.00 (m, 1H), 1.46 (s, 9H); LCMS found for C16H21N2O3Br (M+H)+: m/z=370.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[C:4]=1[CH:15]=[O:16].C(=O)([O-])O.[Na+]>ClCCl>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[C:4]=1[CH:15]=[O:16]
Reactant: COc1ccc2ccc(OC)c(C=O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2ccc(O)c(C=O)c2c1
Reaction time: 0.58 h

Procedure:
After the dimethoxylated product obtained in Step B (2 g: 9.25 mmol) has been dissolved in anhydrous dichloromethane, 97% BBr3Me2S complex (2.98 g: 9.25 mmol 1 eq.) is introduced at ambient temperature. After 35 minutes of stirring, hydrolysis is carried out with a saturated solution of sodium hydrogen carbonate (pH=8). The product is extracted with dichloromethane and then purified on a silica column AcOEt/PE (3/7).
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[N:5]=[N:6][N:7]([CH3:9])[N:8]=1.[I-:10].[Na+]>CC(C)=O.O>[I:10][CH2:2][S:3][C:4]1[N:5]=[N:6][N:7]([CH3:9])[N:8]=1
Reactant: Cn1nnc(SCCl)n1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1nnc(SCI)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 5-chloromethylthio-2-methyltetrazole (987 mg : 6.0 mMol.) in acetone (10 ml) is added sodium iodide (1.78 g : 12.00 mMol.), and the mixture is stirred at 50° C. for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and concentrated to give 5-iodomethylthio-2-methyltetrazole (1.43 9) as yellow oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:39][CH:38]=2)=[CH:33][C:32]=1[C:48]1[CH:57]=[CH:56][C:55]2[C:54]([CH3:59])([CH3:58])[CH2:53][CH2:52][C:51]([CH3:61])([CH3:60])[C:50]=2[CH:49]=1)(C(C)(C)C)(C)C.O>O1CCCC1>[OH:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[CH:39][C:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:41][CH:42]=2)=[CH:33][C:32]=1[C:48]1[CH:57]=[CH:56][C:55]2[C:54]([CH3:59])([CH3:58])[CH2:53][CH2:52][C:51]([CH3:60])([CH3:61])[C:50]=2[CH:49]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(OCCCO)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
6.9 ml (6.9 mmol) of a solution of tetrabutylammonium fluoride (1 M) are added to a solution of 2.75 g (4.6 mmol) of ethyl 4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate in 20 ml of tetrahydrofuran, in a three-necked flask. The reaction mixture is stirred for 4 h at ambient temperature. The reaction is stopped by adding 20 ml of water and the mixture is then extracted with ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvents are evaporated off. The crude obtained in the form of an oil is chromatographed on silica gel (heptane/ethyl acetate: 70/30) to give 2 g of ethyl 4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate in the form of a colorless oil (yield=89%).
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:17][S:14]([CH2:13][CH2:12][CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:18])=[CH:9][CH:8]=1)(=[O:15])=[O:16]
Reactant: COC(=O)c1ccc(OCCCS(C)(=O)=O)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Product: CS(=O)(=O)CCCOc1ccc(C(=O)N2CCC[C@H]2CN2CCCC2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B and D starting from 4-(3-methanesulfonyl-propoxy)-benzoic acid methyl ester and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 395.3.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:21])[S:7](=[O:20])(=[O:19])[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12][C:9]=2[C:10]=1[OH:11])(OC)=[O:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1(C)C(C)=CC=CC=1>CO>[OH:11][C:10]1[C:9]2[S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:8]=2[S:7](=[O:19])(=[O:20])[N:6]([CH3:21])[C:5]=1[C:1]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:2]
Reactant: Nc1ccccn1
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Solvent: CO
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2sc3ccccc3c2S1(=O)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5 g. of 3-carbomethoxy-4-hydroxy-2-methyl-2H-[1]benzothieno[2,3-e]-1,2-thiazine 1,1-dioxide and 3 g. of 2-aminopyridine are treated with 150 ml. of a xylene isomer mixture and heated so that the resulting methanol distils off azeotropically. After 6 hours, the mixture is left to cool to room temperature. The cyrstals obtained are filtered off under suction and washed with a xylene mixture. After recrystallization from dimethylformamide and addition of methanol, there is obtained 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-[1]benzothieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide in the form of yellow crystals of melting point 222°-224° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[S:3]1.[NH2:32][CH2:33][CH:34]([C:36]1[CH:37]=[CH:38][C:39]([OH:47])=[C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:41]=1)[OH:35]>>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH2:30][CH2:29][CH:28]([NH:32][CH2:33][CH:34]([OH:35])[C:36]5[CH:37]=[CH:38][C:39]([OH:47])=[C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:41]=5)[CH2:27][CH2:26]4)=[CH:23][CH:24]=3)(=[O:16])=[O:17])=[CH:11][CH:10]=2)[S:3]1
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(CC4SC(=O)NC4=O)cc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(NS(=O)(=O)c4ccc(CC5SC(=O)NC5=O)cc4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 4-(2,4-dioxo-thiazolidin-5-ylmethyl)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 231) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.45–1.60 (m, 2 H), 1.85–2.05 (m, 2 H), 2.50–3.50 (m, 7 H), 2.93 (s, 3 H), 3.59 (brd, J=11.9 Hz, 2 H), 4.28 (dd, J=7.0, 3.8 Hz, 1 H), 4.60–4.65 (m, 1 H), 6.70–6.90 (m, 5 H), 7.05 (dd, J=8.3, 1.9 Hz, 1 H), 7.21 (d, J=1.9 Hz, 1 H), 7.33 (d, J=8.3 Hz, 2 H), 7.55 (d, J=8.3 Hz, 2 H); MS (ES) m/z: 690.0 (MH+); HRMS Calcd. for C30H36N5O8S3 (MH+): 690.1726. Found: 690.1714.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[OH:12].[C:13]([CH2:15][C:16](O)=[O:17])#[N:14].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:13]([CH2:15][C:16]([O:12][C:3]1[C:2]([F:1])=[C:7]([F:8])[C:6]([F:9])=[C:5]([F:10])[C:4]=1[F:11])=[O:17])#[N:14]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: N#CCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a solution of 2,3,4,5,6-pentafluorophenol (1.08 g, 5.88 mmol) and 2-cyanoacetic acid (0.50 g, 5.9 mmol) in DCM (20 mL) was added DCC (1.21 g, 5.88 mmol). After stirring for about 4 h at ambient temperature, the reaction was concentrated under reduced pressure and then purified over silica gel (20 g) using DCM as the eluent to afford perfluorophenyl 2-cyanoacetate as a white solid (1.39 g, 94%): 1H NMR (400 MHz, CDCl3) δ 3.85 (s, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:14])[CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[F:15].Br[CH2:17][C:18]([OH:20])=[O:19]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([O:14][CH2:17][C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]=1[F:15]
Reactant: OC1(c2ccc(Cl)c(F)c2)CCC1
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)COC1(c2ccc(Cl)c(F)c2)CCC1
Reaction time: 0.5 h

Procedure:
To an ambient suspension of NaH (0.341 g, 8.52 mmol, 60% dispersion in mineral oil) in N,N-dimethylformamide (7 mL) was added a solution of Example 56A (0.342 g, 1.71 mmol) in N,N-dimethylformamide (1 mL) dropwise. The reaction was stirred for 0.5 h, and 2-bromoacetic acid (0.474 g, 3.41 mmol) was added as a solution in N,N-dimethylformamide (2 mL) dropwise. The reaction was stirred at room temperature for 24 h and was then quenched by the slow addition of H2O (10 mL) and diethyl ether (15 mL). The layers were separated, and the organic discarded. The aqueous was acidified to pH ˜4-5 with 10% HCl and was extracted with diethyl ether (3×15 mL). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil, which was used without further purification in the subsequent step, MS (ESI) m/z 259[M+H]+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[S:12][N:11]=[N:10][C:9]=2[C:13]([NH2:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:17]1([C:22](N)=[NH:23])C=CC=N1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[C:1]1([NH:7][C:8]2[S:12][N:11]=[N:10][C:9]=2[CH2:13][NH:15][C:22]([NH2:23])=[NH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N=C(N)n1cccn1
Reactant: NC(=O)c1nnsc1Nc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NCc1nnsc1Nc1ccccc1
Temperature: 80 °C

Procedure:
To a 2 mL pyridine solution of 5-phenylamino-[1,2,3]thiadiazole-4-carboxylic acid amide (50 mg, 0.24 mmole), was added the powder of 1H-pyrazole-1-carboxamidine hydrochloride (235 mg, 1.59 mmole) and diisopropyl ethylamine (234 mg, 1.8 mmole). Then the mixture was heated to about 80° C. The reaction mixture was cooled to room temperature for 4 hours and the solvent was then evaporated. The residue was loaded onto a preparative TLC plate and eluted sequentially with neat CH2Cl2 and CH2Cl2:MeOH (4:1). A 94 mg of crude product was collected, which was further purified by another preparative TLC (silica gel, CH2Cl2:MeOH:H2O=3.6:0.4:0.06). The title compound was obtained in 40 mg (66%). 1H NMR (ppm, CDCl3): 9.33 (br. t, 1H), 8.01 (br. s, 1H), 7.63-7.82 (m, 2H), 7.20-7.40 (m, 3H), 6.37 (br. s, 2H), 6.08 (br. s, 1H), 4.41 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:32][O:33][CH2:34][CH:35]=[CH2:36])[C:8]([NH:10][CH:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([OH:29])=[O:28])=[C:15]([S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:43]([O:46][CH:47](Br)[CH3:48])(=[O:45])[CH3:44].C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:32][O:33][CH2:34][CH:35]=[CH2:36])[C:8]([NH:10][CH:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([O:29][CH:47]([O:46][C:43](=[O:45])[CH3:44])[CH3:48])=[O:28])=[C:15]([S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OC(C)Br
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(S/C=C\c3cccnc3)CS[C@H]12)c1csc(N)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(S/C=C\c3cccnc3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
To a solution of 7-[2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylic acid (syn isomer) (1.0 g) in N,N-dimethylformamide (20 ml) was added cesium carbonate (0.31 g). The mixture was stirred for 20 minutes at room temperature, and 1-bromoethyl acetate (0.96 g) was added dropwise thereto at 0°-3° C. After the mixture was stirred for 40 minutes, 1-bromoethyl acetate (0.3 g) was added thereto. After stirring for 1 hour, reaction mixture was poured into ethyl acetate (120 ml) and the insoluble material was filtered off. The filtrate was washed with water (120 ml×2), an aqueous solution of sodium bicarbonate (50 ml × 1) and a saturated aqueous solution of sodium chloride successively and dried over magnesium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was pulverized with diisopropyl ether to give 1-acetoxyethyl 7-[2-(2-aminothiazol- 4-yl)-2-allyloxyiminoacetamido]-3-[(Z)-2-(3-pyridyl) vinylthio]-3-cephem-4-carboxylate (syn isomer) (0.27 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([C:9]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:30]=[CH:29][C:24]3[B:25]([OH:28])[O:26][CH2:27][C:23]=3[CH:22]=2)=[CH:16][C:10]=1[O:11][CH2:12][C:13](O)=[O:14])#[N:8]>>[OH:28][B:25]1[C:24]2[CH:29]=[CH:30][C:21]([O:20][C:17]3[CH:18]=[CH:19][C:9]([C:7]#[N:8])=[C:10]([O:11][CH2:12][C:13]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:14])[CH:16]=3)=[CH:22][C:23]=2[CH2:27][O:26]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1OCC(=O)O
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1OCC(=O)N1CCOCC1

Procedure:
Following the general procedure, morpholine (80 μL, 0.93 mmol) was coupled with [2-cyano-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenoxy]-acetic acid ((D39), 150 mg, 0.46 mmol) to give a crude oil containing (D41). Purification by reverse phase HPLC followed by lyophilization gave a white solid of (D41) (38 mg, 21%). 1H NMR 400 MHz (d6-DMSO) δ: 9.32 (br s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.21 (br s, 1H), 7.15 (dd, J=9.0, 1.5 Hz, 1H), 6.90 (d, J=1.5 Hz, 1H), 6.65 (dd, J=8.5, 1.5 Hz, 1H), 5.17 (s, 2H), 5.03 (s, 2H), 3.65-3.55 (m, 4H), 3.49-3.40 (m, 4H); MS (ES) m/z: 395 (M+H)+; HPLC purity 96.02% (Maxplot), 97.64% (220 nm) and 97.18% (254 nm).
Reaction SMILES: [N:1]([CH:4]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][CH:16]=1)[CH2:5][CH:6]1OCC[O:7]1)=[N+:2]=[N-:3].Cl.C(OCC)C>O1CCCC1>[N:1]([CH:4]([C:11]1[CH:16]=[N:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=1)[CH2:5][CH:6]=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC(CC1OCCO1)c1ccc(C(F)(F)F)nc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: [N-]=[N+]=NC(CC=O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-(1-azido-2-(1,3-dioxolan-2-yl)ethyl)-2-(trifluoromethyl)pyridine (7.44 g, 25.8 mmol) in tetrahydrofuran (60 mL) was treated with 20% aq. HCl (60 mL) at 0° C. The mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, ethyl ether was added and the organic layer was separated, dried over MgSO4, and concentrated to yield a crude oil without further purification.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=O.[NH2:14]N.O>C(O)C>[O:10]1[CH2:11][CH2:12][CH:7]([C:5]2[CH:4]=[CH:3][NH:2][N:14]=2)[CH2:8][CH2:9]1
Reactant: CN(C)/C=C/C(=O)C1CCOCC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: c1cc(C2CCOCC2)n[nH]1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of (E)-3-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)prop-2-en-1-one (compound 294.1, 4.3 g, 23.4 mmol) in ethanol (20 mL) was added NH2NH2.H2O (1.41 g, 28.2 mmol). The reaction mixture was stirred for 3 h at 80° C. The resulting mixture was concentrated under reduced pressure to yield 4.45 g (crude) of the title compound as a light yellow solid.