Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:10]2[N:11]=[C:12]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:15]=3)=[C:9]2[CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[H][H]>C(O)C.[Pd]>[CH2:21]([NH:20][C:16]1[N:15]=[C:14]([C:13]2[C:12]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[N:11][N:10]3[C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=[CH:8][C:9]=23)[CH:19]=[CH:18][N:17]=1)[CH2:22][CH2:23][CH3:24]
Reactant: [H][H]
Reactant: C=CCNc1cccc2c(-c3ccnc(NCCCC)n3)c(-c3ccc(F)cc3)nn12
Agent: [Pd]
Solvent: CCO
Product: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(NCCC)cccc23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of N-allyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine (80 mg, 0.19 mmol) in ethanol (5 mL) was added palladium on carbon (10%, 8 mg). The mixture was stirred overnight at room temperature under a balloon filled with hydrogen. The reaction was filtered through a pad of Celite and concentrated to give 3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-propylpyrazolo[1,5-α]pyridin-7-amine (79 mg, 99%) as a gold foam. 1H NMR (CDCl3): δ 8.03 (d, 1H), 7.74 (d, 1H), 7.69 (m, 2H), 7.33 (t, 1H), 7.15 (t, 2H), 6.30 (d, 1H), 6.08–6.01 (m, 2H), 5.08 (broad, 1H), 3.47 (q, 2H), 3.37 (q, 2H), 1.87–1.41 (m, 6H), 1.08 (t, 3H), 0.99 (t, 3H); 19F NMR (CDCl3) δ −113.44; MS m/z 419 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.CC(S(N)=O)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.[NH:70]1[C:74]([CH2:75][NH2:76])=[N:73][N:72]=[N:71]1>CN(C)C=O>[N:70]1[NH:71][N:72]=[N:73][C:74]=1[CH2:75][NH:76][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][C:22]([NH:21][CH:4]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)[CH2:3][CH:2]([CH3:1])[CH3:31])=[N:23][CH:24]=1
Reactant: CC(C)CC(Nc1ccc(C(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: NCc1nnn[nH]1
Agent: CC(C)(C)S(N)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)CC(Nc1ccc(C(=O)NCc2nn[nH]n2)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
A 5 mL vial equipped with a stir bar was charged with 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinic acid (0.100 g, 0.233 mmol) as prepared in Example 1.1 using racemic 2-methylpropane-2-sulfinamide in Step B, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (133.0 mg, 0.350 mmol), N-methylmorpholine (118.0 mg, 1.167 mmol), N,N-dimethylformamide (1.2 mL). The mixture was purged with nitrogen, heated to 50° C. and stirred for 30 minutes. Then, (1H-tetrazol-5-yl)methanamine (39.9 mg, 0.233 mmol) was added. The mixture was stirred at 50° C. overnight. The reaction mixture was purified by prep-HPLC to give (+/−)-N-((2H-tetrazol-5-yl)methyl)-6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinamide (10 mg, 4.2%) as a white solid. 1H NMR (400 MHz, CD3OD, δ): 8.50 (d, 1H), 7.86 (dd, 1H), 7.80 (d, 2H), 7.72 (d, 2H), 7.64 (d, 2H), 7.50 (d2H), 6.58 (d, 1H), 5.11 (m, 1H), 4.82 (s, 2H), 1.89-1.82 (m, 1H), 1.80-1.72 (m, 1H), 1.68-1.62 (m, 1H), 1.03 (d, 3H), 1.00 (d, 3H) ppm. MS (M+1): 510.3
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23](Cl)[N:22]=1.CCN(CC)CC>CN(C=O)C>[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23]([NH:19][C@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:18])[N:22]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1C1CCOCC1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1C1CCOCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
To a 20 mL vial were added (S)-1-(1-methyl-6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (336 mg, 1.296 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (242 mg, 1.425 mmol) and Et3N (1.8 mL, 13 mmol) in DMF (7 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The crude product was purified by preparative HPLC eluting with 25-50% ACN in water (with 0.05% ammonium bicarbonate). The fractions containing the desired product were combined and lyophilized to give the title compound as a white solid (147 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37-1.51 (m, 3 H), 1.58-1.87 (m, 3 H), 1.91-2.07 (m, 1 H), 3.04-3.18 (m, 1 H), 3.43-3.60 (m, 3 H), 3.77-3.88 (m, 3 H), 3.90-4.08 (m, 2 H), 5.64-5.80 (m, 1H), 6.39-6.54 (m, 3 H), 6.56-6.67 (m, 2 H), 6.82-6.96 (m, 1 H), 7.54-7.66 (m, 1 H), 7.81-7.96 (m, 1 H),); ESI-MS m/z [M+H]+ calc'd for C20H24N8O, 393; found 393.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.[ClH:19]>C(Cl)Cl>[ClH:19].[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCN(CC)CCN
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 8.3 g (71 mmol) of N,N-diethylethylenediamine under nitrogen atmosphere add 6.6 g (47 mmol) of 4-fluoronitrobenzene. Stir the mixture at ambient temperature for 1 day and heat at 45° C. for 4 h. Upon completion of the reaction add 100 mL of CH2Cl2 and 100 mL 1M HCl. Separate the layers and add 50% sodium hydroxide to the aqueous layer until it is basic. Extract the aqueous layer with 2×100 mL CH2Cl2, dry the organics over anhydrous Na2SO4. Remove drying agent by filtration and remove solvent in vacuo. Dissolve the residue in methanolic HCl and remove the solvent in vacuo. Recrystallize the solid from EtOH to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.C1C(=O)N([Br:21])C(=O)C1.[OH-].[K+]>OS(O)(=O)=O>[Br:21][C:4]1[C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=[C:12]([CH3:13])[C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2sc(N)nc2cc1C
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: COc1c(C)cc2nc(N)sc2c1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 6-methoxy-5-methylbenzo[d]thiazol-2-amine (5A) (1.0 g, 5.15 mmol) in H2SO4 at 0° C., was added NBS (550 mg, 3.07 mmol). The reaction mixture was stirred at 0° C. for 2 h. Then the reaction mixture was poured to ice-water, neutralized by 50% KOH solution to pH about 3. The precipitation was collected, washed by water and dried over high vacuum. LCMS-ESI+: calc'd for C9H9BrN2OS: 273.0 (M+H+). Found: 273.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].Cl.[NH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][C:26]=1[CH3:38].C1CCN(C(Cl)=[N+]2CCCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:3][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][C:26]=3[CH3:38])=[O:18])=[CH:20][CH:21]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CCOC(=O)COc1ccc(N)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Agent: ClC(N1CCCCC1)=[N+]1CCCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.1 %

Procedure:
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 4-(4-(1,1-dimethylethoxycarbonyl) piperazinyl)benzoic acid (0.75 g, 2.45 mmol), ethyl 4-amino-3-methylphenoxyacetate hydrochloride (0.60 g, 2.45 mmol), chloro-N,N,N',N',-bis(pentamethylene)formamidinium hexafluorophosphate (0.97 g, 2.69 mmol), and CH2Cl2 (30 mL). This mixture was cooled in an ice bath and diisopropylethylamine (1.74 mL, 10.0 mmol) was added. The ice bath was allowed to expire and the solution was stirred at ambient temperature for 48 h. The solution was diluted with CHCl3 and washed with 10% aqueous citric acid, saturated aqueous NaHCO3, and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on 75 g of silica gel using 50% EtOAc-hexane as eluant. There was obtained 1.22 g (100%) of ethyl 2-(4-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)phenylcarbonylamino)-3-methylphenoxy)acetate as a crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:24][CH2:25][CH2:26][O:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: COC(=O)c1ccc(OCCN)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(OCCNC(=O)c2ccc(Br)cc2)cc1
Yield: 56.7 %

Procedure:
p-Bromobenzoic acid (6 g) and 3.35 g of triethylamine were dissolved in 80 ml of chloroform, the mixture was cooled at 0°-5° C. with stirring, and 3.26 g of ethyl chlorocarbonate was dropped thereinto. The mixture was stirred at the same temperature for 30 minutes, 5.86 g of methyl 4-(2-aminoethoxy)benzoate was added, and the mixture was stirred for 7 hours more. The reaction solution was washed with 10% hydrochloric acid, saturated potassium carbonate solution, and with water, dried with anhydrous magnesium sulphate, concentrated in vacuo, the residue was crystallised with n-hexane, and 8.5 g of crystals obtained were recrystallised from ethyl acetate to give 6.4 g of the product, m.p. 134°-136° C.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@H:44]([C:60]([N:62]2[CH2:66][CH2:65][C@H:64]([CH2:67][N:68]3[CH2:72][CH2:71][CH2:70][CH2:69]3)[CH2:63]2)=[O:61])[CH2:43]1>CN(C)C=O.C(N(C(C)C)CC)(C)C>[OH:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:19]2[C:20]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])=[C:16]([S:41][C@@H:42]3[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=4)=[O:48])[C@H:44]([C:60]([N:62]4[CH2:66][CH2:65][C@H:64]([CH2:67][N:68]5[CH2:69][CH2:70][CH2:71][CH2:72]5)[CH2:63]4)=[O:61])[CH2:43]3)[C@H:17]([CH3:40])[C@H:18]12)[CH3:37]
Reactant: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](CN2CCCC2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](CN5CCCC5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 20 h

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (225 mg) in anhydrous dimethylformamide (3 ml), a solution of (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3R)-3-(pyrrolidin-1-ylmethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine (198 ml) in anhydrous dimethylformamide (1 ml) and diisopropylethylamine (97 μl) were added in an ice bath. The resulting mixture was stirred for 20 hours at the same temperature. The reaction mixture was concentrated by evaporation under reduced pressure. The residue was dissolved in ethyl acetate. The resulting mixture was washed successively with water and saturated saline solution and dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue was subjected to chromatography through a silica gel column and from the fraction eluted with ethyl acetate/methanol=4/1, 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3R)-3-(pyrrolidin-1-ylmethyl)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (235 mg) was obtained as a powder.
Reaction SMILES: [CH2:1]([O:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:22].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-:22])=[CH:8][C:7]=2[N:6]=[CH:5]1)[CH3:2]
Reactant: CCOn1cnc2cnc3ccccc3c21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOn1cnc2c[n+]([O-])c3ccccc3c21
Temperature: 0 °C
Yield: 91 %

Procedure:
A solution of 1-ethoxy-1H-imidazo[4,5-c]quinoline (2.45 g, 11.5 mmol) in dichloromethane (100 mL) was cooled to approximately 0° C., and 3-chloroperoxybenzoic acid (3.85 g of approximately 77% pure material, 17 mmol) was added. The reaction was stirred for ten minutes at 0° C., stirred for three hours at room temperature, and then stirred with saturated aqueous sodium bicarbonate (35 mL) for 15 minutes. The aqueous layer was separated and extracted with dichloromethane (5×50 mL), and the combined organic fractions were dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 2.4 g of 1-ethoxy-5-oxido-1H-imidazo[4,5-c]quinoline as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.C1(P(=[N:59][CH:60]2[CH:64]([O:65][CH2:66][CH3:67])[O:63][C:62](=[O:68])[CH2:61]2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:15])[NH:59][CH:60]1[CH2:61][C:62](=[O:68])[O:63][CH:64]1[O:65][CH2:66][CH3:67])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC1OC(=O)CC1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC1OC(=O)CC1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 64.3 %

Procedure:
A solution of (S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.11 g, 0.5 mmol), di-isopropylethylamine (0.18 mL, 1.0 mmol), and tetramethylfluoroformamidinium hexafluorophosphate (TFFH) (0.13 g, 0.5 mmol) in dichloromethane (3 mL) was stirred at room temperature under nitrogen for 3 h. A solution of 4-[(triphenylphosphoranylidene)amino]-5-ethoxy-dihydrofuran -2-one (0.20 g, 0.5 mmol) in dichloromethane (3 mL) was added and the mixture was stirred for 24 h. The reaction was diluted with ethyl acetate, was washed with 10% sodium bisulfate, saturated sodium bicarbonate, and brine, was dried over sodium sulfate, and was evaporated. Purification by flash chromatography (SiO2) eluted with 1:1 ethyl acetate:hexanes provided (R)-2-(2-ethoxy-5-oxo-tetrahydrofuran -3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.11 g, 65% yield) as a very viscous, pale yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[N:10]=[CH:9][N:8]([CH2:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]2=[O:30].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].[CH:44]([S:46]([CH3:49])(=[O:48])=[O:47])=[CH2:45]>CO.C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:45][CH2:44][S:46]([CH3:49])(=[O:48])=[O:47])[CH2:20][CH2:21]1)[N:10]=[CH:9][N:8]([CH2:22][O:23][C:24](=[O:29])[C:25]([CH3:26])([CH3:27])[CH3:28])[C:7]2=[O:30]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCNCC1
Reactant: C=CS(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of 6-methoxy-7-((piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one hydrochloride (0.88 g, 2 mmol) and triethylamine (0.3 ml, 2.1 mmol) in methanol (10 ml) and methylene chloride (10 ml) was added potassium carbonate (280 mg, 2 mmol) and methyl vinyl sulfone (0.4 ml, 2.1 mmol). After stirring for 2 hours at ambient temperature, the volatiles were removed under vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and evaporated to give 6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (0.55 g, 54%).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH:32]1([CH2:35]Br)[CH2:34][CH2:33]1>CN(C)C=O>[CH:32]1([CH2:35][N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[CH3:28])[CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])[CH2:34][CH2:33]1
Reactant: BrCC1CC1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC2CC2)C1
Yield: 53 %

Procedure:
The title compound was synthesized in analogy to example 51, from (RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 42, intermediate a)), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless foam (53%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][N:6]([C@@H](C2C=CC=CC=2)C)[C:5](=[O:16])[NH:4]1.[H-].[Na+].Cl[C:20]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=2)[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2.[CH3:40]C(N(C)C)=O>>[CH3:39][O:38][C:32]1[CH:31]=[C:30]([C:28]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[N:25]3)=[C:20]([O:1][CH2:2][C@@H:3]3[N:4]([CH3:40])[C:5](=[O:16])[NH:6][CH2:7]3)[N:29]=2)[CH:35]=[CH:34][C:33]=1[O:36][CH3:37]
Reactant: COc1ccc(-c2cc3ncccc3c(Cl)n2)cc1OC
Reactant: CC(=O)N(C)C
Reactant: C[C@H](c1ccccc1)N1C[C@H](CO)NC1=O
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2cc3ncccc3c(OC[C@H]3CNC(=O)N3C)n2)cc1OC
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
174 mg (R)-4-Hydroxymethyl-1-((R)-1-phenyl-ethyl)-imidazolidine-2-one (2.28) was placed in 2 mL dimethylacetamide under nitrogen at ambient temperature before 37.8 mg sodium hydride (60% dispersion in oil) was added. The reaction was stirred for 10 min and then 296 mg 5-chloro-7-(3,4-dimethoxy-phenyl)-[1,6]naphthyridine (6.37) as a solution in 2 mL dimethylacetamide was added. The mixture was heated to 90° C. where it was maintained for 2 h. After this time additional sodium hydride was added and the reaction was stirred at 90° C. for a further 16 h and then at ambient temperature for 3 d. After this time the reaction was heated to 90° C. for 24 h and then it was cooled to ambient temperature. The reaction was quenched by the addition of 5 mL water and extracted with ethyl acetate (×3). The organic fractions were combined, dried over sodium sulfate, filtered and the solvent was removed from the filtrate under reduced pressure. Purification by silica gel chromatography (ethyl acetate/dichloromethane: 5-7% then switching to methanol/ethyl acetate: 10%) provided the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:20][C:6]2[N:7]=[C:8]([NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:12])[S:9][C:5]=2[C:4]([CH3:22])([CH3:21])[CH2:3]1.[CH2:24]1OCO[CH2:26][O:25]1.S(=O)(=O)(O)O.[OH-].[Na+]>O>[CH3:23][C:2]1([CH3:1])[CH2:20][C:6]2[N:7]=[C:8]([N:10]3[C:11](=[O:12])[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:26][O:25][CH2:24]3)[S:9][C:5]=2[C:4]([CH3:22])([CH3:21])[CH2:3]1
Reactant: CCCCCCNC(=O)Nc1nc2c(s1)C(C)(C)CC(C)(C)C2
Reactant: C1OCOCO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCN1COCN(c2nc3c(s2)C(C)(C)CC(C)(C)C3)C1=O
Temperature: 5 °C
Reaction time: 16 h

Procedure:
Sulfuric acid, 85% concentration, (40 grams) is charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and is cooled to about 5° C. N-(5,5,7,7-tetramethyl-4,5,6,7-tetrahydrobenzothiazol-2-yl)-N'-hexylurea (0.015 mole) and s-trioxane (0.015 mole) are added portionwise, with stirring to the cold sulfuric acid. Stirring is continued for a period of about 16 hours at room temperature. The reaction mixture is then diluted 1:1 with water and neutralized with aqueous 40% sodium hydroxide. The neutralized mixture is filtered and the filtered-off solid is washed with 3-100 ml portions of water and air dried to yield the desired product 3-(5,5,7,7-tetramethyl-4,5,6,7-tetrahydrobenzothiazol-2-yl)-5-hexyltetrahydro-1,3,5-oxadiazin-4-one.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7]Br.[NH2:9][CH:10]1[C:36](=[O:37])[N:12]2[C:13]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:14](/[CH:17]=[CH:18]/[Cl:19])[CH2:15][S:16][C@H:11]12.C[Si](CC(N)=O)(C)C>C(Cl)Cl.C(OCC)(=O)C.O>[Br:7][CH2:6][C:2](=[O:1])[CH2:3][C:4]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[C:13]([C:20]([O:22][CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:14](/[CH:17]=[CH:18]/[Cl:19])[CH2:15][S:16][C@H:11]12)=[O:5]
Reactant: C=C1CC(=O)O1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12
Reactant: BrBr
Agent: C[Si](C)(C)CC(N)=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12
Reaction time: 0.33 h
Yield: 101.6 %

Procedure:
To a solution of diketene (1.01 g) in methylene chloride (15 ml) was dropwise added bromine (1.53 g) at -20° C., and the mixture was stirred at the same temperature for 20 minutes and added to a solution of benzhydryl 7-amino-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (3.42 g) and trimethylsilylacetamide (5.3 g) in ethyl acetate (40 ml) at the same temperature. The reaction mixture was stirred at -10° to -15° C. for 10 minutes, poured into water and extracted with ethyl acetate. The extract was washed with 10% aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was triturated with diisopropyl ether and collected by filtration to give benzhydryl 7-(4-bromo-3-oxobutyramido)-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (4.8 g).