Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13]SC3C([N+]([O-])=O)=CC=CN=3)[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[CH2:59][C:60]([C:62]1[CH:63]=[CH:64][C:65]2[O:69][CH2:68][CH2:67][C:66]=2[CH:70]=1)=[O:61].CCN(CC)CC>CC(C)=O.O>[O:69]1[C:65]2[CH:64]=[CH:63][C:62]([C:60](=[O:61])[CH2:59][S:13][C@H:10]3[C:11](=[O:12])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C@@H:9]3[C:24]3[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:37][CH:38]=3)=[CH:70][C:66]=2[CH2:67][CH2:68]1
Reactant: CC(C)(C)OC(=O)COc1ccc([C@@H]2[C@@H](SSc3ncccc3[N+](=O)[O-])C(=O)N2c2ccc(F)cc2)cc1
Reactant: O=C(CCl)c1ccc2c(c1)CCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)CCO4)C(=O)N2c2ccc(F)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of tert-butyl (4-{(2R,3R)-1-(4-fluorophenyl)-3-[(3-nitropyridin-2-yl)dithio]-4-oxoazetidin-2-yl}phenoxy)acetate (50.0 mg, 0.090 mmol) in acetone (6 ml) and water (0.8 ml) was added triphenylphosphine (33.3 mg, 0.013 mmol). The reaction mixture was stirred for 15 minutes. The solvent was removed under reduced pressure and the crude thiol was dissolved in DCM (12 ml). Et3N, (30 pd, 0.22 mmol) was added. After 5 minutes, 2-chloro-1-(2,3-dihydro-1-benzofuran-5-yl)ethanone (37.2 mg, 0.19 mmol) was added and the reaction mixture was stirred overnight. Additional triphenylphosphine (11.6 mg, 0.04 mmol), Et3N (10 μl, 1, 0.07 mmol) and 2-chloro-1-(2,3-dihydro-1-benzofuran-5-yl)ethanone (7.2 mg, 0.04 mmol) were added and the reaction mixture was stirred for 1 hour. The formation of the tert-butyl ester of the title compound was confirmed. M/z: 564.24 (M+1) and 562.21 (MA). To the DCM solution of the previous reaction was added TFA (6 ml) and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was purified with preparative HPLC on a C8 column. A gradient from 20 to 70% ACN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The remaining water solution was diluted with additional water and EtOAc. The water phase was acidified with KHSO4 (2M) to pH 2. The phases were separated and the organic phase was passed through a phase separator and concentrated. The oily residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained. H-NMR (400 MHz, DMSO-d6): 3.17 (t, 2H), 4.23 (ABq, 2H), 4.28 (d, 1H), 4.52 (b, 2H), 4.59 (t, 2H), 5.11 (d, 1H), 6.78-6.88 (m, 3H), 7.09-7.15 (m, 2H) 7.16-7.22 (m, 2H), 7.30 (d, 2H), 7.71-7.76 (m, 1H), 7.79 (s, 1H). M/z: 508.13 (M+1) and 506.22 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:21])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][S:12][C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:21])=[C:8]2[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:13][S:12][C:9]2=[C:10]([Br:22])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2snc(-c3ccccc3)c2c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3)c2c1O
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of 4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (1.07 g, 3.56 mmol) in CCl4 was added N-bromosuccinimide (666 mg, 3.74 mmol) and benzoyl peroxide (43.1 mg, 0.18 mmol). The reaction mixture was refluxed with stirring for 4 h. After cooling to r. t. the mixture was filtered. The filtrate was concentrated in vacuo and purified by flash column chromatography on silica gel. Elution with 0-20% EtOAc/CH2Cl2, gave the title compound as white solid (1.08 g): MS (m/z) 378.9, 380.9 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].C([N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19](=[O:27])[CH2:18]1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.C1COCC1>C(=O)(O)[O-].[Na+]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19](=[O:27])[CH2:18]1)=[O:7]
Reactant: O=C1CN(C(=O)c2ccccc2)c2ccccc2N1
Reactant: O=C(Cl)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CN(C(=O)c2ccco2)c2ccccc2N1
Reaction time: 2 h

Procedure:
2-Furoyl chloride (0.49 ml) is added to a solution of the 1,2,3,4-tetrahydroquinoxalin-2-one (IV, EXAMPLE 1, 710 mg), triethylamine (0.80 ml), and THF (20.0 ml) at 0°. The mixture is stirred for 1.5 hr at 0° and for 2 hr at 20°-25°. The mixture was diluted with aq. sodium bicarbonate and extracted with ethyl acetate and chloroform several times. The organic phases are combined, dried with magnesium sulfate, concentrated, and recrystallized from hot ethyl acetate to give the title compound, mp 229°-230° ; IR (mineral oil) 2954, 2925, 1684, 1648, 1504, 1474, 1391, 1373 and 756 cm-1 ; NMR (CDCl3) 8.53, 7.39, 7.1-7.25, 6.85-7.05, 6.45 and 4.59 δ; MS (m/z) 242 and 95.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:37]([O:39][C:40]1[CH:46]=[C:45]([N:47]2[CH2:52][CH2:51][CH:50]([N:53]3[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]3)[CH2:49][CH2:48]2)[CH:44]=[CH:43][C:41]=1[NH2:42])[CH3:38].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[CH:44][C:45]([N:47]4[CH2:52][CH2:51][CH:50]([N:53]5[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]5)[CH2:49][CH2:48]4)=[CH:46][C:40]=3[O:39][CH2:37][CH3:38])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OCC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 42.3 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.10 g, 0.20 mmol), 2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (0.076 g, 0.20 mmol) and para-toluenesulfonic acid (0.090 g, 0.47 mmol) in i-PrOH (5 mL) was heated in a microwave at 175° C. for 25 min. The reaction mixture was concentrated onto silica gel and purified by flash chromatography. Recrystallization from DCM and diethyl ether afforded N-(2,6-difluorophenyl)-2-(ethyloxy)-5-(3-{2-[(2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)benzamide (0.072 g, 43%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.76 (s, 1H), 9.35 (br. s., 1H), 8.36 (s, 1H), 8.24 (d, J=5.2 Hz, 1H), 8.06 (d, J=1.7 Hz, 1H), 7.66-7.81 (m, 2H), 7.35-7.48 (m, 3H), 7.15-7.32 (m, 3H), 6.89-7.01 (m, 1H), 6.67 (d, J=2.3 Hz, 1H), 6.54-6.60 (m, 1H), 6.44-6.53 (m, 1H), 4.23-4.33 (m, 2H), 4.07 (q, J=6.9 Hz, 2H), 3.66-3.80 (m, 2H), 3.05-3.13 (m, 4H), 2.87 (s, 3H), 2.56-2.73 (m, 5H), 2.36-2.46 (m, 2H), 1.78-1.89 (m, 2H), 1.49-1.61 (m, 2H), 1.44 (t, J=6.9 Hz, 3H), 1.25 (t, J=7.0 Hz, 3H). MS (M−H, ES−) 850.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[N:8][N:7]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4].S1C=CC=C1.COCCO.[H][H]>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C:6](=[O:21])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:10](=[O:11])[CH:9]=[N:8]2)=[CH:17][CH:16]=1
Reactant: CCCCn1c(=O)cnn(-c2ccc([N+](=O)[O-])cc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Solvent: COCCO
Product: CCCCn1c(=O)cnn(-c2ccc(N)cc2)c1=O
Yield: 92.8 %

Procedure:
A mixture of 33.9 parts of 4-butyl-2-(4-nitrophenyl)-1,2,4-triazine-3,5(2H,4H)-dione, 2 parts of a solution of thiophene in methanol 4% and 400 parts of 2-methoxyethanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 29 parts (92.8%) of 2-(4-aminophenyl)-4-butyl-1,2,4-triazine-3,5(2H,4H)-dione as a residue (int. 28).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([N:10]([CH2:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])[CH2:11][CH3:12])[CH3:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:8]([N:10]([CH2:13][C:14]1[CH:15]=[C:16]([NH:17][C:1]([CH3:2])=[CH:4][C:5](=[O:7])[CH3:6])[CH:18]=[CH:19][CH:20]=1)[CH2:11][CH3:12])[CH3:9]
Reactant: CC(=O)CC(C)=O
Reactant: CCN(CC)Cc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCN(CC)Cc1cccc(NC(C)=CC(C)=O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.00 g (9.99 mmol) Acetylacetone, 1.78 g (9.99 mmol) 3-[(diethylamino)methyl]-aniline, and 0.15 g (2.5 mmol) 4-toluenesulfonic acid are dissolved in 100 ml toluene. The reaction mixture is refluxed overnight with a Dean-Stark trap to remove water. 0.05 g (0.83 mmol) 4-toluenesulfonic acid are again added and the mixture is refluxed overnight. As tlc control showed that there is some 3-[(diethylamino)-methyl]aniline left, 0.2 g (2 mmol) acetylacetone are added and refluxing is continued for 4 h. To drive the reaction to completion, 0.6 ml (9.98 mmol) acetic acid and 0.2 g (2 mmol) acetylacetone are added and the mixture is refluxed overnight with a Dean-Stark trap. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with dichloromethane/methanol mixtures as eluent.
Reaction SMILES: O.[C:2]1(C)[CH:7]=CC(S(O)(=O)=O)=C[CH:3]=1.C[C:14]([CH3:25])(/[C:20](/[CH2:23][CH3:24])=[CH:21]/[CH3:22])[C@@H:15]([OH:19])[CH2:16][CH2:17][OH:18].[C:26](=O)(O)[O-].[Na+]>CC(C)=O.S([O-])([O-])(=O)=O.[Cu+2].N1C=CC=CC=1>[CH3:3][C:2]1([CH3:7])[O:19][C@H:15](/[C:14](/[CH3:25])=[C:20](\[CH2:21][CH3:22])/[CH:23]([CH3:24])[CH3:26])[CH2:16][CH2:17][O:18]1
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C/C=C(\CC)C(C)(C)[C@@H](O)CCO
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: O
Product: CC/C(=C(/C)[C@@H]1CCOC(C)(C)O1)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
Anhydrous copper sulfate (478 mg, 3.0 mmol, 1.5 equiv), p-toluenesulfonic acid monohydrate (76 mg, 0.4 mmol, 0.2 equiv), and pyridine (24 μl, 0.3 mmol, 0.15 equiv) are added to a solution of (S)-(E)-4,4-dimethyl-5-ethyl-heptane-1,3-diol 28 (372 mg, 2.0 mmol) in acetone (30 ml). The mixture is stirred for 24 h at r.t. Saturated aqueous sodium bicarbonate solution (40 ml) is added, and the aqueous layer is extracted with diethyl ether (4×60 ml). The combined organic extracts are dred over magnesium sulfate and carefully concentrated in vacuo. Purification of the residue by flash column chromatography (pentane/diethyl ether 40:1) affords the title compound 29 (812 mg, 90%) as a colourless oil. 13C-NMR (50 MHz, CDCl3): δ=146.2; 119.3; 98.3; 74.2; 60.4; 42.9; 29.9; 26.2; 24.3; 21.2; 19.2; 14.4; 13.7
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([Cl:13])(=[O:12])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl.Cl.[CH2:16]1[C:26]2=[C:27]3[C:22](=[CH:23][CH:24]=[CH:25]2)[CH2:21][CH2:20][N:19]([CH2:28][CH2:29][CH2:30][NH2:31])[CH:18]3[CH2:17]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[ClH:13].[CH2:16]1[C:26]2=[C:27]3[C:22](=[CH:23][CH:24]=[CH:25]2)[CH2:21][CH2:20][N:19]([CH2:28][CH2:29][CH2:30][NH:31][S:10]([C:8]2[CH:7]=[CH:6][C:5]4[O:1][CH2:2][CH2:3][C:4]=4[CH:9]=2)(=[O:12])=[O:11])[CH:18]3[CH2:17]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)CCO2
Reactant: NCCCN1CCc2cccc3c2C1CC3
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCCCN1CCc2cccc3c2C1CC3)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
2,3-Dihydro-benzofuran-5-sulfonyl chloride (24.05 mg, 0.11 mmol) was added to a solution of 3-(2,2a,4,5-Tetrahydro-1H-3-aza-acenaphthylen-3-yl)-propylamine dihydro-chloride (28.92 mg, 0.1, mmol) and N,N′-diisopropylethylamine (51.7 mg, 0.4 mmol) in CH2Cl2 (10 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×10 mL), dried over Na2SO4 and evaporated to dryness. The free base was dissolved in ethyl acetate (1 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.10 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (33 mg, 77%).
Reaction SMILES: [OH:1][C@H:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3]C(NN)=O.Cl.C([O:18][CH2:19]C)(=O)C.[N:21]([O-])=O.[Na+]>O.CO>[C:8]1([C@H:2]2[O:1][C:19](=[O:18])[NH:21][CH2:3]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(C)=O
Reactant: NNC(=O)C[C@H](O)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1NC[C@@H](c2ccccc2)O1
Temperature: 5 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
In a 1 liter four-necked flask were put 150 g (0.83 mol) of (S)-3-hydroxy-3-phenylpropionohydrazide (optical purity: >99.9%e.e.), 150 g (1.44 mol) of 35% concentrated hydrochloric acid, 220 ml of water, and 100 ml of ethyl acetate. After cooling to 5° C., a solution of 57.5 g (0.83 mol) of sodium nitrite in 80 ml of water was added thereto dropwise at 5° C. over a 1 hour period, followed by stirring at that temperature for 30 minutes. The aqueous layer of the reaction mixture was extracted with 100 ml of ethyl acetate, and the extract was combined with the ethyl acetate layer of the reaction mixture. The combined ethyl acetate extract was washed twice with a 5% sodium chloride aqueous solution. The ethyl acetate layer was added dropwise to 100 ml of hot water at 100° C. thereby to conduct thermal decomposition and to recover the ethyl acetate. After the addition, the residue was cooled to room temperature, 200 ml of ethyl acetate added, and the mixture dried over anhydrous sodium sulfate. The solvent was evaporated to give 123.5 g of a crude product, which was dissolved in a mixed solvent of 150 ml of water and 90 ml of methanol. The solution was cooled to 5° C. to yield crystals of (R)-5-phenyl-2-oxazolidinone (113.1 g, 83%). Melting point: 96.4° C. Optical purity: >99.9%e.e..
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][N:14]=2)[C:10]#[N:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH3:19][C:20]([CH3:22])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[CH:20]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][N:14]=2)[C:10]#[N:11])[CH2:6][CH2:5]1)([CH3:22])[CH3:19]
Reactant: CC(C)=O
Reactant: N#Cc1ccnc(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCN(c2cc(C#N)ccn2)CC1
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a solution of 2-piperazin-1-yl-isonicotinonitrile (10 g, 53 mmol), glacial acetic acid (4.26 ml, 4.5 g, 74.4 mmol, 1.4 equiv) and acetone (4.29 ml, 3.39 g, 58 mmol, 1.1 equiv) in anhydrous dichloromethane was added sodium triacetoxyborohydride (13.5 g, 63.8 mmol, 1.2 equiv). The reaction was stirred overnight, then an aqueous solution of 1N NaOH solution was added (150 ml) and the mixture was extracted once with dichloromethane, then twice with a solution of 10% methanol/dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography (5% methanol/CH2Cl2 grading to 10% methanol/CH2Cl2) provided the desired product (6.52 g, 59%). MS m/z 231 (M++1).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([CH3:16])=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:22][CH:23]1[C:40](=[O:41])[N:25]2[C:26]([C:37]([OH:39])=[O:38])=[C:27]([CH2:30][S:31][C:32]3[S:33][CH:34]=[N:35][N:36]=3)[CH2:28][S:29][C@H:24]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][C:6]([CH3:16])=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10]([NH:22][CH:23]2[C:40](=[O:41])[N:25]3[C:26]([C:37]([OH:39])=[O:38])=[C:27]([CH2:30][S:31][C:32]4[S:33][CH:34]=[N:35][N:36]=4)[CH2:28][S:29][C@H:24]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: CON=C(C(=O)O)c1nc(NC=O)sc1C
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nc(NC=O)sc1C
Reaction time: 1.5 h
Yield: 105.8 %

Procedure:
A solution of 2-(2-formamido-5-methylthiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 1.2 g.), dimethylformamide (0.46 ml.) and phosphoryl chloride (0.54 ml.) in dry ethyl acetate (12 ml.) was added to a solution of 7-amino-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (2.12 g.) and trimethylsilylacetamide (6.7 g.) in dry ethyl acetate (20 ml.) at -10° to -20° C. and stirred at the same temperature for 1.5 hrs. The reaction mixture was washed with water and adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated and adjusted to pH 2 with hydrochloric acid. The precipitates were collected by filtration and dried to give 7-[2-(2-formamido-5-methylthiazol-4-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 2.9 g.).
Reaction SMILES: [CH2:1]([N:3]1[C@@H:8]([CH3:9])[C:7](=[O:10])[NH:6][C:5]2[CH:11]=[C:12]([CH2:15]O)[CH:13]=[N:14][C:4]1=2)[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][N:27]([CH2:15][C:12]3[CH:13]=[N:14][C:4]4[N:3]([CH2:1][CH3:2])[C@@H:8]([CH3:9])[C:7](=[O:10])[NH:6][C:5]=4[CH:11]=3)[CH2:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: CCN1c2ncc(CO)cc2NC(=O)[C@@H]1C
Reactant: Clc1ccc(C2=CCNCC2)cc1
Product: CCN1c2ncc(CN3CC=C(c4ccc(Cl)cc4)CC3)cc2NC(=O)[C@@H]1C

Procedure:
Compound 63 was prepared using a procedure analogous to that described in connection with compound 1D, except that (S)-4-ethyl-7-(hydroxymethyl)-3-methyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one was used instead of (S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one and 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine was used instead of 1-(4-chlorophenyl)piperazine. 1H NMR (CHLOROFORM-d) δ (ppm): 7.79 (d, J=1.5 Hz, 1H), 7.68 (br. s., 1H), 7.27-7.34 (m, 4H), 7.02 (s, 1H), 6.06 (br. s., 1H), 4.21 (q, J=6.8 Hz, 1H), 3.98-4.12 (m, 1H), 3.44-3.61 (m, 2H), 3.07-3.26 (m, 3H), 2.75 (t, J=5.2 Hz, 2H), 2.55 (br. s., 2H), 1.36 (d, J=6.8 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H); [M+H] calc'd for C22H25ClN4O, 397. found, 397.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl.O>[CH3:19][S:20]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)(=[O:22])=[O:21]
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Temperature: 0 °C

Procedure:
To an ice cold solution of the alcohol from Step 1 (4.59 g, 29 mmol) and triethylamine (8.0 mL, 57 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (3.3 mL, 43 mmol). The reaction was then diluted with water (80 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried over MgSO4 and concentrated to give the title compound as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:13])[C:10](Cl)=[O:11].[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]1[CH2:26][NH:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=1>ClCCl>[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]1[CH2:26][N:25]([C:10]([N:9]([CH3:13])[CH3:8])=[O:11])[CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=1
Reactant: CN(C)C(=O)Cl
Reactant: Fc1ccc(F)c(C2=CC(c3ccccc3)NC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1
Reaction time: 2 h

Procedure:
Triethylamine (1.37 mL, 9.79 mmol, 5.00 equiv) and dimethylcarbamoyl chloride (0.180 mL, 1.96 mmol, 1.00 equiv) were added to a solution of 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (24, 1.96 mmol) in dichloromethane (50 mL) at 23° C., and the resulting mixture was stirred for 2 h, then concentrated. The residue was partitioned between saturated aqueous sodium bicarbonate solution (75 ml) and ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide 4-(2,5-difluorophenyl)-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (2-5) as an off-white solid. 1H NMR (500 M, CDCl3) δ 7.35-7.29 (m, 4H), 7.25 (m, 1H), 7.05 (m, 1H), 7.00 (m, 1H), 6.96 (m, 1H), 6.40 (br s, 1H), 6.13 (m, 1H), 4.88 (ddd, 1H, J=13.7, 5.6, 2.0 Hz), 4.52 (d, 1H, J=13.7 Hz), 2.88 (s, 6H). LRMS m/z (M+H) 329.1 found, 329.1 required.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]([O:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:34](=[O:35])[C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[O:31][C:30]2[CH:40]=[CH:41][CH:42]=[CH:43][C:29]1=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)=O>C1COCC1.C(OCC)(=O)C>[CH2:13]([O:20][N:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:34](=[O:35])[C:33]2[CH2:36][CH2:37][CH:38]=[CH:39][C:32]=2[O:31][C:30]2[CH:40]=[CH:41][CH:42]=[CH:43][C:29]1=2)[CH:1]=[O:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C1c2ccccc2Oc2ccccc2N1CCCCCCNOCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CN(CCCCCCN1C(=O)C2=C(C=CCC2)Oc2ccccc21)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
1,1′-Carbonyldiimidazole (1.26 g, 7.8 mmol) was dissolved in THF (15 mL) and the mixture was cooled at 0° C. Title compound 402 (0.646 g, 1.56 mmol) and formic acid in solution in THF (5 mL) was added. The reaction mixture was stirred at room temperature for 3 hours then diluted in ethyl acetate. The organic phase was washed with a saturated aqueous solution of bicarbonate, water and brine, then evaporated. The residue was purified by flash chromatography (30-50% ethyl acetate in hexanes) to afford title compound 403 (348 mg, 50%) as a colorless oil. MS (m/z): 445.2 (M+H).
Reaction SMILES: P(Br)(Br)[Br:2].N1C=CC=CC=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]O)=[CH:14][CH:13]=1>C1COCC1>[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][Br:2])=[CH:14][CH:13]=1
Reactant: OCc1ccc(O)cc1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Oc1ccc(CBr)cc1
Temperature: -20 °C
Reaction time: 18 h

Procedure:
To a stirred solution of PBr3 (1.38 g, 5.0 mmol) in dry THF (2 ml) at −5° C. was added a solution of dry pyridine (0.201 ml) in dry THF (0.4 ml). A solution of 4-Hydroxybenzyl alcohol (1.89 g, 15.2 mmol) in dry THF (23 ml) was added drop wise to the reaction mixture. The reaction mixture was allowed to stand at room temperature for 18 hours, then diluted with THF and filtered through celite pad. The filtrate was evaporated, the resulting semisolid was redissolved in dry toluene (16 ml). The solution was maintained at −20° C. for 2 hours, and then filtered through celite pad to provide the title compound as a light yellow solution which was used without further purification.