Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>CN(C=O)C>[CH3:12][N:13]([CH3:15])/[CH:14]=[CH:10]/[C:9](=[O:11])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CCc1ccccc1
Solvent: CN(C)C=O
Product: CN(C)/C=C/C(=O)CCc1ccccc1
Yield: 36.9 %

Procedure:
A solution of 4-phenylbutan-2-one (3.96 g, 20 mmol) and DMF-DMA (2.4 g, 20 mmol) in DMF (10 mL) was stirred at 100° C. overnight. The reaction mixture was cooled, concentrated, and purified by silica gel column (PE/EA=4:1-2:1) to give the title compound (1.5 g, 37%) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[C:13]([CH:16]=C)=[CH:14][N:15]=[C:8]1[C:7]([NH:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:6]2.C[N+]1([O-])CC[O:29]CC1.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O.O.[Os](=O)(=O)(=O)=O>[OH:22][CH2:21][CH2:20][CH2:19][NH:18][C:7]1[C:8]2[N:9]([C:13]([CH:16]=[O:29])=[CH:14][N:15]=2)[C:10]2[C:5]([N:6]=1)=[CH:4][C:3]([C:2]([F:23])([F:1])[F:24])=[CH:12][CH:11]=2
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Temperature: 30 °C
Reaction time: 96 h

Procedure:
To a suspension of 3-{[7-(trifluoromethyl)-1-vinylimidazo[1,2-a]quinoxalin-4-yl]amino}propan-1-ol (33 mg, 0.099 mmol) in acetone-water (9:1, 1 mL), was added osmium tetroxide (2.5% wt. in t-BuOH, 53 mg, 0.05 mmol) and 4-methylmorpholine 4-oxide (25 mg, 0.20 mmol). The reaction mixture was stirred for 4 days at 30° C. under argon, and then a suspension of sodium periodate (85 mg, 0.40 mmol) in water (500 μL) was added. The mixture was stirred for one day at 30° C. under argon. Then it was filtered, washed with an aqueous saturated solution of Na2SO3 and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, concentrated in vacuo, filtered, concentrated to give, after purification by preparative TLC (dichloromethane/methanol 9/1), the title compound (24 mg, 70%) as a pale yellow solid.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][C:11]#[CH:12])[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:20]>C(O)(=O)C.O>[C:11]([CH2:10][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:8]=[O:9])(=[O:20])[CH3:12]
Reactant: C#CCC(C=O)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)CC(C=O)(c1ccccc1)c1ccccc1
Yield: 103.9 %

Procedure:
A solution of 2,2-diphenyl-2-(2-propynyl)acetaldehyde (83.0 g) in acetic acid (83 ml) was added dropwise to a solution of mercuric acetate (3.1 g) and sulfuric acid (18.3 g) in a mixture of acetic acid (300 ml) and water (75 ml) over a period of 2 hours at room temperature. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed successively with water and aqueous solution of sodium bicarbonate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate (5:1) as an eluent to give 3-acetyl-2,2-diphenylpropionaldehyde (48.9 g).
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH:2]1[C:4](OCC)=[O:5].[NH3:14]>C(O)C>[C:4]([CH:2]1[CH2:3][N:1]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:5])[NH2:14]
Reactant: N
Reactant: CCOC(=O)C1CN1C(=O)OCC
Solvent: CCO
Product: CCOC(=O)N1CC1C(N)=O
Reaction time: 8 h

Procedure:
To 4.67 g. (0.025 mole) diethyl 1,2-aziridine-dicarboxylate in 30 ml. ethanol there is added the equimolar amount of gaseous ammonia dissolved in ethanol and the reaction mixture then left to stand overnight in a refrigerator. The reaction mixture is subsequently evaporated and the desired ethyl 2-carbamoyl-1-aziridine-carboxylate isolated by column chromatography (200 g. silica gel: elution agent acetone/toluene 1:1 v/v). There is obtained 1.4 g. (about 32% of theory) of the ester; m.p. 125°-128° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:12]([C:17](=O)[CH3:18])[C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:21][C:22]([NH2:29])=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].CN1CCOCC1>C(O)(C)C>[NH2:21][C:22]1[NH:29][C:17]([CH3:18])=[C:12]([C:13]([O:15][CH3:16])=[O:14])[CH:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[O:1][CH2:2][CH2:3][CH2:4]3)[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: COC(=O)C(=Cc1ccc2c(c1)CCCO2)C(C)=O
Reactant: CCOC(=O)C=C(N)N
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC(C)O
Product: CCOC(=O)C1=C(N)NC(C)=C(C(=O)OC)C1c1ccc2c(c1)CCCO2
Temperature: 90 °C

Procedure:
A mixture of methyl 2-(chroman-6-ylmethylene)-3-oxobutanoate (8.27 g, 31.8 mmol), ethyl 3,3-diaminoacrylate, hydrochloride (5.29 g, 31.8 mmol) and 4-methylmorpholine (3.49 mL, 31.8 mmol) in Isopropanol (76.0 mL) was heated to 90° C. overnight. The mixture was concentrated, dissolved in ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated to provide crude 3-ethyl 5-methyl 2-amino-4-(chroman-6-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate which was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.00-6.87 (m, 3 H), 6.64-6.58 (m, 1 H), 6.20 (br. s., 2 H), 4.83-4.77 (m, 1 H), 4.15-4.05 (m, 4 H), 3.71-3.63 (m, 3 H), 2.71 (t, J=6.3 Hz, 2 H), 2.27-2.16 (m, 3 H), 1.99-1.93 (m, 2 H), 1.27-1.22 (m, 3 H); LC/MS (m/z) ES+=373.3 (M+1). A solution of crude 3-ethyl 5-methyl 2-amino-4-(chroman-6-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate in dichloromethane (DCM) (216 mL) was treated with DDQ (7.22 g, 31.8 mmol) and then stirred at ambient temperature (mixture turned dark within one minute). The mixture was filtered over Celite™. The filtrate was diluted with saturated sodium bicarbonate and the layers were separated. The aqueous phase was extracted with DCM. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-100% hexane/EA) to afford 3-ethyl 5-methyl 2-amino-4-(chroman-6-yl)-6-methylpyridine-3,5-dicarboxylate (7.64 g, 20.63 mmol, 64.9% yield) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.86 (d, 1 H), 6.81 (s, 1 H), 6.73 (d, J=8.4 Hz, 1 H), 6.23-6.02 (m, 2 H), 4.17 (t, J=4.7 Hz, 2 H), 3.99-3.77 (m, 2 H), 3.52-3.43 (m, 3 H), 2.73 (br. s., 2H), 2.45-2.35 (m, 3 H), 1.98 (br. s., 2 H), 0.83-0.67 (m, 3 H); LC/MS (m/z) ES+=371.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([C:35]([F:46])([F:45])[F:34])[CH:41]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: COC(=O)[C@H](Cc1ccc(-c2cccc(C(F)(F)F)c2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Yield: 49.7 %

Procedure:
The resin-bound 3-(4-bromo-phenyl)-(2S)-[(4′-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester (50 mg, 0.1 mmol) prepared as described in above Example 44 was reacted with 3-trifluoromethyl-phenyl boronic acid (57.2 mg, 0.3 mmol) by following as generally described in Example 44 to give title compound (29.2 mg, 50%). LC/MS (m/z): 588 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13]3=[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[N:12]3[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]2([CH3:23])[CH3:22])[CH:15]=1.C([Li])CCC.[B:29](OC)([O:32]C)[O:30]C>C1COCC1.C1CCCCC1>[CH3:22][C:5]1([CH3:23])[C:4]2[C:13]3=[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[N:12]3[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=3)[CH:15]=[C:2]([B:29]([OH:32])[OH:30])[CH:3]=2
Reactant: COB(OC)OC
Reactant: CC1(C)c2ccccc2-n2c3ccccc3c3cc(Br)cc1c32
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC1(C)c2ccccc2-n2c3ccccc3c3cc(B(O)O)cc1c32
Temperature: 25 °C

Procedure:
93.7 g (259 mmol) of 6-bromo-8,8-dimethyl-8H-indolo[3,2,1-de]acridine are dissolved in 1500 ml of dry THF, 135 ml (337 mmol) of a 2.5 M solution of n-butyllithium in cyclohexane are added dropwise at −70° C., after 1 h 37 ml of trimethyl borate (336 mmol) are added dropwise, the mixture is warmed to room temperature over the course of 1 h, the solvent is removed, and the residue, which is uniform according to 1H-NMR, is employed in the subsequent reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].[CH2:16]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[C:25](=[C:34](SC)SC)[C:24]1=[O:39])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH2:16]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([OH:33])=[C:25]([C:34]2[NH:1][C:2]3[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=3[S:7](=[O:8])(=[O:9])[N:10]=2)[C:24]1=[O:39])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CSC(SC)=C1C(=O)c2ccccc2N(Cc2ccccc2)C1=O
Reactant: COCOCc1csc(N)c1S(N)(=O)=O
Solvent: Cc1ccccc1
Product: COCOCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2
Yield: 72.6 %

Procedure:
The product of Example 309G (35 mg, 0.14 mmol) and the product of Example 309B (50 mg, 0.14 mmol) were reacted in toluene (3 mL) at 100° C. for 3 hours. The resulting precipitate was collected by filtration and washed with toluene and diethyl ether to give the title compound (52 mg, 73.3%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.26 (s, 3 H), 4.65 (s, 2 H), 4.72 (s, 2 H), 5.62 (s, 2 H), 7.28 (m, 7 H), 7.43 (s, 2 H), 7.51 (d, J=8.09 Hz, 1 H), 7.75 (m, 1 H), 8.22 (d, J=8.09 Hz, 1 H).
Reaction SMILES: C1(S([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=2)[N:25]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[N:24]=[CH:23]4)=[N:16][CH:15]=[N:14]3)=O)C=CC=CC=1.C(OC([NH:44][C@@H:45]1[CH2:49][CH2:48][NH:47][CH2:46]1)=O)(C)(C)C>C(Cl)Cl>[NH2:44][C@@H:45]1[CH2:49][CH2:48][N:47]([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=2)[N:25]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[N:24]=[CH:23]4)=[N:16][CH:15]=[N:14]3)[CH2:46]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=S(Cc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)c1ccccc1
Solvent: ClCCl
Product: N[C@@H]1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)C1
Temperature: 130 °C
Yield: 14 %

Procedure:
A mixture of (5-benzenesulfinylmethyl-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (100 mg, 0.20 mmole) and (3R)-3-(N-tert-butoxycarbonylamino)pyrrolidine; (380 mg, 10 equiv) in a sealed tube was heated at 130° C. for 35 hr. The reaction mixture was taken up in DCM, washed water and dried (Na2SO4). After removal of the solvent the residue was taken up in DCM (1.5 mL) and TFA (1 mL) was added. The solvents were removed and the residue was dissolved in DCM, washed with water, and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate employing gradient elution with DCM containing 1 to 5% MeOH) to afforded the title compound as an oil (13 mg, 14%). 1H NMR (CDCl3) δ 1.49 (br s, 2H), 1.66 (m, 1H), 2.29 (m, 1H), 2.43 (m, 1H), 3.69 (m, 1H), 3.87 (d, 1H, J=13.5 Hz), 3.96 (d, 1H, J=13.5 Hz), 5.58 (s, 2H), 6.49 (d, 1H, J=3 Hz), 6.8-7.6 (m, 7H), 7.92 (s, 1H), 8.04 (s, 1H), 8.26 (d, 1H, J=2 Hz); MS: 457 (M+H)+; HPLC Ret Time: 1.15 min (YMC Xterra ODS S7 C18, 3.0×50 mm column, 2 min gradient, 5 mL/min).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](Cl)=O.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.O1CCCC1>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)=[N:1][C:2]=2[CH:6]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]c(-c2ccccn2)nc2cc(Br)sc12
Temperature: 25 °C
Yield: 97.4 %

Procedure:
To a mixture of 3-amino-5-bromothiophene-2-carboxamide (221 mg) produced in Example 1, step D, triethylamine (0.42 mL) and tetrahydrofuran (15 mL) was added pyridine-2-carbonylchloride hydrochloride (214 mg) with stirring at room temperature. The mixture was stirred at room temperature for 30 min and at 50° C. overnight. Triethylamine (0.42 mL) and pyridine-2-carbonylchloride hydrochloride (214 mg) were added to the reaction mixture. 2 hr later, aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with water and brine (5 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethanol (10 mL) and 2M aqueous sodium hydroxide solution (3.0 mL) were added to the residue, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was neutralized with 6M hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine (10 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product (300 mg) of the title compound as a pale-orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[CH2:19]([O:21][C:22](=[O:28])[C:23](OCC)=[NH:24])[CH3:20]>C(O)C>[CH2:19]([O:21][C:22]([C:23]1[N:24]=[C:4]([OH:6])[C:3]2[C:2](=[CH:10][CH:9]=[C:8]([OH:11])[CH:7]=2)[N:1]=1)=[O:28])[CH3:20]
Reactant: CCOC(=N)C(=O)OCC
Reactant: Nc1ccc(O)cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1nc(O)c2cc(O)ccc2n1
Temperature: 60 °C

Procedure:
2-amino-5-hydroxy-benzoic acid (15 mmol) are suspended in ethanol (water free, 600 ml) and heated up to 60° C. and stirred. Then triethylamine (30 mmol) is added and a clear solution is formed. Ethoxy-imino-acetic acid ethyl ester (16.5 mmol) is added at 60° C. and after 15 minutes another portion of triethylamine (15 mmol) is added and the mixture stirred for another 30 minutes. The mixture is cooled down to RT and left at RT without stirring over night. The solid material formed was filtered off, washed with ethanol/ether and dried (vacuum). A pale brown powder with mp. 258-260° C. (decomposition) is obtained.
Reaction SMILES: C[Si](Cl)(C)C.[Na+].[I-].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:20]=[C:19]([O:21]C)[C:18](=[O:23])[C:17]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:26][CH:25]=2)=[N:16]1.O>CC#N>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:20]=[C:19]([OH:21])[C:18](=[O:23])[C:17]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:26][CH:25]=2)=[N:16]1
Reactant: COc1cn(-c2ccccc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=c1c(O)cn(-c2ccccc2F)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
TMSCl (1.27 mL, 10 mmol) was added at room temperature to a solution of NaI (1.50 g, 10 mmol) in CH3CN (60 mL). After stirring for 30 min, 1-(2-fluorophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (0.725 g, 2 mmol) was added to the resulting suspension. The mixture was stirred for 30 min at room temperature and then refluxed for 1 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with hexane/AcOEt (1/1) and recrystallized from MeOH/H2O to give the title compound (0.648 g, 93% yield) as off-white prisms: mp 218-220° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 6.99 (1H, d, J=1.9 Hz), 7.10 (1H, dt, J=1.5, 7.9 Hz), 7.21-7.26 (1H, m), 7.32-7.54 (7H, m), 7.80 (1H, d, J=1.9 Hz), 8.44 (1H, d, J=2.6 Hz). Anal. Calcd for C19H13FN4O2: C, 65.51; H, 3.76; N, 16.08. Found: C, 65.73; H, 3.88; N, 16.24.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([CH2:12][O:13][N:14]=[C:15]([C:43]2[N:44]=[C:45]([NH:48][C:49](=[O:54])[C:50]([F:53])([F:52])[F:51])[S:46][CH:47]=2)[C:16]([NH:18][CH:19]2[C:41](=[O:42])[N:21]3[C:22]([C:28]([O:30]CC4C=CC([N+]([O-])=O)=CC=4)=[S:29])=[C:23]([CH:26]=[CH2:27])[CH2:24][S:25][C@H:20]23)=[O:17])=[O:11])=CC=1)([O-])=O.C(O)C.P([O-])([O-])([O-])=O.[H][H]>[Pd].O1CCCC1>[C:10]([CH2:12][O:13][N:14]=[C:15]([C:43]1[N:44]=[C:45]([NH:48][C:49](=[O:54])[C:50]([F:51])([F:52])[F:53])[S:46][CH:47]=1)[C:16]([NH:18][CH:19]1[C:41](=[O:42])[N:21]2[C:22]([C:28]([OH:30])=[S:29])=[C:23]([CH:26]=[CH2:27])[CH2:24][S:25][C@H:20]12)=[O:17])([OH:11])=[O:9]
Reactant: [H][H]
Reactant: C=CC1=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCc3ccc([N+](=O)[O-])cc3)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCO
Product: C=CC1=C(C(O)=S)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Yield: 67.5 %

Procedure:
p-Nitrobenzyl 7-[2-(p-nitrobenzyloxycarbonylmethoxyimino)-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-vinylthio-3-cephem-4-carboxylate (syn isomer) (2.3 g) was hydrogenated in the presence of 5% palladium on carbon in a mixture of tetrahydrofuran (100 ml), ethanol (11.5 ml) and 0.025M phosphate buffer solution (pH 6.85) (125 ml) at ambient temperature for 5 hours under 1 atmospheric pressure of hydrogen. The catalyst was filtered off and washed with ethyl acetate and a saturated aqueous solution of sodium bicarbonate successively. The filtrate and washings were combined and adjusted to pH 8 with dilute hydrochloric acid. The aqueous layer was separated, adjusted to pH 6 with dilute hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated in vacuo and triturated with diisopropyl etherto give 7-[2-carboxymethoxyimino-2-{2-(2,2,2 -trifluoroacetamido)thiazol-4-yl}acetamido]-3-vinylthio-3-cephem-4-carboxylic acid (syn isomer) (1.05 g).
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=O)[CH2:3][CH2:2]1.[NH2:8][CH2:9][CH2:10][C:11]1[N:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1.[BH4-].[Na+].Cl>C1COCC1.C(O)C>[CH3:16][N:12]1[C:11]2[CH2:10][CH2:9][N:8]3[CH:4]([C:15]=2[CH:14]=[CH:13]1)[CH2:3][CH2:2][C:1]3=[O:7]
Reactant: Cn1cccc1CCN
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1ccc2c1CCN1C(=O)CCC21
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A mixture of 110.9 g (1.098 mole) of succinic anhydride and 985 ml of THF was cooled to 10° C. and a solution of 140.53 g (1.098 mole) of 2-(2-aminoethyl)-1-methylpyrrole in 1400 ml of THF was added dropwise over a period of thirty minutes while stirring under an atmosphere of argon, the temperature being maintained at 10 to 15° C. After the addition was complete, stirring was continued an additional one hour and then the solvent removed in vacuo to give a dark-brown, oily residue. The residue was stirred and heated at 175° in an oil bath for three hours under an atmosphere of argon. The residue was distilled on a Kugelrohr apparatus, collecting the product imide at 170° C./0.06 mm, which crystallized to yield an off white solid, mp 116°-121° C. A small sample of the intermediate imide was recrystallized from ethanol to yield a white solid, mp 120°-122° C. A solution of 100 g (0.485 mole) of the above-obtained crude imide was added to 3-1 of 90% aqueous ethanol and the mixture cooled in an ice bath to about 3° C. Sodium borohydride (68.42 g; 1.81 moles) was added and about 25 ml of 2N hydrochloric acid was added dropwise with stirring over a five hour period by means of a metering pump while maintaining a temperature of 0° to 3° C. After the addition was complete (pH=8-9), the reaction was acidified with 1-1 of 2N hydrochloric acid over a period of 1.5 hours while maintaining a temperature of less than 10° C. Stirring (under nitrogen) was continued overnight as the temperature was allowed to gradually warm to ambient, during which time the mixture became a clear, colorless solution. The solvent was partially removed in vacuo using low heat to a final volume of about 800 mls, diluted with 800 mls of water and extracted three times with 300 ml portions of methylene chloride. The combined extracts were washed with 300 ml of water, 300 ml of brine, and dried over anhydrous potassium carbonate. The solvent was removed in vacuo to give 31.07 g of a crude tan solid. The crude solid was recrystallized from about 100 ml of hot EtOAc to give 23.76 g of nearly pure 4,5,7,8,9,9a-hexahydro-3-methyl-3H-pyrrolo[2,3-g]indolizin-7-one, an off-white solid, mp 122°-125° C.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@@H:7]([C:15]([OH:17])=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:5])=[O:4])[CH3:2].[NH:18]1[CH2:32][CH2:31][CH2:30][C@H:19]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1>[CH2:1]([S:3]([NH:6][C@@H:7]([C:15]([N:18]1[CH2:32][CH2:31][CH2:30][C@H:19]1[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 20 h

Procedure:
To a stirring suspension of EtSO2—D—Phe—OH (257 g, 100 mmol), Pro—OBn.HCl (26.6 g, 110 mmol), HOBT (13.5 g, 100 mmol) and N,N-diisopropylethylamine (43.5 mL, 250 mL) in THF (1 L) at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23 g, 120 mL). After stirring for 20 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 1 N citric acid. The organic phase was washed twice with 1 N KHCO3, twice with brine, dried with MgSO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a step gradient of hexanes through 50% ethyl acetate/hexanes. The product containing fractions were combined and concentrated in vacuo to give 29 g (65%) of a clear, thick oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C>[C:21]([O:20][C:18](=[O:19])[CH2:17][O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Br:1])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(F)cc1Br
Yield: 83.3 %

Procedure:
A solution of 2-bromo-4-fluorophenol (2.15 g, 11.25 mmol) in DMF (60 ml) was treated with potassium carbonate (7.77 g, 96.25 mmol) and t-butyl bromoacetate (1.99 ml, 13.5 mmol) at 60° C. for 12 hours. The reaction mixture was filtered through celite, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 5%-10% ethyl acetate/hexanes gradient to give the product as colorless oil (2.86 g, 83%).