Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:31]=[CH:30][N:29]=[CH:28][C:13]3=[C:14]([CH2:19][C:20]3[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=3)[CH:15]=2)[N:10]=[CH:9]1.[CH3:32][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:31]=[CH:30][N:29]=[CH:28][C:13]3=[C:14]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH:24]([OH:25])[CH3:32])=[CH:26][CH:27]=3)[CH:15]=2)[N:10]=[CH:9]1
Reactant: O=Cc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccncc23)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccncc23)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-({3-[(1S,2S)-2-hydroxycyclohexyl]-4-oxo-3,4-dihydropyrido[3,4-h]quinazolin-6-yl}methyl)benzaldehyde (Example 10, 0.035 g, 0.085 mmol) in 2 mL of THF at −50° C. was added methylmagnesium bromide (0.028 mL, 3.0 M diethyl ether solution, 0.85 mmol). After 3 h, additional methylmagnesium bromide (0.028 mL, 3.0 M diethyl ether solution, 0.85 mmol) was added. After 1 h, the mixture was treated with saturated aqueous ammonium chloride and extracted 2× with ethyl acetate. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 430.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 8.53 (s, 1H), 8.42 (d, J=4.5 Hz, 1H), 8.23 (s, 1H), 8.01 (s, 1H), 7.25 (d, J=9.2 Hz, 2H), 7.18 (d, J=8.1 Hz, 2H), 4.88-4.84 (m, 1H), 4.56 (br s, 1H), 4.47 (s, 2H), 4.14-4.12 (m, 1H), 3.65-3.63 (m, 1H), 2.31-2.28 (m, 1H), 2.05-1.84 (m, 4H), 1.62-1.48 (m, 2H), 1.46 (d, J=6.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)C(C)(C)C)=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27]C(=O)C(C)(C)C.Cl>O1CCOCC1>[NH2:27][C:26]1[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]([F:34])=[C:3]([N:35]2[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]2)[C:2]=1[F:1]
Reactant: CN1CCN(c2c(F)c(NC(=O)C(C)(C)C)c3c(=O)cc(-c4ccc(NC(=O)C(C)(C)C)c(F)c4)oc3c2F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(c2c(F)c(N)c3c(=O)cc(-c4ccc(N)c(F)c4)oc3c2F)CC1
Yield: 48.7 %

Procedure:
340 mg (0.594 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-(4-methylpiperazin-1-yl)-5-pivaloylamino-4H-1-benzopyran-4-one was dissolved in 20 mL of 1,4-dioxane, 10 mL of concentrated hydrochloric acid was added and the mixture was heated at reflux for 2.5 hours. The reaction solution was cooled on ice, adjusted to pH 10 and extracted twice with chloroform (containing a small amount of methanol). The organic layer was washed once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=12:1) to give 117 mg of Compound 98 (yield: 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[O:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:18]1[CH2:19][CH2:20][C:15]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:16][CH2:17]1
Reactant: COc1cccc(C=O)c1
Reactant: C1CC2(CCN1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cccc(CN2CCC3(CC2)OCCO3)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 82.8 %

Procedure:
A mixture of 3-methoxybenzaldehyde (10.0 g, 73.4 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (21.0 g, 146.9 mmol), sodium triacetoxyborohydride (31.1 g, 146.9 mmol), and acetic acid (4.4 mL, 73.45 mmol) in 1,2-dichloroethane (100 mL), was stirred at ambient temperature. After 19 h, a 2 N aqueous sodium carbonate solution (220 mL) was added portionwise. After stirring for 15 min, the aqueous layer was separated and extracted with methylene chloride (200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to provide 8-(3-methoxybenzyl)-1,4-dioxa-8-azaspiro[4.5]decane (16.0 g, 82%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 7.27-7.20 (m, 1H), 6.93-6.88 (m, 2H), 6.79 (dd, J=2.4, 8.2 Hz, 1H), 3.94 (s, 4H), 3.82-3.78 (m, 3H), 3.50 (s, 2H), 2.56-2.47 (m, 4H), 1.74 (t, J=5.6 Hz, 4H); ESI MS (m/z) 264 [M+H].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:47])[S:27]([C:30]2[CH:39]=[CH:38][C:37]3[NH:36][C:35](=[O:40])[C:34]4[NH:41][CH:42]=[C:43]([C:44]([OH:46])=[O:45])[C:33]=4[C:32]=3[CH:31]=2)(=[O:29])=[O:28])=[CH:22][CH:21]=1>CN(C)C=O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:47])[S:27]([C:30]2[CH:39]=[CH:38][C:37]3[NH:36][C:35](=[O:40])[C:34]4[NH:41][CH:42]=[C:43]([C:44]([O:46][CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[O:45])[C:33]=4[C:32]=3[CH:31]=2)(=[O:29])=[O:28])=[CH:22][CH:21]=1
Reactant: CN(c1ccc(F)cc1)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]cc(C(=O)O)c3c2c1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(c1ccc(F)cc1)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]cc(C(=O)OCCCNC(=O)OC(C)(C)C)c3c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.2 %

Procedure:
9 mg (0.04 mmol) of 3-bromo-N-tert-butoxycarbonyl-propylamine and 8 mg (0.06 mmol) of potassium carbonate are added to a solution of 21 mg (0.05 mmol) of 8-[(4-fluorophenyl)-methyl-sulfamoyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid dissolved in 0.5 mL of dimethylformamide. The reaction mixture is stirred for 18 hours at room temperature then the solvents are evaporated. The residue is purified by chromatography on silica (eluent cyclohexane/ethyl acetate 2/8) then triturated in diethyl ether to give 6 mg (21%) of 3-tert-butoxycarbonylamino-propyl 8-[(4-fluorophenyl)-methyl-sulfamoyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylate in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([CH2:21][OH:22])[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:42][C:43]([F:52])([F:51])[C:44]1[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=1.N(C(OCC)=O)=NC(OCC)=O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([N:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([CH2:21][O:22][C:47]4[CH:48]=[CH:49][C:44]([C:43]([F:52])([F:51])[F:42])=[CH:45][CH:46]=4)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=C(N1CCCCC(CO)C1)C1(c2ccc(Cl)cc2)CCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(N1CCCCC(COc2ccc(C(F)(F)F)cc2)C1)C1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C
Yield: 26 %

Procedure:
To a room temperature solution of [1-(4-Chloro-phenyl)-cyclobutyl]-(3-hydroxymethyl-azepan-1-yl)-methanone (0.3307 g, 1.15 mmol) in tetrahydrofuran (5.75 mL, 0.2M) under N2 was added triphenyl phosphine (0.9050 g, 3.45 mmol) and 4-trifluoromethylphenol (0.56 mL, 3.45 mmol). The solution was cooled to 0° C., then diethyl azodicarboxylate (0.54 mL, 3.1 mmol) was added dropwise over 10 minutes. When the reaction was complete by HPLC (2 hours), ethyl acetate and 10% aqueous NaOH was added. The organics were removed, dried with Na2SO4, concentrated, then taken up in Hexanes/ ethyl acetate (70:30) and filtered to remove triphenyl phosphine oxide. The remaining yellow oil was purified by silica gel chromatography (3:1 to 2:3 Hexanes: ethyl acetate). The product was further purified by silica gel chromatography with 9:1 hexanes: ethyl acetate to obtain pure product in 26% yield (0.1301 g). Partial 1H NMR (CDCl3, 300 MHz) 7.55 (2H, t, J=8.7 Hz), 7.36-7.26 (4H, m), 6.92 (2H, dd, J=34.9, 8.7 Hz), 4.00-3.85 (2H, m), ppm. Partial 13C NMR (CDCl3, 75 MHz) 174.95, 161.66, 142.17, 132.35, 129.10, 126.95, 126.77, 114.61,114.61,71.50, 71.10 ppm. LRMS: 465.26.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.Br[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][N:18]=1>C1COCC1.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][N:18]=3)[S:10][C:3]=12
Reactant: O=Cc1ccc(Br)nc1
Reactant: Clc1ccnc2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
7-Chlorothieno[3,2-b]pyridine (6) (4.02 g, 23.70 mmol) was dissolved in THF (150 mL) to give a colorless solution. The solution was cooled to −40° C. in an acetonitrile/dry ice bath. n-BuLi (9.95 mL, 24.88 mmol, 2.5M in hexanes) was added dropwise. The dark mixture was then stirred for 15 min followed by an addition of zinc chloride (24.88 mL, 24.88 mmol, 1M in ether). The mixture was warmed to 0° C., then tetrakistriphenylphosphine palladium (1.095 g, 0.948 mmol) was added. The mixture was then stirred for 10 min and 6-bromonicotinaldehyde (7) (4.41 g, 23.70 mmol) was added. The mixture was heated to reflux and a precipitate formed rapidly. After 3 h, the reaction mixture was cooled down to r.t., quenched with 2 mL NH4Cl and left overnight. The solid was isolated by suction filtration, rinsed with small amount of THF and triturated with a mixture of water (200 mL) and EtOAc (100 mL) followed by an additional trituration with acetic acid (1×100 mL), to afford intermediate 50 (4.95 g, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.13 (s, 1H), 9.14 (d, J=1.4 Hz, 1H), 8.70 (d, J=5.1 Hz, 1H), 8.65 (s, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.39 (dd, J=2.1, 8.4 Hz, 1H), 7.65 (d, J=4.9 Hz, 1H). MS (m/z): 275.1 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=C(OC)C=CC=1C[N:13]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][N:21]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:20]2)(=[O:16])=[O:15].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:38][C:35]1[CH:34]=[CH:33][C:32]([NH:13][S:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[CH2:22][N:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20]3)(=[O:16])=[O:15])=[CH:37][CH:36]=1
Reactant: COc1ccc(CN(c2ccc(F)cc2)S(=O)(=O)c2ccc3c(c2)CN(c2ccccc2)C3)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccc(F)cc1)c1ccc2c(c1)CN(c1ccccc1)C2
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of N-(2,4-dimethoxybenzyl)-N-(4-fluorophenyl)-2-phenyl-2,3-dihydro-1H-isoindole-5-sulfonamide obtained (135 mg) in chloroform (4.5 mL) while cooling in ice, and the mixture was stirred at the same temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (chloroform only→chloroform:methanol=19:1). To the resulting crude compound were added ethyl acetate, diethyl ether and hexane, and the mixture was powdered and then collected by filtration to afford the title compound as a light gray powder (74 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][O:36]C(=O)C4C=CC=CC=4)[C@@H:23]([O:24]C(=O)C4C=CC=CC=4)[C@H:13]3[O:14]C(=O)C3C=CC=CC=3)[C:4]=2[N:5]=[CH:6][N:7]=1.C[O-].[Na+]>CO>[NH2:1][C:2]1[C:3]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:23]([OH:24])[C@H:13]3[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1sc(=O)n2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ncnc2c1sc(=O)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Compound 32 (0.76 g, 1.2 mmol) was deblocked in the same manner as described for 31 above using sodium methoxide (200 mg, 3.7 mmol) in dry MeOH (50 mL). The title compound (34) was obtained (0.12, 32%) after crystallization from water: mp 248°-250° C.: UV λmax (pH 1) 222 nm (ε35100), 265 (14300), 290 (11400): UV λmax (pH 7, 11) 215 nm (ε45000), 262 (13200): 1H NMR (DMSO-d6) δ5.91 (d, J=5.43 Hz, 1H, C1,H), 7.44 (b, 1H, NH2), 8.22 (s, 1H, C5H), and other sugar protons. Anal. Calcd. for C10H12N4O5S: C, 40.00: H, 4.03: N, 18.66: S, 10.68. Found: C, 39.80: H, 3.99: N, 18.39: S, 10.57. ##STR7##
Reaction SMILES: [Na].[CH2:2]([OH:4])[CH3:3].[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8](Cl)[N:7]=1.Cl>O>[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8]([O:4][CH2:2][CH3:3])[N:7]=1
Reactant: CCO
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: Cl
Agent: [Na]
Solvent: O
Product: CCOc1nc(N)nc2nc[nH]c12

Procedure:
Sodium (0.68 g, 29.5 mmol, Aldrich lot #9621CL) was added in portions to anhydrous ethanol (50 mL). Upon complete dissolution 2-amino-6-chloropurine (1 g, 5.9 mmol Sigma lot #69F4064) was added and the reaction heated at reflux for 96 hours. The reaction was cooled, diluted with 20 mL water, and neutralized with 1N HCl. The solvents were evaporated and the residue slurried in 100 mL water. The product was filtered off and air dried to give 0.95 g (5.3 mmol; 89.9%); mp=252-°253° C.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:34])[C@@H:24]([C:25](=[O:33])[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@H:21]3[S:20][C:19]([NH2:35])=[C:18]2[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:52])C=1>C(Cl)Cl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:34])[C@@H:24]([C:25](=[O:33])[CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C@H:21]3[S:20](=[O:52])[CH:19]([NH2:35])[C:18]=2[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NC1=C(Cc2ccc(O)cc2)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](C(=O)Cc3ccccc3)[C@H]2S1
Solvent: ClCCl
Product: NC1C(Cc2ccc(O)cc2)=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](C(=O)Cc3ccccc3)[C@H]2S1=O

Procedure:
A solution of 1.51 g of 3-(4-hydroxy-benzyl)-7βphenylacetyl-amino-ceph-2-em-4ξ-carboxylic acid diphenylmethylester in 40 ml of methylene chloride is cooled in an ice bath and treated with 0.52 g of purified 3-chloro-perbenzoic acid. The mixture is allowed to react for 1 hour at room temperature and the reaction solution is extracted successively with a 5% aqueous sodium hydrogen sulphite solution, a 0.5 molar aqueous dipotassium phosphate solution and water. The aqueous phases are re-extracted twice with small amounts of methylene chloride. The organic extracts are combined, dried over anhydrous magnesium sulphate and evaporated to dryness under reduced pressure. The residue is crystallised from a mixture of methyl acetate and cyclohexane and yields the 3-(4-hydroxybenzyl)-7β-phenylacetyl-amino-ceph-3-em-4-carboxylic acid diphenylmethyl ester-1-oxide, which after further crystallisation from a mixture of methyl acetate and cyclohexane and drying under a high vacuum for 20 hours at 35° melts at 192°-193°; [α]D20 = +36° ± 1° (c = 1.025 in dioxane); thin-layer chromatogram (silica gel: development with iodine): Rf = 0.18 (system: toluene/ethyl acetate 2:1), Rf = 0.36 (system: toluene/ethyl acetate 1:1), Rf = 0.24 (system: toluene/acetone 4:1), Rf = 0.07 (system: toluene/acetone 9:1) and Rf = 0.52 (system: methylene chloride/acetone 6:1); ultraviolet absorption spectrum (95% ethanol): λmax = 268 mμ (ε = 11300) and λmin = 241 mμ: infrared absorption spectrum (in mineral oil): characteristic bands at 2,94μ, 3,00μ, 5,60μ, 5,78μ, 5,85μ, 6,58μ, 6,65μ, 7,30μ, 7,99μ, 8,48μ, 8,70μ, 9,02μ, 9,78μ, 12,03μ, 13,45μ and 14,26μ.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([NH2:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:23]#[C:24]Br>CCO.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:24]([NH2:23])=[N:22][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(OCc2ccccc2)nc1Nc1ccccc1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(OCc3ccccc3)nc2n1-c1ccccc1
Yield: 13.2 %

Procedure:
A solution of 6-(benzyloxy)-N2-phenylpyridine-2,3-diamine (3.106 g, 10.66 mmol), and cyanogen bromide (1.694 g, 15.99 mmol) in EtOH (50 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc and saturated NaHCO3. The layers were separated and the aqueous phase was back-extracted with EtOAc. The organics were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (446 mg). LCMS m/z=317.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=4[F:50])[CH:34]=3)[O:32][C@@:10]1([CH2:51][OH:52])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>C(OCC)(=O)C>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=4[F:50])[CH:34]=3)[O:32][C@@:10]1([CH:51]=[O:52])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cc2cc([C@]34OC[C@](C=O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 25 °C
Yield: 105.2 %

Procedure:
To a solution of [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6,8-dioxa bicyclo[3.2.1]octan-1-yl]methanol 210 (0.52 g, 0.68 mmol) in ethyl acetate (20 mL) was added 2-iodoxybenzoic acid (0.58 g, 2.06 mmol) at room temperature. The mixture was refluxed for 20 hours and cooled to room temperature, then filtered. The filtrate was concentrated in vacuo to give the title compound 21p as a white solid (0.52 g, 100%). This material was not further purified.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[N:19]=2)=[C:9]1[CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:20]1[N:19]=[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:9]=2[CH3:38])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21]1(=[O:28])=[O:29]
Reactant: Cc1c(C2=NN(Cc3cccc(F)c3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(Cc3cccc(F)c3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
{3-[2-(3-Fluoro-benzyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.17 (d, 1H), 7.95 (t, 1H), 7.86 (t, 1H), 7.42 (m, 3H), 7.19 (m, 3H), 6.89 (dt, 1H), 6.61 (dd, 1H), 5.09 (bs, 2H), 4.53 (s, 2H), 2.09 (s, 3H) ppm. MS calculated for C25H19F2N3O4S—H: 494, observed: 494.
Reaction SMILES: [CH3:1][C:2]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:7]([S:16][C:17]#N)[CH:6]=[CH:5][C:3]=1[NH2:4].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].CI>C(O)C.O>[CH3:1][C:2]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:7]([S:16][CH3:17])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Cc1ccccc1-c1c(SC#N)ccc(N)c1C
Agent: [Na+]
Agent: [S-2]
Solvent: CI
Solvent: O
Solvent: CCO
Product: CSc1ccc(N)c(C)c1-c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.0 g (7.9 mmol) of 2-methyl-3-(2-methylphenyl)-4-thiocyanoaniline in 15 mL of ethanol was added dropwise over a 20-min period with stirring to a solution of 2.2 g of sodium sulfide nonahydrate (9.1 mmol) in 5 mL of water. The mixture was stirred at ambient temperature for 2 hours and was then cooled with an ice/salt bath. A solution of 1.5 g (11 mmol) of methyl iodide in 5 mL of ethanol was added with stirring over a 10-min period. The mixture was diluted with water and the resulting mixture was extracted with ether. The ethereal extract was washed with water, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The 2.0 g of residue was the title compound of about 80 percent purity.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].COC(C1NN=C(OCC2C(C3C=CC=CC=3)=NOC=2C)C=1)=O.[F:48][C:49]([F:53])([F:52])[CH2:50][NH2:51]>>[F:48][C:49]([F:53])([F:52])[CH2:50][NH:51][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n[nH]1
Agent: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NCC(F)(F)F)[nH]n1
Yield: 21 %

Procedure:
As described for example 1b, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.3 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted, using 2,2,2-trifluoroethylamine instead of morpholine, to the title compound (25 mg, 21%), which was obtained as a white solid. MS: m/e=400.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[C:22]([O:24]C)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[C:22]([OH:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CC(Oc2ccc(F)cc2F)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)cc2F)CC1C(=O)O
Reaction time: 8 h
Yield: 45.6 %

Procedure:
To a stirred solution of methyl 1-(tert-butoxycarbonyl)-4-(2,4 difluorophenoxy)pyrrolidine-2-carboxylate (5.82 g, 16.3 mmol) in THF (130 ml) was added 0.25 N NaOH (130 ml, 32.6 mmol). The resulting mixture was stirred overnight. The mixture was poured into 1 N HCl (100 ml) and extracted with CHCl3 (2×200 ml). The extracts were dried over MgSO4 and evaporated. The residue was chromatographed on silica gel with CHCl3-EtOAc (4:1) as eluent to give 1-(tert-butoxycarbonyl)-4-(2,4-difluorophenoxy)pyrrolidine-2-carboxylic acid (2.55 g, 46%) as a colorless foam. 1H-NMR (CDCl3) δ 1.42–1.47 (m, 9 H), 2.29–2.74 (series of m, 2 H), 3.66–3.71 (m, 2 H), 4.46–4.51 (m, 1 H), 4.83 (m, 1 H), 6.73–6.95 (m, 3 H).