Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[C:5]([CH3:11])[C:4]=1[CH3:12])=[O:2].[CH2:13]([C:15]1[CH:20]=[C:19]([C:21](=[NH:24])[NH:22]O)[CH:18]=[C:17]([CH3:25])[C:16]=1[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH3:14]>>[CH2:13]([C:15]1[CH:20]=[C:19]([C:21]2[N:22]=[C:8]([C:6]3[S:7][C:3]([CH:1]=[O:2])=[C:4]([CH3:12])[C:5]=3[CH3:11])[O:10][N:24]=2)[CH:18]=[C:17]([CH3:25])[C:16]=1[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH3:14]
Reactant: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)O
Reactant: Cc1c(C=O)sc(C(=O)O)c1C
Product: CCc1cc(-c2noc(-c3sc(C=O)c(C)c3C)n2)cc(C)c1CCC(=O)O

Procedure:
The title compound is prepared according to Method A starting from 5-formyl-3,4-dimethyl-thiophene-2-carboxylic acid and 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid; LC-MS: tR=1.08 min; [M+1]+=399.05.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=O.[CH3:11][O:12][C:13](=[O:30])[C:14]1[C:15](=[C:20]([NH:24]CCCCC)[CH:21]=[CH:22][CH:23]=1)[C:16]([O:18][CH3:19])=[O:17].C([O-])(O)=O.[Na+]>>[CH3:11][O:12][C:13](=[O:30])[C:14]1[C:15](=[C:20]([NH:24][CH2:1][C:3]2[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=2)[CH:21]=[CH:22][CH:23]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Reactant: O=Cc1ccc(C(=O)O)o1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1cccc(NCc2ccc(C(=O)O)o2)c1C(=O)OC

Procedure:
5-Formyl-furan-2-carboxylic acid (1 g, 7.14 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester except the combined aqueous NaHCO3 extracts were washed with methylene chloride (1×70 ml) and the pH adjusted to 2-3 by dropwise addition of concentrated HCl. The mixture was then extracted with ethyl acetate (3×75 ml). The combined ethyl acetate extracts were washed with brine (1×100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated in vacuo to give 0.90 g product as an off-white solid: 1H NMR (CDCl3) δ 7.42-7.36 (m, 1H), 7.16 (d, J=3.5 Hz, 1H), 7.03-6.97 (m, 2H), 6.90 (dd, J=1.0 Hz and 7.3 Hz, 1H), 6.48 (d, J=3.5 Hz, 1H), 4.60 (d, J=5.2 Hz, 2H), 3.82 (s, 3H), 3.81 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[N:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:8][N:9]=1)(=[O:3])[NH2:2].[Br:40]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:40][C:23]1[CH:22]=[C:21]([NH:20][C:5]2[C:4]([C:1](=[O:3])[NH2:2])=[N:9][CH:8]=[C:7]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[N:6]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2Br)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a mixture of tert-butyl 4-(4-{[3-carbamoyl-6-(3-nitrophenoxy)pyrazin-2-yl]amino}phenyl)piperazine-1-carboxylate (1 g) and chloroform (30 mL) was added N-bromosuccinimide (349 mg), followed by stirring at room temperature for 30 minutes. Then, N-bromosuccinimide (100 mg) was added thereto, followed by further stirring at room temperature for 30 minutes. To the reaction mixture was added silica gel, and the solvent was evaporated under reduced pressure and then purified by silica gel column chromatography (eluent; chloroform) to obtain tert-butyl 4-(2-bromo-4-{[3-carbamoyl-6-(3-nitrophenoxy)pyrazin-2-yl]amino}phenyl)piperazine-1-carboxylate (682 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][N:23]3[CH2:22][CH2:21][N:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])[CH2:25][CH2:24]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=Cc1nnn(-c2cccc(Cl)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)N1CCN(Cc2nnn(-c3cccc(Cl)c3)n2)CC1
Reaction time: 8 h
Yield: 46.4 %

Procedure:
2-(3-Chloro-phenyl)-2H-tetrazole-5-carbaldehyde (22.3 mg, 0.107 mmol) was dissolved in 1,2-dichloroethane under argon and ethyl-1-piperazine carboxylate (16.4 uL, 0.112 mmol) was added followed by sodium triacetoxy borohydride (31.8 mg, 0.150 mmol). The reaction was allowed to stir overnight. Ethyl acetate was added and the solution was washed with sodium bicarbonate (sat.), brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using 45% EtOAc/Hexanes and 100% EtOAc to yield the title compound as a white solid (17.4 mg, 46%). 1H NMR (CDCl3) δ (ppm): 8.190 (s, 1H); 8.070 (m, 1H); 7.469 (m, 2H); 4.139 (q, 2H); 3.983 (s, 2H); 3.541 (m, 4H); 2.604 (m, 4H); 1.263 (t, 3H).
Reaction SMILES: [ClH:1].[CH2:2]([C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])=[O:6])[CH2:3][CH3:4].[N:15]1([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16]1>ClC1C=CC=CC=1.CN(C)C1C=CN=CC=1>[ClH:1].[CH2:2]([C:5]([NH:7][C:8]1[CH:9]=[C:10]([NH:11][C:20]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[NH:21])[CH:12]=[CH:13][CH:14]=1)=[O:6])[CH2:3][CH3:4]
Reactant: N#CN1CCCC1
Reactant: CCCC(=O)Nc1cccc(N)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Clc1ccccc1
Product: CCCC(=O)Nc1cccc(NC(=N)N2CCCC2)c1
Temperature: 25 °C

Procedure:
To a stirred suspension of the product of step (a), 2.3 g, 0.0135 moles, in 35ml of chlorobenzene was added 4-dimethylaminopyridine. To this was added 1-pyrrolidinecarbonitrile, 1.2 ml, 0.006 moles, and the reaction was heated to reflux for 8 hours. The reaction cooled to room temperature and the solvent was decanted. To the residue was added 25 ml of isopropanol and 150 ml of ethyl acetate. A solid crystallized and was collected by filtration. The above solid was then dried at 80° C. for 24 hours giving N-(3-(((propyl)carbonyl)amino)phenyl)-1-pyrrolidinecarboximidamide hydrochloride, 1.5 g, m.p. 207°-208° C.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].C1(C)C=CC(S(O[CH2:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)(=O)=O)=CC=1>>[CH:32]1([CH2:31][N:8]2[C:9]([O:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:35][CH2:34][CH2:33]1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2CC2CCC2)c1
Yield: 47.9 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (cyclobutyl)methyl para-toluenesulfonate were reacted by the same way with the example 1 to obtain the titled compound (164 mg, yield: 47.9%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C(C)=CC=CC=1>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: O=C1CCCc2ccc(O)cc21
Temperature: 25 °C
Yield: 79.1 %

Procedure:
In xylene (450 ml) was dissolved 7-methoxy-1-tetralone (50.0 g) under argon atmosphere. To the mixture was added aluminum chloride (75.7 g), and the mixture was refluxed for 4.5 hours. The mixture was cooled to room temperature. To the mixture was added 3N hydrochloric acid (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give 7-hydroxy-1-tetralone (36.4 g) as dark green crystals.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[CH:17]=1.[OH-].[K+]>C(#N)C>[CH3:21][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[O:20][N:19]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1cc(CCCCCBr)on1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cc(CCCCCOc2ccc(C=O)cc2)on1
Yield: 67 %

Procedure:
A solution of 7.2 g of 4-hydroxybenzaldehyde, 14.6 g of 5-(5-bromopentyl)-3-methylisoxazole, 4 g of potassium hydroxide in 100 ml of acetonitrile was heated at reflux for 1.5 hours. The reaction mixture was cooled and filtered, the solvent removed, and the residue recrystallized from isopropyl acetate-hexane to give 10.8 g of 4-[5-(3-methyl-5-isoxazolyl)pentyloxy]benzaldehyde as a pale yellow powder.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1.C(N(CC)CC)C>C(Cl)Cl>[OH:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])[CH2:9][CH2:10]1
Reactant: OCC1CCNCC1
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
Isopropyl chloroformate (1.0M in toluene, 43.4 mL, 43.4 mmol) was added dropwise to a mixture of 4-piperidinemethanol (5 g, 43.4 mmol) and triethylamine (12.1 mL, 86.8 mmol) in CH2Cl2 (150 mL) at 0° C. over 20 min. The mixture was stirred at ambient temperature overnight. The mixture was washed with water, followed by brine. The organic layer was separated and dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 5% MeOH/CH2Cl2 to give 7.76 g (89%) of 1-methylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate as a clear oil. 1H NMR (400 MHz, CDCl3): δ 4.93-4.78 (m, 1H), 4.19-4.09 (m, 2H), 3.47 (d, 2H, J=6.2 Hz), 2.75-2.65 (m, 2H), 1.75-1.56 (m, 3H), 1.21 (d, 6H, J=6.2 Hz), 1.17-1.06 (m, 2H); LRMS (ESI), m/z 202 (M+H).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Br:7][C:8]1[CH:32]=[CH:31][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][S:28][CH2:29][CH3:30])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:33])[CH:9]=1>O.CO>[Br:7][C:8]1[CH:32]=[CH:31][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][S:28]([CH2:29][CH3:30])=[O:1])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:33])[CH:9]=1
Reactant: O=S([O-])OO
Reactant: CCSCCOc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCS(=O)CCOc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.4 %

Procedure:
A solution of OXONE, (trade mark of E.I. du Pont de Nemours & Co.,Inc), (150 mg) in water (2 ml) was added to a solution of 4-(4-bromo-2-fluoroanilino)-7-(2-ethylthioethoxy)-6-methoxyquinazoline (125 mg, 0.28 mmol), (prepared as described in Example 24), in methanol (10 ml). The reaction mixture was stirred for 16 hours at ambient temperature, the methanol was removed by evaporation, the aqueous residue was basified with sodium hydrogen carbonate solution and then extracted with ethyl acetate (3×30 ml). The extracts were combined, washed with water (×2), and then brine, and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by column chromatography eluting with ethyl acetate and then with methylene chloride/methanol (9/1) to give 4-(4-bromo-2-fluoroanilino)-7-(2ethylsulphinylethoxy)-6methoxyquinazoline (32 mg, 31%).
Reaction SMILES: [CH3:1][C:2]([O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([N+:30]([O-])=O)=[CH:22][CH:21]=1)([CH3:18])[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=1.[H][H]>CO.CC(O)=O.[Pt]>[NH2:30][C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]([O:19][C:2]([CH3:18])([CH3:1])[CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH:5]=2)=[CH:21][CH:22]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Nc1cc(CC(C)(C)Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cc(CC(C)(C)Oc2ccc(N)c3ccccc23)ccn1
Yield: 98.6 %

Procedure:
tert-Butyl 4-(2-methyl-2-(4-nitronaphthalen-1-yloxy)propyl)pyridin-2-ylcarbamate (27) (100 mg, 0.229 mmol) in MeOH (30 mL) and AcOH (8.0 mL) was passed through a Thales H-cube (1.0 mL·min−1, 30° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode). The volatiles were removed under reduced pressure to give tert-butyl 4-(2-(4-aminonaphthalen-1-yloxy)-2-methylpropyl) pyridin-2-ylcarbamate (28) (92 mg, 99%) as a purple oil: m/z 408 (M+H)+ (ES+).
Reaction SMILES: [F:1][C:2]([F:14])([S:11]([OH:13])=[O:12])[CH2:3][O:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].[Na:15].[OH:16]O>O>[F:14][C:2]([F:1])([S:11]([OH:16])(=[O:13])=[O:12])[CH2:3][O:4][C:5](=[O:10])[C:6]([CH3:8])([CH3:9])[CH3:7].[Na:15]
Reactant: CC(C)(C)C(=O)OCC(F)(F)S(=O)O
Reactant: OO
Agent: [Na]
Solvent: O
Product: CC(C)(C)C(=O)OCC(F)(F)S(=O)(=O)O
Reaction time: 1 h
Yield: 91 %

Procedure:
A glass flask equipped with a thermometer, a condenser and a dropping funnel was charged with 290 g (0.74 mole) of 65% purity sodium 1,1-difluoro-2-(pivaloyloxy)ethane-1-sulfinic acid obtained by Comparative Example 1-2, a catalytic amount of sodium tungstate(IV) dehydrate and 600 ml of water, followed by stirring. Then, 170 g (1.5 moles) of 30% hydrogen peroxide solution was added dropwise in an iced bath. After the termination of the dropping, stirring was conducted for 1 hour at room temperature. Then, the termination of the reaction was confirmed by 19F NMR. The reaction solution was condensed and then rinsed with 500 ml of diisopropyl ether. Subsequently, filtration was conducted and a solid obtained therewith was dried, thereby obtaining 278 g of sodium 1,1-difluoro-2-(pivaloyloxy)ethanesulfonic acid in the form of a white solid (91% yield, 65% purity). In this case, 2-bromo-2,2-difluoroethyl pivalate was detected to be formed as a by-product in an amount of 8%.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:11][CH2:10][CH2:9][C:5]21[CH2:8][NH:7][CH2:6]2.F[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([NH:22][C:23]2[N:28]=[C:27]([C:29]3[CH:30]=[N:31][N:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=34)[CH:26]=[CH:25][N:24]=2)=[C:15]([O:38][CH3:39])[CH:14]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:39][O:38][C:15]1[CH:14]=[C:13]([N:7]2[CH2:8][C:5]3([N:4]([CH3:3])[CH2:11][CH2:10][CH2:9]3)[CH2:6]2)[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)[CH:26]=[CH:25][N:24]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Reactant: CN1CCCC12CNC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC3(CCCN3C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 100 °C
Yield: 83.3 %

Procedure:
8-Methyl-2,8-diazaspiro[3.4]octane (Intermediate 47, 133 mg, 0.88 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(pyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-amine (Intermediate 155, 280 mg, 0.74 mmol) and DIPEA (0.153 mL, 0.88 mmol) in DMA (3 mL) and the mixture was heated at 100° C. for 1 h. The mixture was then part-purified by ion exchange chromatography, using an SCX column, eluting with 7M methanolic ammonia. Clean fractions were combined and concentrated in vacuo. Further purification by FCC, eluting with 1-8% CH3OH in CH2Cl2 gave the title compound (300 mg) as an orange dry film; 1H NMR: 1.71 (2H, dt), 2.05 (2H, dd), 2.40 (3H, s), 2.67 (2H, t), 3.75 (2H, d), 3.95 (3H, s), 4.11 (2H, d), 6.31 (1H, s), 7.09 (1H, td), 7.28 (1H, d), 7.35-7.41 (1H, m), 8.25 (1H, s), 8.36 (1H, d), 8.47 (1H, s), 8.50 (1H, d), 8.79 (1H, s), 8.79-8.82 (1H, m); m/z: ES+ MH+ 487.30.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]([OH:31])([CH2:29][CH3:30])[CH2:27][CH3:28])[CH:5]=[C:6]([CH:25]=1)[O:7][CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:20]3[CH:24]=[CH:23][O:22][CH:21]=3)=[CH:14][C:15](=[O:19])[O:16]2)=[CH:11][CH:10]=1.[OH-:32].[Na+:33]>C1COCC1>[Na+:33].[Na+:33].[O:22]1[CH:23]=[CH:24][C:20]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][O:7][C:6]3[CH:25]=[C:2]([F:1])[CH:3]=[C:4]([C:26]([OH:31])([CH2:27][CH3:28])[CH2:29][CH3:30])[CH:5]=3)=[CH:18][C:17]=2[OH:32])=[CH:14][C:15]([O-:16])=[O:19])=[CH:21]1.[O:22]1[CH:23]=[CH:24][C:20]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][O:7][C:6]3[CH:25]=[C:2]([F:1])[CH:3]=[C:4]([C:26]([OH:31])([CH2:27][CH3:28])[CH2:29][CH3:30])[CH:5]=3)=[CH:18][C:17]=2[OH:32])=[CH:14][C:15]([O-:16])=[O:19])=[CH:21]1
Reactant: [OH-]
Reactant: CCC(O)(CC)c1cc(F)cc(OCc2ccc3c(-c4ccoc4)cc(=O)oc3c2)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(O)(CC)c1cc(F)cc(OCc2ccc(C(=CC(=O)[O-])c3ccoc3)c(O)c2)c1
Reaction time: 16 h

Procedure:
A solution of the lactone from Step 1 in THF was treated with 2 equivalents of 1N NaOH and the mixture heated at reflux for 2 hrs. The solvent was removed in vacuo and the residue was lyophilized for 16 hrs to afford the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[C:9]([C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=3)[C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[N+:30]([O-:32])=[O:31].Cl.Cl[CH2:35][CH2:36][CH:37]1[CH2:41][CH2:40][CH2:39][N:38]1[CH3:42]>CN(C)C=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:23]([CH2:35][CH2:36][CH:37]3[CH2:41][CH2:40][CH2:39][N:38]3[CH3:42])[C:24](=[O:29])[C:25]([F:28])([F:26])[F:27])=[C:9]([C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=3)[C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[N+:30]([O-:32])=[O:31]
Reactant: CN1CCCC1CCCl
Reactant: Cc1cc(C)cc(-c2c(NC(=O)C(F)(F)F)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(-c2c(N(CCC3CCCN3C)C(=O)C(F)(F)F)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
To a suspension of 10 mg sodium hydride in 1.0 mL N,N-dimethylformamide was added 90 mg N-[7-chloro-3-(3,5-dimethylphenyl)-6-nitro-2-oxo-1,2-dihydroquinolin-4-yl]-2,2,2-trifluoroacetamide and the mixture stirred at room temperature for 1 hour. At this time, 75 mg of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride and the mixture heated to 80° C. on an oil bath. After 6 hours, the mixture was cooled to room temperature, diluted with ethyl acetate and extracted with water. The organic portion was washed with brine and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 95:5+1% ammonium hydroxide) gave the title compound (50 mg).
Reaction SMILES: C([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:42][O:43][CH3:44])[C:11]([NH:13][CH:14]2[C:40](=[O:41])[N:16]3[C:17]([C:37]([OH:39])=[O:38])=[C:18]([CH2:21][S:22][C:23]4[S:24][C:25]([CH2:28][NH:29]C(OC(C)(C)C)=O)=[N:26][N:27]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1)=O.CO.Cl>C(O)=O>[NH2:3][C:4]1[N:9]=[C:8]([C:10](=[N:42][O:43][CH3:44])[C:11]([NH:13][CH:14]2[C:40](=[O:41])[N:16]3[C:17]([C:37]([OH:39])=[O:38])=[C:18]([CH2:21][S:22][C:23]4[S:24][C:25]([CH2:28][NH2:29])=[N:26][N:27]=4)[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CNC(=O)OC(C)(C)C)s3)CS[C@H]12)c1cccc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CN)s3)CS[C@H]12)c1cccc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A solution of 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-(5-t-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(1.12 g.) in 98% formic acid (11 ml.) was stirred at room temperature for 2 hours. Methanol (20 ml.) and conc. hydrochloric acid (0.3 ml.) were added to the resultant solution and then stirred at room temperature for 30 minutes. After the reaction mixture was concentrated in vacuo, water (25 ml.) was added to the residue, and then the solution was adjusted to pH 3 to 4 with a saturated aqueous solution of sodium bicarbonate. The solution was subjected to column chromatography on macroporous, non-ionic adsorption resin "Diaion HP-20" (Trademark, manufactured by Mitsubishi Chemical Industries Ltd.) with an eluent of aqueous methanol. The eluate was concentrated under reduced pressure and lyophilized to give 7-[2-(6-aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.48 g.), mp. 248° to 251° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:19])[CH2:15][CH2:16][CH:17]=[CH2:18])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=1[Cl:28]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:19])[CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([Cl:28])[CH:23]=2)=[CH:6][CH:7]=1
Reactant: C=CCCC(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: Clc1ccc(I)cc1Cl
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CC/C=C/c1ccc(Cl)c(Cl)c1

Procedure:
Prepared according to the procedure described in Example 168, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-pent-4-en-1-ol and 1,2-dichloro-4-iodo-benzene.
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1.I[CH3:18]>O1CCCC1>[S:3]1[C:7]2[CH:8]=[C:9]([N:12]([CH3:18])[S:13]([CH3:16])(=[O:14])=[O:15])[CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1
Reactant: CI
Reactant: CS(=O)(=O)Nc1ccc2ncsc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccc2ncsc2c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
Sodium hydride (2.56 g of a 60% dispersion in mineral oil, 64.0 mmol) was added to a solution of N-benzothiazol-6-yl-methanesulfonamide (Example 7a, 13.3 g, 58.2 mmol) in tetrahydrofuran at 0° C. After 15 min, iodomethane (36.2 mL, 581 mmol) was added and the reaction mixture was warmed to 25° C., stirred for 4 h, then was partitioned between 1.0 M aqueous hydrochloric acid solution (300 mL) and ethyl acetate (2×250 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Trituration of the residue with diethyl ether afforded a solid that was collected by vacuum filtration and dried in vacuo to afford the desired product, N-benzothiazol-6-yl-N-methyl-methanesulfonamide (12.1 g, 50 mmol, 86% yield) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.00 (3H, s), 3.31 (3H, s), 7.57 (1H, dd, J1=2.2 Hz, J2=8.7 Hz), 8.07 (1H, d, J=8.5 Hz), 8.23 (1H, d, J=1.7 Hz), 9.40 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][CH:20]([C:42]3[CH:47]=[C:46]([CH3:48])[C:45]([CH2:49][CH2:50][OH:51])=[C:44]([CH3:52])[CH:43]=3)[C:21]([N:23]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-])=O)[CH:26]=3)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][N:23]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21](=[O:22])[CH:20]([NH:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[C:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[N:10][CH:11]=[CH:12]2)[C:42]1[CH:47]=[C:46]([CH3:48])[C:45]([CH2:49][CH2:50][OH:51])=[C:44]([CH3:52])[CH:43]=1
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(CC(=O)OC(C)(C)C)Cc2cccc([N+](=O)[O-])c2)cc(C)c1CCO
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(CC(=O)OC(C)(C)C)Cc2cccc(N)c2)cc(C)c1CCO
Yield: 91.1 %

Procedure:
A solution of 52D (230 mg, 0.28 mmol) in MeOH (5 mL) with Pd/C (15 mg) was stirred under H2 (60 psi) for 3 h. The reaction mixture was filtered through Celite and concentrated in vacuo to afford 52E (200 mg, 90%) as a yellow solid. MS (ESI) m/z 784.85 (M+H)+.