Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9][CH2:10][NH:11][CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH2:13][OH:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41].C(OCC)(=O)C>O1CCOCC1>[C:44]1([CH2:43][O:42][C:40]([N:11]([CH2:10][CH2:9][CH:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH2:13][OH:14])=[O:41])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(CC(CO)NCCC(c2ccccc2)c2ccccc2)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(CC(CO)N(CCC(c2ccccc2)c2ccccc2)C(=O)OCc2ccccc2)cc1OC
Reaction time: 4 h
Yield: 54 %

Procedure:
To a magnetically stirred solution of β-[(3,3-diphenylpropyl)amino]-3,4-dimethoxybenzenepropanol, monohydrochloride (3.66 mole, 1.62 g; see example 2) and triethylamine (7.32 mmole, 1.02 ml) in p-dioxane (14 ml) at room temperature under nitrogen was added benzyl chloroformate (4.39 mmole, 0.63 ml). The reaction was complete in 4 hours. The mixture was filtered and the filtrate reduced in vacuo to yield an oil. The oily residue was taken into ethyl acetate and washed with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered and evaporated. Flash chromatography (160 g of LPS-1 silica, 1:1 ethyl acetate:hexane, eluted ~50 ml/min.) afforded 1.28 g of the title compound as an oil.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:14]2[C:13](=[CH:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:31][CH2:32][CH3:33])[C:26]([O:28]CC)=[O:27])=[CH:20][CH:19]=3)[C:12]3[CH:34]=[CH:35][CH:36]=[CH:37][C:11]=3[O:10][CH2:9][O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(O)C>[CH:3]1[C:14]2[C:13](=[CH:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:31][CH2:32][CH3:33])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)[C:12]3[CH:34]=[CH:35][CH:36]=[CH:37][C:11]=3[O:10][CH2:9][O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(Cc1ccc(OCC=C2c3ccccc3OCOc3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCC=C2c3ccccc3OCOc3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 15% aqueous solution of NaOH (4 ml) was added to a solution of ethyl 3-(4-(2-(12H-dibenzo(d,g)-1,3-dioxocine-12-ylidene)ethoxy)phenyl)-2-ethoxypropionate (0.95 g, 2.0 mmol) in ethanol (15 ml), and the-mixture stirred at room temperature for 2 h, then left to stand overnight. The resulting solution was evaporated, water (20 ml) and benzene (25 ml) were added, and the mixture acidified to pH 6 with acetic acid. The benzene layer was separated, and the water layer further extracted with benzene (2×10 ml). The combined benzene extracts were washed with water (20 ml), brine (15 ml), dried (MgSO4) and evaporated to give 3-(4-(2-(12H-dibenzo(d,g)-1,3-dioxocine-12-ylidene)ethoxy)phenyl)-2-ethoxypropionic acid,: 0.79 g (83.2%). This acid (0.76 g, 1.6 mmol) was dissolved in acetone (30 ml), L-lysine (0.234 g, 1.6 mmol) and water (3 ml) were added and the mixture stirred at room temperature for 2 h. The solution was filtered, evaporated, and the residue stirred with a mixture of Et2O (20 ml) and acetone (20 ml) overnight. The resulting solid was collected by filtration, washed with Et2O (2×30 ml) and dried to give the title compound as a partial hydrate: 0.90 g (93.5%).
Reaction SMILES: [N:1]1([C:7](=[O:12])[C:8]([S:10][CH3:11])=S)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[NH2:18][CH2:19]C#N.C([N:24](CC)CC)C>CO>[N:1]1([C:7]([C:8]2[S:10][C:11]([NH2:24])=[CH:19][N:18]=2)=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CSC(=S)C(=O)N1CCOCC1
Reactant: CCN(CC)CC
Reactant: N#CCN
Agent: O=S(=O)(O)O
Solvent: CO
Product: Nc1cnc(C(=O)N2CCOCC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a stirring mixture of methyl 4-morpholinyl(oxo)ethanedithioate (Preparation 25, 500 mg) and aminoacetonitrile bisulfate (564 mg) in MeOH (10 mL) at 0° C. is added triethylamine in MeOH (5 mL). The mixture is stirred overnight and allowed to warm to ambient temperature. The solution is filtered, and solvent removed from the filtrate. The residue is washed with water (15 mL) and extracted with EtOAc (3×20 mL), dried over MgSO4, and the solvent removed. The residue is purified by SiO2 flash column chromatography (eluent 3/1 EtOAc/hexane) to afford 161 mg (31%) of the title compound as a light brown solid. Physical characteristics: 1H NMR (CDCl3) δ3.78, 4.35, 7.05; IR (diffuse reflectance) 3321, 3217, 2858, 1580, 1438, 1418, 1348, 1276, 1178, 1113, 1003, 834, 783, 731, 619 cm−1; MS (ESI+) m/z 214 (M+H)+. Anal. Found: C, 45.24; H, 5.33; N, 19.42.
Reaction SMILES: C1(C[CH:8]([NH:12][C:13]([C:15]2[CH:45]=[CH:44][C:18]3[N:19]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[C:27](C4C=CC=CC=4)[CH:26]=[N:25]5)=[N:21][C:17]=3[CH:16]=2)=[O:14])[C:9]([OH:11])=[O:10])CCCCC1.N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H](C(O)=O)C[CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>>[CH:15]1([CH:8]([NH:12][C:13]([C:15]2[CH:45]=[CH:44][C:18]3[N:19]([CH:38]4[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]4)[C:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[C:27]([C:54]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[CH:26]=[N:25]5)=[N:21][C:17]=3[CH:16]=2)=[O:14])[C:9]([OH:11])=[O:10])[CH2:45][CH2:44][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(N[C@@H](CC1CCCCC1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(NC(CC1CCCCC1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Product: O=C(NC(C(=O)O)C1CCCCC1)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Yield: 48 %

Procedure:
The general procedure described for Compound 242 was used with Fmoc-Cha Wang resin (250 mg, 0.4 mmol/g), producing 29 mg of the title compound (48% yield). MS: 586.27 (M−H+) HPLC Procedure A, retention time=14.94 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][CH:20]=2)=[N:10]1.C(=O)([O-])[O-:29].[K+].[K+].OO.O>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH2:27])=[O:29])=[CH:21][CH:20]=2)=[N:10]1
Reactant: N#CCc1ccc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)Cc1ccc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
To a solution of (4-(1-(2,6-difluorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (80.0 mg) obtained in Example 39 in DMSO (0.8 mL) was added potassium carbonate (36.6 mg), and then 30% aqueous hydrogen peroxide (0.068 mL) was added thereto. The reaction mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the white precipitate was collected by filtration, washed with water, and dried in vacuum to give the title compound (7.5 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C[O-].[Na+:27].CO>C(C(C)=O)C.CC(C)=O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[Na+:27]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Solvent: CCC(C)=O
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 27 °C

Procedure:
A solution of esomeprazole (19.5 g, 56.5 mmol; 1.3% sulfone, 1.05% R-enantiomer) in methyl ethyl ketone (60 mL) and acetone (60 mL) was cooled to 15° C. 30% sodium methoxide in methanol (10.7 mL, 57.6 mmol) was added in 15 min. Subsequently, the solution was stirred at 27° C. A solid started to crystallize. The resulting slurry was stirred overnight at room temperature. The solid was collected by filtration, rinsed with acetone (2×20 mL) and dried under reduced pressure at 50° C. to yield esomeprazole sodium. Yield: 10.8 g (52%). Sulfone content: 0.05%. R-enantiomer content: 0.00%.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CS[C:25]1[C:26]2[CH:39]=[CH:38][CH:37]=[CH:36][C:27]=2[NH:28][C:29]2[N:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>CO.ClCCl>[C:2]1([C:1]2[N:31]3[C:30]4[CH:32]=[CH:33][CH:34]=[N:35][C:29]=4[NH:28][C:27]4[CH:36]=[CH:37][CH:38]=[CH:39][C:26]=4[C:25]3=[N:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CSC1=Nc2cccnc2Nc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: c1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 90 °C

Procedure:
To a solution benzoic hydrazide (0.98 g, 7.2 mmol) and p-toluenesulfonic acid monohydrate (0.68 g, 3.6 mmol) in methanol (50 ml) was added a solution of 6-(methylthio)-11H-benzo[e]pyrido[3,2-b][1,4]diazepine (0.87 g, 3.6 mmol) in dichloromethane (25 ml). The reaction mixture was heated at 90° C. for 3 hours. The solvent was removed under reduced pressure and the crude product purified using flash chromatography (SiO2, 2% MeOH in DCM). The desired product, 3-phenyl-9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepine, was obtained as a tan solid (0.352 mg, 31%). M.p.=273-275° C.; 400 MHz 1H NMR (CDCl3) δ: 8.20 (d, J=7.8 Hz, 1H), 8.17 (d, J=3.9 Hz, 1H), 7.5-7.3 (m, 6H), 7.18 (t, J=7.6 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.79 (dd, J=7.8, 4.7 Hz, 1H), 6.49 (s, 1H); LCMS [M+H]: 312; Calculated for C19H13N5. 0.44 water, C, 71.48; H 4.38; N 21.94, found, C 71.48, H 4.43, N 21.67.
Reaction SMILES: C(=O)(O[CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](Br)[N:12]=2)[N:7]([C:15](=[O:17])[CH3:16])[C:6]([CH2:19]C2C=CC=CC=2)(C)[CH2:5]1)N.C([O-])=O.[NH4+:30].[H][H]>C(O)C.[C].[Pd]>[C:15]([N:7]1[C:8]2[C:13](=[N:12][CH:11]=[CH:10][CH:9]=2)[CH:4]([NH2:30])[CH2:5][CH:6]1[CH3:19])(=[O:17])[CH3:16]
Reactant: [NH4+]
Reactant: [H][H]
Reactant: CC(=O)N1c2ccc(Br)nc2C(OC(N)=O)CC1(C)Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Solvent: CCO
Product: CC(=O)N1c2cccnc2C(N)CC1C
Yield: 62.1 %

Procedure:
[Step 3] 279 mg of the benzyl-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl carbamate and 126 mg of ammonium formate were dissolved in 5 mL of ethanol followed by adding 112 mg of 10% palladium carbon and stirring for 6 hours under normal pressure in a hydrogen atmosphere at room temperature. Following completion of the reaction, the solution was filtered with celite and concentrated under reduced pressure. The resulting residue was neutralized with saturated sodium bicarbonate and extracted five times with chloroform. After washing with saturated brine and dehydrating with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (saturated ammonia/methanol:chloroform=1:10) to obtain 85 mg of 1-acetyl-4-amino-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine in the form of a red solid (62%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:12][C:13]([C:15]1[C:20]([I:21])=[C:19]([NH2:22])[C:18]([I:23])=[C:17]([C:24]([NH:26][CH:27]([CH2:33][O:34][C:35](=[O:37])[CH3:36])[CH2:28][O:29][C:30](=[O:32])[CH3:31])=[O:25])[C:16]=1[I:38])=[O:14])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[Br:39][CH:40]([CH2:44][CH2:45]Br)[C:41](Br)=[O:42].C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)(=O)C>CN(C)C(=O)C.N1C=CC=CC=1>[C:30]([O:29][CH2:28][CH:27]([NH:26][C:24]([C:17]1[C:18]([I:23])=[C:19]([N:22]2[CH2:45][CH2:44][CH:40]([Br:39])[C:41]2=[O:42])[C:20]([I:21])=[C:15]([C:13]([NH:12][CH:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:7][O:8][C:9](=[O:11])[CH3:10])=[O:14])[C:16]=1[I:38])=[O:25])[CH2:33][O:34][C:35](=[O:37])[CH3:36])(=[O:32])[CH3:31]
Reactant: O=C(Br)C(Br)CCBr
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(N)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(N2CCC(Br)C2=O)c1I
Temperature: 25 °C
Reaction time: 13 h
Yield: 45.8 %

Procedure:
A solution of N,N'-bis-[2-acetyloxy-1-(acetyloxymethyl)ethyl]-5-[amino]-2,4,6-triiodo-1,3-benzenedicarboxamide, (8.73 g, 10 mmol) in dry N,N-dimethylacetamide (100 ml) was treated with 2,4-dibromobutyroyl bromide (4.017 g, 13 mmol) under nitrogen and the mixture was stirred for 13 hours at 25° C. The dimethylacetamide was removed by distillation at 55°-60° C. under high vacuum. The resulting thick paste was dissolved in dry N,N-dimethylacetamide (160 ml) and potassium carbonate (1.80 g, 13 mmol) was added. The mixture was stirred for 60 minutes. An additional portion of potassium carbonate (1.80 g, 13.0 mmol) was added and the mixture stirred for 80 minutes. The suspended salts were filtered off and the volume of the reaction mixture was reduced to about 80 ml by vacuum distillation at 0.05-0.10 mm/Hg. The residual solution was poured slowly with rapid stirring into ice-water (900 ml). The resulting mixture was stirred overnight at 0° C. and then filtered. The collected precipitate was dried in a vacuum desiccator (P2O5) and then crystallized from acetonitrile to give an off-white powder. This product was treated with acetic anhydride (30 ml) and pyridine (42 ml) for 32 hours at 25°, after which the volatile components were completely removed under high vacuum to obtain N,N'-bis-[2-acetyloxy-1-(acetyloxymethyl)ethyl]-5-[3-bromo-2-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as a white powder (4.67 g, 45% yield), m.p. 232°-234°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](O)=[C:9]([C:14]#[N:15])[CH:10]=[N:11]2)=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:21].P(Cl)(Cl)(Cl)=O>CCCCCC>[Cl:21][C:8]1[C:7]2[C:12](=[CH:13][C:4]([O:3][CH2:1][CH3:2])=[C:5]([N+:17]([O-:19])=[O:18])[CH:6]=2)[N:11]=[CH:10][C:9]=1[C:14]#[N:15]
Reactant: CCOc1cc2ncc(C#N)c(O)c2cc1[N+](=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: CCOc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Yield: 58.2 %

Procedure:
A mixture of 3.45 g (13 mmol) of 7-Ethoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile, 5.55 g (26 mmol) of phosphorous pentachloride, and 10 ml of phosphorous oxychloride was refluxed for 3 hours. The mixture was diluted with hexane and the solid was collected. The solid was dissolved in 500 ml of ethyl acetate and washed with cold diluted sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through a pad of silica gel. The solvent was removed giving 2.1 g of beige solid: mass spectrum (electrospray, m/e) M+H 277.7.
Reaction SMILES: [OH2:1].O.O.C([O-])(=O)C.[Na+].[F:9][C:10]1[CH:11]=[CH:12][C:13]([OH:18])=[C:14]([CH:17]=1)[CH:15]=O.[NH2:19]O.Cl>O.C(O)C>[F:9][C:10]1[CH:11]=[CH:12][C:13]([OH:18])=[C:14]([CH:17]=1)[CH:15]=[N:19][OH:1]
Reactant: O
Reactant: NO
Reactant: O=Cc1cc(F)ccc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1cc(F)ccc1O
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A solution of sodium acetate trihydrate (1.94 g, 14.28 mmol) in H2O (8 mL) was added to a warm solution of 5-fluoro-2-hydroxy-benzaldehyde (1.0 g, 7.14 mmol) and NH2OH HCl (992 mg, 14.28 mmol) in 80% ethanol (30 mL). The reaction mixture was refluxed for 3 hr. Removal of ethanol, the mixture was cooled to rt, collected the precipitate and washed with water, dried to afford the title compound (920 mg, 83%). MS (DCI/NH3) m/z 217 (M+62)+. 1HNMR (500 MHz, DMSO-d6) δ ppm 6.89 (dd, J=9.15, 4.88 Hz, 1H) 7.07 (td, J=8.54, 3.05 Hz, 1H) 7.29 (dd, J=9.46, 3.05 Hz, 1H) 8.30 (s, 1H) 10.02 (brs, 1H) 11.46 (brs, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH:9]1[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[O:12]1[C:11]2([CH2:16][CH2:17][NH:8][CH:9]([CH2:18][N:19]3[C:20](=[O:29])[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]3=[O:28])[CH2:10]2)[O:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1CN1C(=O)c3ccccc3C1=O)OCCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccccc2C(=O)N1CC1CC2(CCN1)OCCO2
Temperature: 25 °C
Yield: 100 %

Procedure:
7-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (1.55 g, 3.85 mmol) was cooled in an ice bath and then dissolved in a solution of 20% trifluoroacetic acid/dichloromethane (15 ml). The reaction was stirred and allowed to slowly warm to ambient temperature during 3 hours. The solution was concentrated in vacuo to give crude 2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)isoindole-1,3-dione which was used directly in the following step (assumed 100% yield).
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH2:8]([O:12][S:13]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:15])=[O:14])[CH2:9][CH2:10][CH3:11]>>[CH2:8]([O:12][S:13]([O-:16])(=[O:15])=[O:14])[CH2:9][CH2:10][CH3:11].[CH2:1]([P+:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:17][CH2:18][CH2:19][CH3:20])[CH3:2]
Reactant: CCP(CC)CC
Reactant: CCCCOS(=O)(=O)OCCCC
Product: CCCCOS(=O)(=O)[O-]
Product: CCCC[P+](CC)(CC)CC
Reaction time: 1.25 h
Yield: 85 %

Procedure:
Triethylphosphine (7.2 g, 99%, 0.06 mol) was added dropwise to a 125 mL flask containing 12.6 (99%, 0.06 mol) di-n-butylsulfate at 80° C. under nitrogen and with stirring over a period of 75 minutes. The liquid was stirred at 140° C. for an additional 3.5 hours. The liquid was cooled, moved to a rotary evaporator and dried at 125° C./5 mm Hg for 6 hours. The product (16.73 g, yield 85%) was a wax-like solid at room temperature (m.p. from DSC measurement: 40.0° C.). 1H-NMR (CDCl3, 300.13 MHz, δ): 3.98 (t, 2H, CH3CH2CH2—CH2—O—), 2.34 (m, 8H, 3×CH3—CH2P+ and CH3CH2CH2—CH2P+), 1.54 (m, 8H, CH3—CH2CH2—CH2O— and CH3—CH2CH2—CH2P+), 1.25 (m, 3×CH3—CH2P+), 0.91 (m, 6H, CH3CH2CH2—CH2O— and CH3CH2CH2—CH2P+). 31P-NMR (CDCl31 81.015 MHz, δ): 38.88 (s, P+).
Reaction SMILES: C1(C[O:8][CH2:9][CH:10]2[S:14][CH2:13][CH:12]([S:15][C:16](=[O:18])[CH3:17])[CH2:11]2)C=CC=CC=1.B(F)(F)F.CCOCC>C(Cl)(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:8][CH2:9][CH:10]1[S:14][CH2:13][CH:12]([S:15][C:16](=[O:18])[CH3:17])[CH2:11]1
Reactant: CC(=O)SC1CSC(COCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: FB(F)F
Agent: [I-]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(=O)SC1CSC(CO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 0° C. solution, under argon, of 0.123 g of product from Example 139 in 1.0 ml of dry chloroform is treated with 51.1 microliter of boron trifluoride etherate and 0.193 g of tetra n-butylammonium iodide. the reaction mixture is stirred at room temperature overnight and concentrated in vacuo. The residue is purified by chromatography (silica gel: 0-100% ethyl acetate/hexane) to give 0.079 g of the desired. product.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:33])[CH:12]([NH:13][C:14](=[O:32])[C:15](=[N:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:16]3[N:17]=[C:18]([NH:21]C=O)[S:19][CH:20]=3)[C@H:4]2[S:3]1.Cl>CO.O1CCCC1>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:33])[CH:12]([NH:13][C:14](=[O:32])[C:15](=[N:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1
Reactant: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(NC=O)n1
Agent: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(=NC=O)[nH]1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(N)n1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
A solution of 2-methyl-7-[2-hexyloxyimino-2-(2-formylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-hexyloxyimino-2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (5.3 g) and concentrated hydrochloric acid (4.2 g) in a mixture of methanol (53 ml) and tetrahydrofuran (40 ml) was stirred for 2 hours at 30° C., and then evaporated to dryness. The residue was dissolved in an aqueous solution of sodium bicarbonate (500 ml) and then filtered. The filtrate was adjusted to pH 3.5 with 10% hydrochloric acid with stirring under ice-cooling and further stirred for 30 minutes at the same temperature. The precipitates were collected by filtration, washed with water and then dried to give 2-methyl-7-[2-hexyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-hexyloxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (4.45 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[S:35](Cl)(=[O:37])=[O:36].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][C:26]=1[S:35]([N:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:2]([CH3:1])[CH2:7]1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2Br)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (1.20 g, 5.99 mmol) and DIPEA (5.45 ml, 31.2 mmol) in dry DCM (60 ml) at 0° C. under Ar was added 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (2.04 g, 6.29 mmol) and the resulting clear solution stirred at 0° C. for 2 h. EtOAc (100 ml) and saturated aqueous NaHCO3 (100 ml) were added, the layers separated, then the organic layers washed with 2M aqueous HCl (100 ml) and passed through an hydrophobic frit. The solvent was removed to leave the title compound (2.36 g).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][C:3]=1[C:25]#[C:26][C:27]1[N:31]2[N:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][CH:28]=1.[Cl:36]C1C=CC(C2NC3C=C(CN4CCN(C)CC4)C=CC=3N=2)=CC=1I>>[Cl:36][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([CH2:17][N:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)[CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][C:3]=1[C:25]#[C:26][C:27]1[N:31]2[N:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][CH:28]=1
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1cnc2cccnn12
Reactant: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(I)c4)[nH]c3c2)CC1
Product: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(C#Cc5cnc6cccnn56)c4)[nH]c3c2)CC1

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine (as prepared in Example 3) and 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzoimidazole in a manner similar to that described for in Example 1. The intermediate compound 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole was made as for Example 1 (Step 4 to 7) with the spectra below: 1H NMR (300 MHz, CDCl3) δ: 8.52 (1H, s), 7.95-7.98 (1H, d, J=9.0 Hz), 7.45-7.48 (1H, d, J=9.0 Hz), 7.43-7.46 (1H, d, J=9.0 Hz), 7.23 (1H, s), 7.21-7.24 (1H, d, J=9.0 Hz), 3.59 (2H, s), 2.51 (8H, brs), 2.29 (3H, s).