Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]#[N:25])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:26][OH:27]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24](=[NH:25])[NH:26][OH:27])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC#N
Reactant: NO
Solvent: CCO
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC(=N)NO
Yield: 90.4 %

Procedure:
To a suspension of {[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}acetonitrile (14.7 g; 39.3 mmol) in EtOH (600 ml) was added a 50% aqueous solution of NH2OH (24.1 ml; 393 mmol) and the reaction mixture was refluxed for 2 hours. The solvent was evaporated off and the residue was triturated with ether, collected by filtration and dried under vacuum to give 2-{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}-N-hydroxyethanimidamide (14.5 g; 90% yield). 1H NMR (400 MHz; DMSO-d6): 3.98 (s, 3H), 4.58 (s, 2H), 5.70 (s, 2H), 7.38 (s, 1H), 7.65 (d, 1H), 7.84 (s, 1H), 7.89 (dd, 1H), 8.26 (d, 1H), 8.55 (s, 1H), 9.41 (s, 1H), 9.64 (s, 1H); MS (EI) for C17H15Cl2N5O3: 408.05 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH2:15]OS(C)(=O)=O)=[CH:11][C:10]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH2:15][N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)=[CH:11][C:10]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccccc3)n2)ccc1F
Reactant: CN1CCNCC1
Product: Cc1cc(-c2cc(CN3CCN(C)CC3)c(=O)n(Cc3ccccc3)n2)ccc1F
Yield: 81.3 %

Procedure:
Following the procedure of Example 1(10), 2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 81.3%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:30][C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=1)[C:34]([O:36][CH3:37])=[O:35]>CS(C)=O.O>[CH3:1][C:2]1[N:6]([CH2:30][C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34]([O:36][CH3:37])=[O:35])[N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[N:8]=2)[N:3]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)no3)nc2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To a solution of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (311 mg, 1.0 mmol) in DMSO (5 mL), Cs2CO3 (652 mg, 2.0 mmol) and methyl 3-(bromomethyl)benzoate (252 mg, 1.1 mmol) were added at RT. The mixture was stirred at RT for 2 h. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (4×40 mL). The combined organic layers werewashed with H2O (20 mL) and brine (2×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by a silica gelchromatography (EtOAc/Hexane 10% to 60% EtOAc) to give methyl 3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)benzoate as a white solid (310 mg, 68%). MS (ES+) C21H16F3N5O4 requires: 459. found: 460 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.29 (d, J=8.8 Hz, 2H), 8.04 (d, J=7.4 Hz, 1H), 7.95 (s, 1H), 7.48 (t, J=7.5 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.3 Hz, 2H), 5.51 (s, 2H), 3.92 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]2[C:7]([C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[NH:10][C:11]2=[O:17])=[CH:6][CH:5]=1>CC(O)=O>[NH2:3][C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]2[C:7]([C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[NH:10][C:11]2=[O:17])=[CH:6][C:5]=1[Br:1]
Reactant: CC1(C)C(=O)NC(=O)c2c1ccc(N)c2[N+](=O)[O-]
Reactant: BrBr
Solvent: CC(=O)O
Product: CC1(C)C(=O)NC(=O)c2c1cc(Br)c(N)c2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Bromine (9.27 mL, 188.6 mmol) was added dropwise to a solution of 7-amino-4,4-dimethyl-8-nitroisoquinoline-1,3(2H,4H)-dione (4.70 g, 18.86 mmol) in AcOH (190 mL). The reaction mixture was stirred at 25° C. for 2 h then was concentrated under reduced pressure. The residue was diluted with EtOAc, and successively washed with water, aqueous saturated NaHCO3, aqueous saturated Na2S2O3, and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (6.10 g, 99% yield).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.[NH2:44][CH2:45][CH2:46][N:47]1[CH:51]=[CH:50][C:49]([C:52]2[CH:59]=[CH:58][C:55]([C:56]#[N:57])=[C:54]([Cl:60])[CH:53]=2)=[N:48]1>C(Cl)Cl.O>[Cl:60][C:54]1[CH:53]=[C:52]([C:49]2[CH:50]=[CH:51][N:47]([CH2:46][CH2:45][NH:44][C:7]([C:5]3[N:4]=[CH:3][C:2]([C:10]([OH:12])=[O:11])=[N:1][CH:6]=3)=[O:9])[N:48]=2)[CH:59]=[CH:58][C:55]=1[C:56]#[N:57]
Reactant: O=C(O)c1cnc(C(=O)O)cn1
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cnc(C(=O)O)cn3)n2)cc1Cl
Yield: 49.9 %

Procedure:
Pyrazine-2,5-dicarboxylic acid (0.53 g; 3.18 mmol), anhydrous HOBt (0.43 g; 3.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.61 g; 3.18 mmol) and DIPEA (0.55 ml; 3.18 mmol) were dissolved in 5 ml of dry DCM. 4-(1-(2-Aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.6 g; 2.12 mmol) and DIPEA (0.55 ml; 3.18 mmol) were dissolved in 5 ml of dry DCM and added dropwise to the previous mixture. The reaction mixture was stirred overnight after which pyrazine-2,5-dicarboxylic acid (0.27 g; 1.59 mmol), anhydrous HOBt (0.52 g; 3.81 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.41 g: 2.12 mmol) and DIPEA (0.37 ml; 2.12 mmol) were added to drive the reaction to completion. After 2.5 h the mixture was diluted with 20 ml of DCM. After addition of 10 ml of water, the product precipitated and was filtered yielding 0.42 g of crude product which was used without further purification.
Reaction SMILES: ClC1C=CC(C(C2CC2)C2C3C(=C(CSC)C([F:18])=CC=3)NC=2)=CC=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:37]2[C:45]3[C:40](=[C:41]([CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:42]=[CH:43][CH:44]=3)[NH:39][CH:38]=2)([CH:34]2[CH2:36][CH2:35]2)C)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH:34]2[CH2:36][CH2:35]2)[C:37]2[C:45]3[C:40](=[C:41]([CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[C:42]([F:18])=[CH:43][CH:44]=3)[NH:39][CH:38]=2)=[CH:28][CH:27]=1
Reactant: CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1
Reactant: CSCc1c(F)ccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Product: CS(=O)(=O)Cc1c(F)ccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 238 mg (0.66 mmol) of the compound from Example 234 in analogy to the synthesis of the compound from Example 209. 144 mg (55% of theory) of the target compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][CH2:35][OH:36])[CH2:28]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][CH2:35][OH:36])[CH2:28]2)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1
Reactant: OCCCC1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOC(CCCO)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 70.5 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.26 g, 2.5 mmol) was reacted with 3-(morpholin-2-yl)propan-1-ol (0.43 g, 3 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (1.0 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:19]=[C:20](\[F:31])/[C:21]([NH:23][O:24]C2CCCCO2)=[O:22])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10]1>CCO>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4](/[CH:19]=[C:20](\[F:31])/[C:21]([NH:23][OH:24])=[O:22])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:10]1
Reactant: O=C(NOC1CCCCO1)/C(F)=C/c1cnc(N[C@@H]2CCN(C3CCCC3)C2)c(Cl)c1
Solvent: CCO
Product: Cl
Product: O=C(NO)/C(F)=C/c1cnc(N[C@@H]2CCN(C3CCCC3)C2)c(Cl)c1
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 248.1 %

Procedure:
A solution of 2NHCl-EtOH solution (3.4 ml) was added to a mixture of (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (620 mg) in EtOH (5 ml) and stirred at 20-25° C. for 2 hours. IPE (20 ml) was added to a reaction mixture and the resultant mixture was stirred at ambient temperature for 20 minutes. The precipitate was collected by filtration to give (2Z)-3-(5-chloro-6-{[(3R)-1-cyclopentyl-3-pyrrolidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamide dihydrochloride (500 mg).
Reaction SMILES: C[O-].[Na+].CO.[F:6][C:7]([F:14])([F:13])[C:8]([O:10]CC)=O.[N:15]1([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[N:16]1>C(OC(C)(C)C)C>[F:14][C:7]([F:6])([F:13])[C:8](=[O:10])[CH2:27][C:26]([C:23]1[CH:22]=[CH:21][C:20]([N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)=[CH:25][CH:24]=1)=[O:28]
Reactant: CC(=O)c1ccc(-n2cccn2)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)(C)C
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-n2cccn2)cc1
Temperature: 20 °C
Reaction time: 22 h
Yield: 63.4 %

Procedure:
A 5.4 N solution of sodium methoxide in methanol (3.0 mL, 16.2 mmol) was added drop wise over 10 min to a solution of ethyl trifluoro-acetate (1.81 mL, 15.2 mmol) in 2-ethoxy-2-methyl-propane (20 mL) at 20° C. followed by the addition of a suspension of 1-(4-pyrazol-1-yl-phenyl)-ethanone (2.57 g, 13.8 mmol) in 2-ethoxy-2-methyl-propane (10 mL). The reaction mixture was stirred for 22 h at 20° C. and then poured onto ice-water (50 mL). The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The remaining solid was recrystallized from ethyl acetate/heptane to give the title compound (2.47 g, 63%) as off-white solid. Mp 96° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18].C(O)(C)C>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:21][CH:20]([O:23][CH2:24][CH3:25])[O:19][CH2:17][CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CCOC(COC1CCN(Cc2ccccc2)CC1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
1-Benzyl-4-hydroxy piperidine (11.5 g.) dissolved in dry dimethylformamide (DMF) (25 ml.) was added dropwise to a stirred suspension of sodium hydride (2.8 g. of 50% dispersion in oil in dry DMF [25 ml.]), under dry nitrogen, and then stirred at room temperature for 3 hours. The suspension was cooled in an ice/water bath while 2-bromoacetaldehyde diethylacetal (13.0 g.) in dry dimethylformamide (25 ml.) was added dropwise, followed by stirring at room temperature for 24 hours. The above process was repeated to add more sodium hydride (2.8 g.) and the acetal (13.0 g.). Iso-propyl alcohol (50 ml.) was added, and the mixture was stirred for 1/2 hour, followed by filtration through "Hyflo" (Trademark). The filtrate was concentrated in vacuo, suspended in water (100 ml.) and basified to pH 11 with 5 N sodium hydroxide. After extraction with chloroform (2×100 ml.) the combined extracts were taken to dryness in vacuo to give an orange oil which was distilled in vacuo to give 1-benzyl-4-(2,2-diethoxyethoxy)-piperidine (14.1 g.), b.p. 152° C.@0.1 mm.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][NH:7][C:6](=[S:9])[NH:5][CH2:4]2)[CH2:2]1.C[I:11].[CH2:12](O)C>C(OCC)(=O)C>[IH:11].[CH3:12][S:9][C:6]1[NH:7][CH2:8][C:3]2([CH2:2][CH2:1]2)[CH2:4][N:5]=1
Reactant: S=C1NCC2(CC2)CN1
Reactant: CI
Reactant: CCO
Solvent: CCOC(C)=O
Product: CSC1=NCC2(CC2)CN1
Product: I
Temperature: 45 °C
Yield: 93.5 %

Procedure:
A mixture of 5,7-diazaspiro[2.5]octane-6-thione (7.53 g; 0.053 mol), methyl iodide (8.43 g; 0.0594 mol) and absolute ethanol (26 ml) is stirred and heated at 45° C. for one hour until the reaction mixture becomes straw colored and homogeneous. Ethyl acetate is added with cooling, the precipitated crystalline material is collected and dried to afford 14.05 g (93.5% yield) of title product, m.p. 128°-130° C.
Reaction SMILES: O.[NH2:2][NH2:3].[N:4]1([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18](OC)=[O:19])=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1>CO>[NH:2]([C:18](=[O:19])[C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)=[CH:11][CH:12]=1)=[O:22])[NH2:3]
Reactant: COC(=O)C(=O)Nc1ccc(N2CCOCC2)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)C(=O)Nc1ccc(N2CCOCC2)cc1
Temperature: 75 °C
Yield: 95.7 %

Procedure:
Hydrazine hydrate (1.25 mL, 25 mmol) was added to a stirred suspension of methyl [(4-morpholin-4-ylphenyl)amino](oxo)acetate (intermediate 1, 6.6 g, 25 mmol) in methanol (150 mL). The reaction was heated to 75° C. for 2 h during which time the precipitate thickened. After cooling the precipitate was filtered and washed with diethyl ether (50 mL) and dried to give the title compound (6.32 g, 94%):
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[Br-].[Ca+2].[Br-].[OH2:27]>>[CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]([C@H:14]([OH:15])[C@@H:13]([OH:16])[C:12]([OH:17])=[O:11])[C@H:10]([OH:27])[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O
Agent: [Br-]
Agent: [Ca+2]
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)CO
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 8 °C
Reaction time: 8 h

Procedure:
Maltose (1 kg, 2.92 moles) is dissolved into 3.8 , l deionized water with heating, in the range of about 40° C. to 60° C. , or sufficient to dissolve the maltose Calcium carbonate (381 g, 3.81 moles) and calcium bromide (51 g, 0.26 mole) are added with mixing. The solution is poured into an electrolysis chamber equipped with a cooling loop and cooled. Six volts DC are applied to opposite graphite electrodes. At 8 hour intervals, the potential is reversed. After 24 h, maltose (1 kg, 2.92 moles) is added and electrolysis is continued until essentially all of the maltose is converted to its acid form (as measured by HPLC), about 104 h total time. The solution is filtered to remove excess calcium carbonate and the pH of the filtrate is adjusted to 2.0 with sulfuric acid. The solution is cooled about 12 to 16 h to 8° C., and filtered to remove calcium sulfate. Calcium ions are removed by batch adsorption to Amberlite IRA 120 resin in the hydrogen form. The sulfate and bromide ions are removed by batch adsorption to Amberlite IRA 68 resin in the hydroxide form. The solution is spray dried with a Bowen 3 ft (1 m) flat bottom laboratory spray drier with a 2 fluid nozzle atomizer. The inlet temperature is kept at about 280° F. to 300° F. (138° C. to 149° C.) with all ports closed. The cellobionic acid is produced in the same manner from cellobiose.
Reaction SMILES: [Cl:1][C:2]([Cl:27])([Cl:26])[C:3](=[NH:25])[O:4][C@H:5]1[O:22][C@H:21]([CH2:23][Cl:24])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9].[C:28](O)(=O)[CH3:29].[NH2:32]N.C[N:35]([CH3:38])C=O>>[Cl:1][C:2]([Cl:27])([Cl:26])[C:3]#[N:25].[N:32]12[CH2:29][CH2:28][CH2:38][N:35]=[C:5]1[CH2:6][CH2:11][CH2:16][CH2:21][CH2:23]2.[Cl:27][C:2]([Cl:1])([Cl:26])[C:3](=[NH:25])[O:4][C@H:5]1[O:22][C@H:21]([CH2:23][Cl:24])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9]
Reactant: NN
Reactant: CN(C)C=O
Reactant: CC(=O)O
Agent: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(=N)C(Cl)(Cl)Cl)O[C@H](CCl)[C@H]1OC(C)=O
Product: C1CCC2=NCCCN2CC1
Product: N#CC(Cl)(Cl)Cl

Procedure:
Compound 54 is then converted in two steps into O-(2,3,4-tri-O-acetyl-6-chloro-6-deoxy-α-D-glucopyranosyl) trichloroacetimidate (55). First, the anomeric acetate group of compound 54 is selectively removed by reaction with hydrazine acetate. Preferably, this reaction is conducted by contacting compound 54 with from about 1.1 to about 1.5 equivalents of hydrazine acetate (prepared by known procedures from hydrazine and acetic anhydride) at a temperature of from about 0° C. to about 20° C. for about 5 to about 10 hours. Typically, the reaction is conducted in an anhydrous solvent, such as dimethylformamide. Treatment of the resulting product with trichloroacetonitrile in the presence of an amine, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), provides compound 55. This reaction is typically conducted in an anhydrous inert organic solvent, such as dichloromethane, using an excess of trichloroacetonitrile.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:13]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[CH:25][CH:24]=1.CN(C)C=O>O>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][C:13]1[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:10][N:11]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:28])=[CH:37][CH:38]=2)[CH:12]=1)[CH3:20]
Reactant: CCOC(=O)CCc1c[nH]nc1-c1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(C(=O)OCc3ccccc3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 87.6 %

Procedure:
Sodium hydride (60%, oily, 180 mg) was added to a mixture of ethyl 3-(3-phenyl-1H-pyrazol-4-yl)propionate (1.00 g), benzyl 4-chloromethylbenzoate (1.17 g), and N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred for 2.5 days at room temperature. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and benzyl 4-[4-(3-ethoxy-3-oxo-1-propyl)-3-phenyl-1H-pyrazole-1-ylmethyl]benzoate (1.68 g, yield: 88%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1)[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C=C(C(C)(C)C)C=1O)[CH:41]=[O:42])(C)(C)C.C1C=CC=CC=1.[Pb](=O)=O>CO.ClCCCl>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@:15]([NH2:16])([O:42][CH3:41])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1)[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: O=[Pb]=O
Solvent: CO
Solvent: ClCCCl
Solvent: c1ccccc1
Product: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(C(CCC(=O)OC(C)(C)C)Sc3nnn[nH]3)CS[C@@H]21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.19 g. (2.4 mmol.) of 7-amino-3-[1-(2-t-butoxycarbonylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 0.56 g. (2.4 mmol.) of 3,5-di-t-butyl-4-hydroxybenzaldehyde in 100 ml. of dry benzene was refluxed for 4 hours under a Dean-Stark trap. The solution was evaporated under reduced pressure to leave a residue which was dissolved in 100 ml. of 1,2-dichloroethane and cooled to ca. 5° in an ice bath. Three grams of freshly prepared lead dioxide was added in portions over 20 minutes until the starting material was completely consumed. The mixture was filtered through Celite and the filter cake was washed with two 20 ml. portions of cold, 1,2-dichloroethane. The filtrate was treated with 25 ml. of methanol (distilled from magnesium) and the reaction mixture was allowed to stand at room temperature until complete consumption of the oxidized intermediate and formation of a new slower-moving product was shown by thin layer chromatography (ca. 3 hours). The mixture was evaporated to yield a brown semi-solid which was dissolved in 30 ml. of methanol and treated with 2.5 g. of Girard reagent T (trimethylaminoacetohydrazide chloride). The reaction mixture was stirred at room temperature for 3 hours, then evaporated to give a solid residue which was partitioned between 100 ml. of ethyl acetate and 100 ml. of 20% sodium chloride solution. The organic phase was washed with three 100 ml. portions of 10% sodium chloride solution, two 100 ml. portions of water and 100 ml. of a saturated sodium chloride solution. The organic phase was dried (MgSO4), filtered and evaporated to dryness to give 7β-amino-7α-methoxy-3-[1-(2-t-butoxycarbonylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5].[O-][CH2:33][CH3:34].[Na+].[CH:36](=O)C>C(O)C>[CH:9]([C:8]1[CH:7]=[C:6]([CH:31]=[CH:30][CH:29]=1)[C:4]([O:3][CH2:2][CH3:36])=[O:5])=[CH:33][CH3:34]
Reactant: CC[O-]
Reactant: COC(=O)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC=O
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: CC=Cc1cccc(C(=O)OCC)c1

Procedure:
The preparation of XIII begins with the known methyl 3-(bromomethyl)benzoate. This halide is heated in xylene solution with triphenylphosphine to yield (3-methoxycarbonylbenzyl)triphenylphosphonium bromide. The phosphonium salt is converted to the ylide with sodium ethoxide in ethanol and the ylide caused to react with acetaldehyde to yield ethyl 3-(1-propenyl)benzoate. [Note that the ethyl ester has been obtained as a result of transesterification with solvent ethanol.] The ester is heated with N-bromosuccinimide in carbon tetrachloride for an extended period to yield ethyl 3-(3-bromo-1-propenyl)benzoate. This compound is treated with the anion derived from methyl methylthiomethyl sulfoxide as described in previous examples. The resulting dimethyl mercaptal S-oxide is hydrolyzed with acid catalysis to the aldehyde reagent XIII.