Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Br[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>CN(C=O)C>[CH:15]1([CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:10]#[N:11])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: BrC1CCCC1
Reactant: COc1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(C#N)C2CCCC2)c1
Yield: 89.8 %

Procedure:
By working in a way similar to that described in example 16 but using 3-methoxy-phenyl-acetonitrile (4.4 g, 30 mmoles), anhydrous DMF (30 ml), NaH (55-65%, 1.44 g, 36.3 mmoles) and bromocyclopentane (5.4 g, 36.3 mmoles), 5.8 g of the title compound were obtained (yield: 90%).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16]C(=O)C)=[CH:12][CH:11]=2)[CH:6]=[C:5]([CH3:20])[N:4]=1>Cl>[ClH:1].[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:7]2[CH:6]=[C:5]([CH3:20])[N:4]=[C:3]([NH2:2])[N:8]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)Nc1ccc(Nc2cc(C)nc(N)n2)cc1
Agent: Cl
Product: Cc1cc(Nc2ccc(N)cc2)nc(N)n1
Yield: 99.3 %

Procedure:
To a suspension of 16 (6.0 g, 20 mmol) was added 2N HCl (40 mL) and the mixture was refluxed for 20 h. The solvents were evaporated to dryness, residue boiled in MeOH and diluted with EtOAc. The resulting precipitate was filtered and washed with EtOAc and dried to give essentially pure 17 (5.0 g, 97%); mp (MeOH/EtOAc) 275-280° C.; 1H NMR [(CD3)2SO] δ 12.50 (br, 1H, N+H), 10.75 (br s, 1H, NH), 9.75 (br s, 2H, NH2), 7.85 (br s, 4H, NH2 & ArH)), 7.34 (d, J=8.6 Hz, 2H, ArH), 6.24 (br s, 1H, ArH), 2.79 (s, 3H, CH3), HRMS (FAB+) calc. for C11H14N5 (M+1) m/z 216.1249, found 216.1247.
Reaction SMILES: [N+]([C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)([O-])=O.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(OCC)(=O)C>[O:17]([C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccc([N+](=O)[O-])s1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 69.2 %

Procedure:
5-Nitrothiophene-2-carbonitrile (0.80 g, 5.2 mmol), phenol (1.0 g, 10.4 mmol) and potassium carbonate (2.2 g, 15.6 mmol) were suspended in dimethylsulfoxide (30 mL), and the mixture was stirred at room temperature for 15.5 hours. Water and ethyl acetate were added for partitioning, and the organic layer was washed three times with water. NH silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption, purification was carried out by NH silica gel column chromatography (hexane:ethyl acetate=8:1), and 5-phenoxythiophene-2-carbonitrile (720 mg, 3.6 mmol, 69.2%) was obtained as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:10][C:11]([C:13]1([C:18](=[O:21])[CH2:19]Br)[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CN(C=O)C>[CH2:3]([N:10]1[CH2:19][C:18](=[O:21])[C:13]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[C:11]1=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(CBr)C1(C(=O)NCc2ccccc2)CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN(Cc2ccccc2)C(=O)C12CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a suspension of NaH (60% mineral oil suspension, 7.40 g, 185.00 mmol) in DMF (450 mL) was added a solution of N-benzyl-1-(2-bromoacetyl)cyclopentanecarboxamide (50.00 g, 154.22 mmol) in DMF (100 mL) dropwise at 0° C. After addition, the reaction mixture was stirred at rt overnight and then quenched with water (200 mL) and extracted with EtOAc (300 mL×3). The combined organic phases were washed with brine (300 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10) to give the product as yellow oil (21.00 g, 56.0%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1.ClC(OC(Cl)(Cl)Cl)=[O:21]>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[N:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[O:13][C:14]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccnc1Nc1cccc(F)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=c1oc(=O)n(-c2cccc(F)c2)c2ncccc12
Yield: 82 %

Procedure:
To a solution of methyl 2-(3-fluorophenylamino)-nicotinate (4.90 g, 16.2 mmol; synthesized according to WO, A, 01/42244) in 1,2-dichloroethane (80 ml ) was added at 80° C. trichloromethyl chloroformate (also called: diphosgene, 5.9 ml, 48.3 mmol) gradually dropwise over about 30 minutes. Three hours later, activated carbon (130 mg) was added, and the mixture was heated under reflux for 30 minutes, filtered off, and then evaporated. The resultant residue was washed with isopropyl ether, and dried to give 1-(3-fluorophenyl)-2H-pyrido[2,3-d][1,3]oxazin-2,4(1H)-dione(3.42g, 82%) as crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:37]1([CH2:43][CH2:44]O)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N:37]1([CH2:43][CH2:44][O:1][C:2]2[CH:7]=[N:6][C:5]([C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])=[N:4][CH:3]=2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: COC(=O)c1cccc(-c2ncc(O)cn2)c1
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2ncc(OCCN3CCOCC3)cn2)c1

Procedure:
A solution, kept under nitrogen, of 10.1 g (44 mmol) of methyl 3-(5-hydroxypyrimidin-2-yl)benzoate, 17.3 g (66 mmol) of triphenylphosphine and 5.9 ml (48.4 mmol) of 2-morpholin-4-ylethanol in 100 ml of THF is cooled in an ice bath, and 12.95 ml (66 mmol) of diisopropyl azodicarboxylate are slowly added dropwise with stirring. After stirring at room temperature for 2 hours, the reaction mixture is evaporated in vacuo. The residue is taken up in 100 ml of dichloromethane and 100 ml of water. The organic phase is dried over sodium sulfate and evaporated. The residue is recrystallised from isopropanol: methyl 3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzoate as beige crystals; m.p. 89-91°; ESI 344 (M+H); HPLC: 2.06 min (method A).
Reaction SMILES: [BH4-].[Na+].[Li+].[Cl-].C([O:7][C:8]([CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:12]1([CH3:25])[CH3:24])=O)C>CCO.C1COCC1>[OH:7][CH2:8][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:12]1([CH3:25])[CH3:24]
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCO)C(C)(C)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 59.4 %

Procedure:
To a slurry of NaBH4 (204 mg, 5.40 mmol) and LiCl (229 mg, 5.40 mmol) in EtOH (8 mL) was added a solution of tert-butyl 4-{(ethoxycarbonyl)methyl}-3,3-dimethylpiperidine-1-carboxylate (538 mg, 1.80 mmol) in THF (10 mL) at 0° C. After stirring for 10 h at rt, the resulting mixture was quenched with water and the product portion was extracted with Et2O. The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography (gradient: 40% EtOAc/hexane to 90% EtOAc/hexane) to provide the titled compound (275 mg, 59%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15][CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CCO>[CH2:1]([O:8][C:9]1[C:10]([CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CCCc2ncccc2OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(CCCc2ncccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.7 %

Procedure:
Methyl 4-[3-(3-benzyloxy-2-pyridyl)propyl)benzoate (0.3 g, 0.83 mmol) was dissolved in EtOH (3 ml) and treated with 1N NaOH (1.66 ml). The reaction was stirred at ambient temperature for 18 hours. A solution of hydrochloric acid (1N, 1.66 ml) was added and the resulting precipitate was filted and recrystallised from ethanol to give the title product as a white solid (0.054 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[Cl:11][C:12]1[CH:19]=[C:16]([CH:17]=O)[C:15]([OH:20])=[CH:14][CH:13]=1>C(O)C>[OH:20][C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:19][C:16]=1[CH:17]=[N:10][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][C:5]=1[N:9]=[CH:17][C:16]1[CH:19]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: CCO
Product: Oc1ccc(Cl)cc1C=Nc1cc(Cl)c(Cl)cc1N=Cc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A slurry of 177.0 g (1.0 mole) of 4,5-dichloro-o-phenylenediamine in 750 ml. ethanol was added to a warm near solution of 313.1 g (2.0 mole) of 5-chlorosalicylaldehyde in 2250 ml. of ethanol with mechanical stirring in a 5000 ml, 3-neck flask. A brown solution formed, and a light brown solid began to precipitate after 10-15 minutes. Stirring at room temperature was continued for six days. Thin-layer chromatography indicated that the reaction was substantially complete at the end of six days.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][NH2:35])[CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.N>ClCCl.CO>[N:20]1([CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][NH:35][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: NCCN1CCCC(CN2CCCCC2)C1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCC(CN3CCCCC3)C2)c2ccccc21
Yield: 38 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[(piperidin-1-yl)methyl]-piperidin-1-yl]ethanamine in a yield of 38% of theory. Colourless amorphous substance, RF 0.16 (Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/methanol/conc. ammonia 90/10/1 v/v).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][N:10]([CH3:21])[C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[C:7]([CH3:22])[N:6]=[C:5]([C:23]2[C:28]([CH2:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:31][CH3:32])[N:4]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)(Cl)Cl>[CH2:29]([C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:31][CH3:32])[C:23]=1[C:5]1[N:4]=[C:3]([CH2:2][NH:1][C:33](=[O:35])[CH3:34])[C:8]([CH2:9][N:10]([CH3:21])[C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[C:7]([CH3:22])[N:6]=1)[CH3:30]
Reactant: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(CN)n1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(CNC(C)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vial containing (1S)-N-{[4-(aminomethyl)-2-(2,6-diethylphenyl)-6-methylpyrimidin-5-yl]methyl}-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (9 mg, 0.021 mmol) in CHCl3 (2.0 mL) is added acetic anhydride (0.05 mL, 25.0 eq., 0.53 mmol) and allowed to stir at room temperature for 2 h. All solvent is then removed and excess acetic anhydride is removed azeotropically with toluene (3×2 mL). The sample is re-dissolved in CHCl3 and eluted through a plug of SiO2, washing with CHCl3. Concentration affords the title compound as a colorless gum. [mass expected (470.65); mass found (470.34)].
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:13]([O:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cn(C)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(C)nc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of ethyl 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (25.50 g), benzyl bromide (17.8 ml), potassium carbonate (31.10 g) and N,N-dimethylformamide (250 ml) was stirred overnight at 50° C. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dilute hydrochloric acid, washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-benzyloxy-1-methyl-1H-pyrazole-4-carboxylate (31.90 g, yield 82%) was obtained as a colorless crystal from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio) and recrystallized from ethyl acetate-hexane. melting point: 66–67° C.
Reaction SMILES: [ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.C(O)(=O)C>C(O)C.[Zn]>[ClH:1].[NH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][NH:3]1
Reactant: Oc1cnnc2ccccc12
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1CNNc2ccccc21
Temperature: -15 °C
Yield: 60 %

Procedure:
69.41 g of the product obtained in stage A are dissolved in 2.5 l of ethanol. 62.79 g of zinc powder are subsequently added, followed, slowly, by a mixture of 300 ml of ethanol and 150 ml of acetic acid at ambient temperature. The mixture is heated at reflux for 30 min. The reaction medium is subsequently separated by settling, and the zinc residue is washed several times with ethanol. After being allowed to cool for 20 minutes in an ice/methanol mixture (−15° C.), a solution of hydrogen chloride gas in ethyl acetate is then added (350 ml; 4M). The precipitate formed is filtered off, washed with ether and then with pentane, and finally dried (under reduced pressure). 42.12 grams (60%) of the expected product are obtained.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[C:9]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[O:10])([O-:5])=[O:4].[CH2:19](I)[CH3:20].C(OCC)(=O)C>CN(C)C=O>[CH2:19]([N:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9](=[O:10])[C:8]1[CH:16]=[CH:17][CH:18]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[CH3:20]
Reactant: CCI
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1cccc1C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
3.2 g (130 mmol) of 50% sodium hydride were suspended, under nitrogen atmosphere, in 100 ml of anhydrous dimethylformamide. A solution of 12 g (55 mmol) of 2-(3'-nitrobenzoyl)pyrrole, prepared, for example, as described in Preparation 3A, in 50 ml of dimethylformamide was added thereto, at room temperature and under stirring. The resulting mixture was stirred for an additional hour and then treated dropwise with a solution of 11.2 ml (70 mmol) of ethyl iodide in 30 ml of dry dimethylformamide. The reaction mixture was stirred for an additional hour and then poured into 500 ml of ethyl acetate. The organic extract was washed with water (5×250 ml), dried and evaporated in vacuo. Crystallization of the residue from acetone-hexane afforded 10.55 g (78%) of 1-ethyl-2-(3'-nitrobenzoyl)pyrrole, the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7])=[N+]=[N-].[ClH:11]>[Pd].CO>[ClH:11].[NH2:1][CH2:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C(=O)CN=[N+]=[N-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)C(=O)CN
Reaction time: 2 h

Procedure:
To a 2 L three-necked round-bottom flask fitted with a mechanical stirrer were added azidopinacolone (28.6 g, 203 mmol, 1.0 equiv), methanol (1145 mL), concentrated HCl (18 mL), and 10% Pd/C (3.5 g, 50% water wet). The reaction mixture was stirred under hydrogen at 20 psi for 2 h, the mixture was filtered through a pad of Celite, and the residue rinsed with methanol (2×50 mL). The filtrate was concentrated under reduced pressure at a temperature below 40° C. The resulting wet solid was azeotroped with 2-propanol (2×100 mL), anhydrous ether (100 mL) was added, and the slurry which formed was stirred for 5 min. The solid product was collected by filtration, and the cake was washed with diethyl ether (2×30 mL) and then dried in vacuo to give aminopinacolone hydrochloride A-2.
Reaction SMILES: [OH:1]O.[Se](=O)=O.[NH2:6]/[C:7](/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:8]1\[C:9](=[O:17])[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[S:12]\1>O.CO>[NH2:6]/[C:7](/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:8]1\[C:9](=[O:17])[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[S:12]\1=[O:1]
Reactant: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Reactant: OO
Agent: O=[Se]=O
Solvent: CO
Solvent: O
Product: N/C(=C1\C(=O)c2ccccc2S1=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 1.1 ml (10.8 mmols) of 30% hydrogen peroxide and 1.1 gm (10 mmols) of selenium dioxide in 5 ml of water was added dropwise, while stirring, to a solution of 2.53 gm (10 mmols) of (E)-2-[(amino)phenylmethylene]-benzo[b]thiophen-3(2H)-one in 20 ml of methanol. The reaction temperature was not allowed to exceed +25° C. After 20 minutes, the reaction mixture was diluted with 100 ml of water, the reaction product was separated by suction filtering and recrystallized from ethanol/ethyl acetate (1:1 v/v) using activated charcoal.
Reaction SMILES: [CH2:1]([C:8]1[S:14][CH:13]2[CH:10]([C:11](=[O:29])[N:12]2[C:15](=[C:26]([OH:28])[CH3:27])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>O1CCCC1.C(N(CC)CC)C>[CH2:1]([C:8]1[S:14][CH:13]2[CH:10]([C:11](=[O:29])[N:12]2[C:15](=[C:26]([O:28][S:31]([CH3:30])(=[O:33])=[O:32])[CH3:27])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)=C(C(=O)OCc1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Reaction time: 0.92 h

Procedure:
One adds to a solution of benzyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (1.424 g) in tetrahydrofuran (15 ml), triethylamine (0.96 ml), and methanesulfonyl chloride (0.28 ml) at -30° to -20° C., stirs for 55 minutes to give benzyl α-[3-benzyl-7-oxo4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate, adds morpholine (0.40 ml) and stirs for 5 hours at -10° C. to -3° C. to give benzyl α-[3-benzyl-7-oxo-4-thia2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate, cools to -35° C. to -30° C., adds pyridine (0.27 ml) and bromine in carbon tetrachloride (1 mmole/ml: 3.2 ml), and stirs for 20 minutes to give benzyl α-[3-benzyl- 7-oxo-4-thia-2,6-diazabicyclo]3,2,0]hept-2-en-6-yl]hept-2-en-6-yl]hept-2-en-6-yl]α-(1-morpholino-2-bromoethylidene)acetate, adds 5% hydrochloric acid (13 ml) and methanol (50 ml), and kept at 0° C. overnight to hydrolyze and cyclize giving the cephem product. The solvent is removed under reduced pressure, and the residual solution is extracted with ethyl acetate. The extract solution is washed with saturated saline and water, dried over sodium sulfate, and purified by chromatography over silica gel containing 10% water. The fractions containing the product are combined and evaporated. Recrystallization of the residue from a mixture of methanol, ether, and hexane gives benzyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate, m.p. 149°-162° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:23])[C:6]=1[C:7]1[C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[F:22])=[N:9][N:10]([CH3:14])[C:11]=1[C:12]#[N:13].[NH2:24][OH:25].CCOC(C)=O.O>CS(C)=O>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:23])[C:6]=1[C:7]1[C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[F:22])=[N:9][N:10]([CH3:14])[C:11]=1[C:12](=[N:24][OH:25])[NH2:13]
Reactant: NO
Reactant: Cc1csc(C)c1-c1c(-c2ccc(O)cc2F)nn(C)c1C#N
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1csc(C)c1-c1c(-c2ccc(O)cc2F)nn(C)c1C(N)=NO
Temperature: 150 °C
Yield: 50.2 %

Procedure:
To a solution of 4-(2,4-dimethylthiophen-3-yl)-3-(2-fluoro-4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbonitrile (7 mg, 0.02 mmol) in DMSO (0.6 mL) was added neutral hydroxylamine solution (16 M in water, 0.33 mL, 5.35 mmol) The reaction was heated at 150° C. in the microwave for 15 min. EtOAc and water were added and the phases were separated. The crude product was purified on preparative HPLC to give 4-(2,4-dimethylthiophen-3-yl)-3-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-1-methyl-1H-pyrazole-5-carboximidamide (3.62 mg, 47%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 361.06 (M+H), 359.14 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.05 (t, 1H, J=8.6 Hz), 6.77 (q, 1H, J=0.9 Hz), 6.59 (dd, 1H, J=8.6, 2.5 Hz), 6.51 (dd, 1H, J=11.7, 2.5 Hz), 4.01 (s, 3H), 2.07 (s, 3H) and 1.88 (d, 3H, J=0.9 Hz).
Reaction SMILES: Br[CH:2]1C(=O)C2C(=CC=CC=2)[O:4][CH2:3]1.CN(CCCO[C:20]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[N:27]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:28]=1)C.Cl.C1CCN2C(=NCCC2)CC1>C(O)C>[OH:4][C:3]1[CH:2]=[CH:22][CH:23]=[CH:24][C:25]=1[C:26]1[CH:21]=[CH:20][N:28]=[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]=1
Reactant: O=C1c2ccccc2OCC1Br
Reactant: CN(C)CCCOc1nn(Cc2ccccc2)c2ccccc12
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: Oc1ccccc1-c1ccnc(-c2ccccc2)n1

Procedure:
A solution of 3-bromo-chroman-4-one (2.5 g) and benzydamine hydrochloride (1.7 g) in dry ethanol (25 ml) was refluxed for 6 hours in the presence of DBU (1.7 g). The reaction mixture was cooled, then evaporated to dryness and the residue was partitioned between ethyl acetate and a diluted hydrochloric acid aqueous solution. The organic layer was washed with a diluted sodium carbonate aqueous solution, with water, dried and evaporated to dryness to give the crude title compound. This was purified through its hydrochloride, prepared by dissolving the free base in acetone and adding an HCI ethereal solution.