Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[N:21]1[C:28](Cl)=[N:27][C:25](Cl)=[N:24][C:22]=1Cl>CS(C)=O.O1CCOCC1>[CH:1]1([O:7][N:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH:11]([O:16][C:22]3[N:24]=[C:25]([O:16][CH:11]4[CH2:10][C:9]([CH3:18])([CH3:17])[N:8]([O:7][CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[C:13]([CH3:14])([CH3:15])[CH2:12]4)[N:27]=[C:28]([O:16][CH:11]4[CH2:12][C:13]([CH3:14])([CH3:15])[N:8]([O:7][CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:9]([CH3:18])([CH3:17])[CH2:10]4)[N:21]=3)[CH2:12][C:13]2([CH3:14])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CC1(C)CC(Oc2nc(OC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)nc(OC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
A mixture of 30.0 g (0.117 mol) of 1-cyclohexyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine, 2.8 g (0.117 mol) of sodium hydride, a few drops of dimethyl sulfoxide, and 150 ml of 1,4-dioxane is heated at reflux for two hours, then allowed to cool. To this mixture is added over 15 minutes solution of 7.2 g (0.039 mol) of cyanuric chloride in 50 ml of dioxane. Salt formation is observed, and the reaction temperature rises from 20° C to 50° C during the addition. The reaction mixture is then heated at reflux for 30 minute and stirred overnight at room temperature. Salts are removed by filtration, and the salt cake is slurried in water and filtered to remove salt from the product, a solid. The crude product is dissolved in boiling methanol and residual salt is removed by filtration. Additional product is recovered from the dioxane filtration. Crude solids are combined and heated in refluxing 2-propanol. Th resulting suspension is allowed to cool, and the solid is isolated by filtration to afford 19.4 g (59% yield) of the title compound, a white solid, m.p. 242°-5° C. (dec.).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[CH3:9][NH:10][O:11][CH3:12].CN1CCOCC1.CN(C)CCCN=C=NCC.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl>[CH3:12][O:11][N:10]([CH3:9])[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CNOC
Reactant: CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCC(=O)N(C)OC
Yield: 84.8 %

Procedure:
Part A: To a magnetically stirred solution of valeric acid (10.9 ml, 0.1 mol) in dichloromethane (200 ml) was successively added: N-methyl-N-methoxy-amine.hydrochloride (10.14 gram, 0.104 mol), N-methylmorpholine (22.9 ml, 0.208 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (EDCI) (19.92 gram, 0.104 mol) and HOBt (14.04 gram, 0.104 mol) and the resulting mixture was reacted for 20 hours at room temperature. The obtained suspension was successively washed with water, aqueous citric acid (a solution of 24 gram citric acid in 250 ml H2O) and 5% aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to give pentanoic acid methoxy-methyl-amide (12.31 gram, 85% yield) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ 0.93 (t, J=7, 3H), 1.31-1.43 (m, 2H), 1.57-1.66 (m, 2H), 2.42 (br t, J=7, 2H), 3.18 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[C:19]=3[NH:24][C:25]([O:27][CH:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:38])[F:37])[CH3:29])=[O:26])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)C.[OH-].[Li+]>CO>[CH3:23][C:20]1[C:19]([NH:24][C:25]([O:27][CH:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:38])([F:37])[F:39])[CH3:29])=[O:26])=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:40])=[O:3])=[CH:11][CH:10]=3)=[CH:13][CH:14]=2)[O:22][N:21]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3C(F)(F)F)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1noc(-c2ccc(-c3ccc(CC(=O)O)cc3)cc2)c1NC(=O)OC(C)c1ccccc1C(F)(F)F

Procedure:
(4′-{3-Methyl-4-[1-(2-trifluoromethyl-phenyl)-ethoxycarbonylamino]-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester (0.41 mmol) was treated with aqueous lithium hydroxide in methanol at 60° C. for 30 minutes. The mixture was purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH2:1]([OH:24])[C:2](=[O:23])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH2:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[O:25]1CCO[CH2:27][CH2:26]1>>[C:26]([O:24][CH2:1][C:2](=[O:23])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH2:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)(=[O:25])[CH3:27]
Reactant: C1COCCO1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CO
Product: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 89 %

Procedure:
1.16 g (3.5 mmoles) of 4-pregnene-3,20-dione-21-ol [prepared as described in Step (c) above] are acetylated as described in Example 2 to give 1.16 g (89% yield) of the aimed product, m.p.: 156°-158° C., [α]D =+174° (c=1.0 in dioxane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]1[N:30]=[CH:31][N:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[CH:33]=1.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[N:30]=[CH:31][N:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])[CH:33]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: Clc1ccccc1-n1cnc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=c1n(Cc2cn(-c3ccccc3Cl)cn2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h

Procedure:
19 mg (0.06 mmol) of the compound from Example 5A were dissolved in 5 ml of acetonitrile, and 17 mg (0.13 mmol) of potassium carbonate and 17 mg (0.06 mmol) of the compound from Example 42A were added. The mixture was stirred at 65° C. for 2 h and then stirred at RT for 20 h. For work-up, 5 ml of water were added and the mixture was extracted twice with in each case 10 ml of ethyl acetate. The organic phase was washed once with 5 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 4 mg (12% of theory) of the target compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[O:28]=[C:29]([CH:31]=[C:32]([CH3:34])[CH3:33])[CH3:30]>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:32]([CH3:34])([CH3:33])[CH2:31][C:29](=[O:28])[CH3:30])=[O:15])[CH3:14]
Reactant: CCOP([O-])CCCCc1ccccc1
Reactant: CC(=O)C=C(C)C
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(CCCCc1ccccc1)C(C)(C)CC(C)=O
Yield: 75.7 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (1 g, 0.0044 mole) in chloroform (40 ml) was added triethylamine (0.68 ml, 0.0049 mole), trimethyl silylchloride (0.62 ml, 0.0049 mole) and mesityl oxide (0.56 ml, 0.0049 mole). The reaction mixture was stirred at reflux for 18 hours. The solution was washed with H2O, followed by extraction with 5% HCl solution and brine, dried over Na2So4 ; solvent was removed in vacuo to give 1.08 g of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[N:13]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)[C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Reactant: O=[N+]([O-])c1cccc(CCBr)c1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncnc3n2CCc2cccc([N+](=O)[O-])c2)c1

Procedure:
The title compound was prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 1-(2-bromo-ethyl)-3-nitro-benzene by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 1H NMR (DMSO-d6) δ 8.28 (s, 1H), 7.96 (dd, J=8.0, 1.3 Hz, 1H), 7.53-7.42 (m, 2H), 7.07-7.03 (m, 1H), 7.00 (d, J=9.0 Hz, 1H), 6.87 (dd, J=3.1, 9.0 Hz, 1H), 6.53 (d, J=2.8 Hz, 1H), 4.60 (t, J=6.9 Hz, 2H), 3.71 (s, 3H), 3.62 (s, 3H), 3.33 (t, J=6.9 Hz, 2H); LC-MS [M+H]+ 453.13.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18].Cl[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1.O>CS(C)=O>[N+:26]([C:23]1[CH:22]=[N:21][C:20]([O:18][C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][C:8]=2[Cl:7])=[CH:25][CH:24]=1)([O-:28])=[O:27]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)nc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
7.6 g of anhydrous sodium carbonate and 9.8 g of 2-chloro-4-trifluoromethylphenol were added to 20 ml of dimethyl sulfoxide, and a solution having 7.9 g of 2-chloro-5-nitropyridine dissolved in 10 ml of dimethyl sulfoxide was added dropwise thereto at room temperature (i.e., about 20° to 30° C.) while stirring. After completion of the dropwise addition, the mixture was allowed to react at 50° C. for 30 minutes. After completion of the reaction, the reaction product was poured into water, followed by extracting with methylene chloride. The extracted phase was washed with water and dried, and the solvent was then distilled off to obtain 13 g of a crystal. The thus obtained crystal was recrystallized from n-hexane to obtain 9.8 g of a titled compound having a melting point of 69° to 72° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[N:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1.[BH4-].[Na+].CC(O)(C)C>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[NH2:8])=[CH:12][CH:11]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: N#Cc1cnccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: NC(c1ccc(Cl)cc1)c1cnccn1
Temperature: 60 °C
Reaction time: 6 h
Yield: 34 %

Procedure:
Pyrazine-2-carbonitrile (10.5 g, 100 mmol) was dissolved in PhMe (100 mL) at 0° C. and 4-chlorophenyl magnesium bromide (100 ml, 1.0 M in Et2O, 100 mmol) was added portion-wise over 5 min. The reaction mixture was stirred for 6 h and NaBH4 (7.58 g, 201 mmol) and tBuOH (100 mL) were added. The reaction mixture was warmed to 60° C. for 18 h and quenched with 1 M aq NaOH solution. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (DCM:EtOH:NH3 200:8:1 to 50:8:1) to give the title compound as a brown oil (7.46 g, 34%). MS (ESI+) m/z=220.0 (M+H)+.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22][Si](C)(C)C)=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(C)C.CO.[OH-].[K+]>C(Cl)Cl>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]#[CH:5])=[CH:8][CH:9]=2)=[CH:16][CH:17]=1)#[CH:22]
Reactant: C[Si](C)(C)C#Cc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(C#Cc2ccc(C#C)cc2)cc1
Yield: 66.8 %

Procedure:
Subsequently, the obtained 4,4′-bis(trimethylsilylethynyl)tolan (149 mg, 0.40 mmol) was added with dist. CH2Cl2 (5 mL), dist. MeOH (1 mL) and an aqueous solution of KOH of 50% by mass (0.09 mL). The resultant mixture was then stirred under a nitrogen atmosphere at room temperature for 18 hours to obtain a reaction mixture. After that, the reaction mixture was diluted with CH2Cl2. The organic layer was washed with sat. NaCl, and the washed organic layer was dried with MgSO4. The dried organic layer was filtered and concentrated to obtain a crude product (II). Subsequently, the obtained crude product (II) was separated and purified by silica gel column chromatography (hexane/EtOAc=10/1) to obtain 4,4′-diethynyltolan (60.5 mg, 86% yield (in two steps)).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]([CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][O:24][N:25]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:30][CH:29]=2)[CH3:27])=[CH:17][CH:16]=1)[C:9]([O:11]CC)=[O:10])[CH2:6][CH3:7])[CH3:4].CO>O1CCOCC1>[CH2:3]([N:5]([CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][O:24][N:25]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:30][CH:29]=2)[CH3:27])=[CH:17][CH:16]=1)[C:9]([OH:11])=[O:10])[CH2:6][CH3:7])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccn3)cc2)cc1)N(CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCN(CC)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccn3)cc2)cc1)C(=O)O
Temperature: 50 °C
Reaction time: 18 h
Yield: 98.3 %

Procedure:
2.75 ml of a 1N aqueous sodium hydroxide solution was added to a mixture of 474 mg of ethyl 2-(N,N-diethylamino)-3-[4-[2-[[1-[4-(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy]phenyl]propionate obtained in Example 7, 5 ml of methanol and 3 ml of dioxane. The resulting mixture was stirred at 50° C. for 18 hours. After the reaction, methanol and dioxane were evaporated under reduced pressure, and then the residue was diluted with water. The pH of the mixture was adjusted to a value of4 by addition of 2.75 ml of 1N hydrochloric acid, and precipitate was collected by filtration. The precipitate was washed with water and isopropyl ether to obtain 440 mg of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2[C:16](=O)[N:17]([CH3:19])[NH:18][C:11]1=2.P(Br)(Br)([Br:23])=O>ClCCl>[Br:23][C:16]1[N:17]([CH3:19])[N:18]=[C:11]2[C:12]=1[CH2:13][CH2:14][CH2:15][N:10]2[C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Cl:1]
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cc(C)c(N2CCCc3c2[nH]n(C)c3=O)c(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C)c(N2CCCc3c2nn(C)c3Br)c(Cl)c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 30.2 %

Procedure:
7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one (3.16 g) and phosphorus oxybromide (15.5 g) were combined and stirred in a 110° C. oil bath for 4 h. After the reaction mixture had cooled to room temperature, it was dissolved in dichloromethane and added to 200 mL of ice/water. This mixture was stirred vigorously for 30 min. The phases were then separated and the aqueous phase was washed with additional dichloromethane. The combined organic phases were washed with aqueous sodium bicarbonate, dried with magnesium sulfate, and concentrated on the rotary evaporator. The residue was chromatographed on silica gel eluting with an acetone/hexane gradient to provide 1.16 g of 3-bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine, mp 106-107° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:18]([NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17](=[O:30])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10].[CH3:31][SH:32]>CN(C)C=O>[CH3:31][S:32][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:18]([NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17](=[O:30])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10]
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(CBr)CS[C@H]12
Reactant: CS
Solvent: CN(C)C=O
Product: CSCC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1

Procedure:
2,2,2-Trichloroethyl 3-bromomethyl-7β-phenoxyacetamidoceph-3-em-4-carboxylate, 1β-oxide (11.48g, 20 mmole) was reacted with methanethiol as in Example D18(i) and the resulting solution in N,N-dimethylformamide used directly in a reduction step as described in Example D18(ii) to provide the solvated title compound as a pale-yellow foam (10.90 g,), [α]D + 37.5° (c, 1.25) λmax. 269 nm (E1cm1% 165) and 276 nm. (E1cm1% 160) inflexion at 263 nm (E1cm1% 151). The P.M.R. spectrum of this product closely resembled that of the product from Example D18(ii)
Reaction SMILES: [NH:1]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:13].P(Cl)(Cl)(Cl)(Cl)Cl.II.[Br:22]Br>C(Cl)(Cl)Cl>[Br:22][CH:3]1[CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:1][C:2]1=[O:13]
Reactant: BrBr
Reactant: O=C1CCCCc2ccccc2N1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClC(Cl)Cl
Product: O=C1Nc2ccccc2CCCC1Br

Procedure:
To a solution of 4.7 g of 3,4,5,6-tetrahydro-1-benzazocin-2(1H)-one, J. Chem. Soc. (C), 2176 (1969) in chloroform (75 ml), phosphorus pentachloride (5.9 g) is added in portions, while maintaining the temperature at 0°-5° C. When addition is complete, iodine (60 mg) is added, followed by bromine (4.5 g), which is added dropwise over five minutes. The mixture is then refluxed for 4 hours. The chloroform solution is evaporated and the residue partitioned between ice/water (60 ml) and dichloromethane (100 ml). The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The crude residue is purified by chromatography on silica gel, eluting with ether/hexane mixtures. Concentration of the appropriate fractions yields 3-bromo-3,4,5,6-tetrahydro-1-benzazocin-2(1H)-one.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: C1CNCCN1
Product: COc1cc(N2CCNCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 17 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using piperazine instead of thiomorpholine to the title compound (SiO2, dichloromethane:(dichloromethane: methanol:ammonia=70:27:3)=92:2 to 50:50, 40 mg, 17%) which was obtained as an off-white solid. MS: m/e=418.3 [M+H]+.
Reaction SMILES: C([O-])=O.[NH4+].[CH2:5]([O:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21](=[O:23])[CH3:22])=[C:15]([N+:24]([O-])=O)[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(C)C=CC=CC=1>[Fe].O>[NH2:24][C:15]1[CH:14]=[C:13]([O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:18]([O:19][CH3:20])=[CH:17][C:16]=1[C:21](=[O:23])[CH3:22]
Reactant: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Yield: 90 %

Procedure:
A mixture of iron powder (27 g, 0.48 g atoms), ammonium formate (31 g, 500 mmol), 1-(4-benzyloxy-5-methoxy-2-nitrophenyl)ethanone (36 g, 120 mmol), toluene (500 mL) and water (500 mL) was heated to reflux overnight. The mixture was filtered through celite and washed with ethyl acetate. The combined organic layers were washed with water and brine. The organic layer was dried over Na2SO4 and concentrated to afford 1-(2-amino-4-benzyloxy-5-methoxyphenyl)ethanone (29.3 g, 90%). 1H NMR (CDCl3): δ 7.41-7.30 (m, 5H), 7.13 (s, 1H), 6.16 (br s, 2H), 6.10 (s, 1H), 5.13 (s, 2H), 3.83 (s, 3H), 2.51 (s, 3H). LC/MS (M+H=272).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]#[N:10])=[N:6][C:7]=1[CH3:8].O.[NH2:12][NH2:13]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9](=[N:12][NH2:13])[NH2:10])=[N:6][C:7]=1[CH3:8]
Reactant: NN
Reactant: Cc1nc(C#N)ccc1Br
Solvent: CCO
Solvent: O
Product: Cc1nc(C(N)=NN)ccc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.2 %

Procedure:
A 500-mL, three-neck, round-bottom flask was equipped with 5-bromo-6-methylpicolinonitrile (101.5 g, 0.515 mol), ethanol (122 mL) and hydrazine hydrate (50 mL, 1.03 mol). The resulting very thick mixture was allowed to stir at ambient temperature for 24 h. More ethanol (50 mL) was added and the mixture was allowed to stir over the weekend. The mixture was filtered and washed with cold ethanol (100 mL) and cold hexanes (50 mL). The solids were dried in a vacuum oven to afford the product (110 g, 93% yield) as an off-white solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][C:8]([CH3:10])=[O:9]>>[CH3:6][O:5][C:1]([CH2:2][CH2:3][CH2:7][C:8](=[O:9])[CH3:10])=[O:4]
Reactant: CC(C)=O
Reactant: C=CC(=O)OC
Product: COC(=O)CCCC(C)=O

Procedure:
52% of the total amount of methyl acrylate has been converted. Calculated with respect to the quantity of converted acetone the efficiency amounts to 76%, and to 81% referred to the quantity of methyl acrylate.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH3:7])[N:5]=[N:4][N:3]=1.[CH3:8][C:9]1[CH2:16][S:15][CH:14]2[N:11]([C:12](=[O:27])[CH:13]2[NH:17][C:18](=[O:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]=1[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29].[Cl-].[Ca+2].[Cl-]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:7][N:6]1[C:2]([S:1][S:15][CH:14]2[N:11]([CH:10]([C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:33])[Cl:34])=[O:29])[C:9]([CH3:16])=[CH2:8])[C:12](=[O:27])[CH:13]2[NH:17][C:18](=[O:26])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:3][N:4]=[N:5]1
Reactant: Cn1nnnc1S
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)C2SC1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: C=C(C)C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc2ccccc2)C1SSc1nnnn1C

Procedure:
A solution of trichloroethyl 6β-phenylacetamido-penicillanate 1β-oxide (28.86 g) and 5-mercapto-1-methyl-tetrazole (6.96 g) in toluene (800 cc.) is heated under reflux for 3 hours, and the water formed during the reaction is removed as it is formed by passing the condensate over calcium chloride before reintroducing it into the reaction mixture. The solvent is evaporated under reduced pressure (12 mm Hg) at 40°C; the residue obtained is dissolved in chloroform (50 cc.) and the solution obtained is chromatographed on a column of silica (400 g) (0.06-0.20 mm, pH neutral; diameter of the column: 4.8 cm., height: 55 cm.). Elution is carried out using chloroform, collecting 250 cc. fractions. Fractions 10 to 17 are combined and concentrated to dryness under reduced pressure (12 mm Hg) at 40°C. 4-(1-Methyl-5-tetrazolyl-dithio)-3-phenylacetamido-1-(1-trichloroethoxycarbonyl-2-methyl-prop-2-en-1-yl)-2-azetidinone (17.4 g.) is obtained in the form of a colourless pastelike product, the characteristics of which are as follows: Rf = 0.50 [silica gel; chloroform/ethyl acetate (50/50 by volume)].