Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:25]OS(C)(=O)=O)=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:37]=1.[C:38]([O-:41])(=[S:40])[CH3:39].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:25][S:40][C:38](=[O:41])[CH3:39])=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:37]=1
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OCC(C(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1)c1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)SCC(C(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1)c1ccccc1

Procedure:
Dissolve 0.3 g (0.56 m mole) of 8-chloro-11-[1-(2-methanesulfonyl-oxy-1-phenylethylcarbonyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine (Formula 5.6 of Example 83) in 5 mL of DMF and add 0.2 g (0.6 m mole) of cesium thioacetate (preparation described in Synthetic Communications, 13, 553, 1983). Stir the reaction at 80° C. for twenty hours then concentrate under vacuo. Purify the residue by silica gel chromatography using 70% EtOAc and 30% hexane as the solvent. The product is obtained as a light brown solid, mp=92.7-93° C.
Reaction SMILES: [C:1]([C:8](=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[C:9]([O:11]CC)=O)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]([C:8]1[C:9](=[O:11])[C:21]2[C:16](=[C:17]([O:22][CH3:23])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)C(=CNc1ccccc1OC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCCCC(=O)c1c[nH]c2c(OC)cccc2c1=O
Yield: 34 %

Procedure:
Ethyl 2-hexanoyl-3-(2-methoxyphenylamino)acrylate (18 g, 0.056 mol) was added in portions to boiling diphenyl ether (200 ml) and the mixture heated under reflux for 1 hour. After cooling, the mixture was diluted with petroleum ether, filtered and the solid washed with petroleum ether to give 3-hexanoyl-8-methoxy-4(1H)-quinolone (5.2 g, 33.8%), m.p. 169°-71° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.O.[CH3:16][N:17](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:16]#[N:17])=[CH:3][C:4]=1[O:10][C:11]([F:14])([F:13])[F:12])=[O:7]
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc(C=O)c(OC(F)(F)F)c1

Procedure:
10.63 g (39.51 mmol) of 4-bromo-2-(trifluoromethoxy)benzaldehyde, 3.43 g (29.24 mmol) of zinc cyanide and 1.37 g (1.19 mmol) of tetrakis(triphenylphosphine)palladium(0) are dissolved in 80 ml of DMF. The reaction mixture is then reacted in several portions in a single mode microwave (Emrys Optimizer, 5 min at 220° C.). The combined mixtures are mixed with water and extracted twice with toluene. The combined organic phases are washed with saturated sodium chloride solution and dried with sodium sulfate, and then the solvent is removed in a rotary evaporator. The residue is purified by column chromatography (silica gel, mobile phase:cyclohexane/ethyl acetate 10:1). 3.32 g (78% of theory) of the title compound are obtained with a purity of 80% (according to LC-MS).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].C(N(CC)CC)C.FC(F)(F)S(O[CH2:46][C:47]([F:50])([F:49])[F:48])(=O)=O>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:46][C:47]([F:50])([F:49])[F:48])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(CC(F)(F)F)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol) in THF (5.0 mL) was added triethylamine (0.06 mL, 0.64 mmol) and stirred for 10 min. Then 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.03, 0.16 mmol) was added and stirred for 16 h at RT. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a brown solid (0.05 g, 44%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: [N-]=[N+]=NCc1cnc2ccccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1cnc2ccccc2c1
Yield: 48.3 %

Procedure:
3(azidomethyl)quinoline (250 mg, 1.36 mmol) and triphenylphosphine (880 mg, 3.36 mmol, 2.5 equiv) were dissolved in 10 mL THF. The reaction mixture was treated with 0.5 mL of H2O and refluxed for 6 hours. The reaction mixture was cooled and partitioned between Et2O and 1N HCl. The aqueous portion was then treated with 1N NaOH until basic and extracted into EtOAc. The organic portion was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (104 mg) as a brown oil. MS(CI) m/e 159 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:17][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:11][CH2:12][C:13]([OH:16])([CH3:17])[CH2:14][CH2:15]2)=[O:9])=[N:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=C1CCN(C(=O)c2ccc(Br)cn2)CC1
Solvent: C1CCOC1
Product: CC1(O)CCN(C(=O)c2ccc(Br)cn2)CC1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
1-(5-Bromo-pyridine-2-carbonyl)-piperidin-4-one (Example 37, step 1) (135 mg, 0.48 mmol) was dissolved in THF (3 ml) and the mixture was cooled to 0-5° C. 3M Methylmagnesium bromide (190 μl, 0.57 mmol, 1.2 equiv.) was added drop wise at 0-5° C. and the mixture was stirred for 2 hours at 0-5° C. The reaction mixture was extracted with saturated NH4Cl solution and two times with ethyl acetate. The organic layers were extracted with water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography with a 20 g silica gel column and eluting with heptane:ethyl acetate 100:0→0:100. The desired (5-bromo-pyridin-2-yl)-(4-hydroxy-4-methyl-piperidin-1-yl)-methanone (35 mg, 25% yield) was obtained as a colorless oil, MS: m/e=299.2/301.1 (M+H+).
Reaction SMILES: C1(S(CC[N:12]2[C:24]3[CH:23]=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)(=O)=O)C=CC=CC=1.[K].CC(C)([O-])C.C(OCC)(=O)C.Cl>O1CCCC1>[N+:25]([C:21]1[CH:22]=[CH:23][C:24]2[NH:12][C:13]3[C:18]([C:19]=2[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc2c(c1)c1ccccc1n2CCS(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2[nH]c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.2 g 9-(2-phenylsulphonyl-ethyl)-3-nitro-9H-carbazole are dissolved in 40 ml of tetrahydrofuran, combined with 700 mg potassium-tert.-butoxide and stirred for 2 hours at ambient temperature. A further 100 mg potassium-tert.-butoxide are added and the mixture is stirred for 4 hours at ambient temperature. Then another 100 mg potassium-tert.-butoxide are added. The mixture is heated for 2 hours to 50° C., divided between ethyl acetate and 1 N hydrochloric acid, the organic phase is washed with saturated sodium chloride solution and dried with magnesium sulphate. After elimination of the solvents in vacuo the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10 to 80:20).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(O)C>P(=O)(O)(O)O.S([O-])([O-])(=O)=O.[Cu+2].C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:27][S:28]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO
Agent: [Cu+2]
Agent: O=P(O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Temperature: 10 °C
Yield: 92.9 %

Procedure:
Dehydrated toluene (500 g), linoleyl alcohol (cis,cis-9,12-octadecadiene-1-ol, 100 g, 375 mmol), and triethylamine (46 g, 450 mmol) were added to a four-necked flask, and agitation was performed in a nitrogen atmosphere. After cooling to 10° C., methanesulfonyl chloride (47 g, 413 mmol) was dropped over 2 hours in such a way that the reaction temperature became 30° C. or lower. One hour from completion of dropping, the reaction solution was sampled, and disappearance of a spot of linoleyl alcohol was ascertained through TLC (chloroform development, phosphoric acid-copper sulfate color development). Ethanol (5.2 g, 113 mmol) was added, and triethylamine hydrochloric acid salts were filtrated. The filtrate was washed with ion-exchanged water (150 g), and the water layer was discarded. The same operation of washing with ion-exchanged water was performed again. The organic layer was dehydrated with anhydrous magnesium sulfate (20 g) and, thereafter, filtration and concentration were performed, so as to obtain linoleyl methane sulfonate (amount of production: 120 g, yield: 93%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:6]=1)([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([C:7]2[N:8]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[C:10]([Br:22])=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[N:6]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(-c2nc(OC(C)C)cc(OC(C)C)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(-c2nc(OC(C)C)c(Br)c(OC(C)C)n2)cc1
Yield: 99 %

Procedure:
111.7 g of 4,6-diisopropoxy-2-p-tolylpyrimidine and 450 ml of carbon tetrachloride are heated to 70°-75° C. To the resultant solution is added 0.5 g of dibenzoyl peroxide, followed by the addition, over 45 minutes, of a mixture of 1 g of azoisobutyronitrile and 70.8 g of N-bromosuccinimide. The mixture is refluxed for 2 hours to bring the reaction to completion. The precipitated succinimide is then filtered off and excess carbon tetrachloride is removed by distillation, affording 141 g of the title compound with a melting point of 74°-75° C. after purification with methanol.
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: CCCCC(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
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: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.C([Li])CCC.CN([CH:21]=[O:22])C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[C:3]=1[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Cl)c(C=O)c1F
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 47.9 %

Procedure:
A −78° C. solution of N-(4-chloro-2-fluorophenyl)acetamide (2.00 g, 10.66 mmol) in THF (40 mL), under Ar, was treated with butyl lithium (16.66 mL, 26.7 mmol), stirred at −78° C. for 2.5 h, treated slowly with DMF (1.651 mL, 21.32 mmol), stirred for 15 min at −78° C. and slowly warmed to RT. The mixture was stirred for 2 h, treated with satd. NH4Cl, the layers separated and the aqueous layer extracted with EtOAc (1×). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(4-chloro-2-fluoro-3-formylphenyl)acetamide (1.1 g, 48% yield) as an off-white solid. MS (ESI) m/z: 216.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[NH:13]2)[C:2]1C=CC=CC=1.C(OCC)(=[O:24])C>[Pd]>[C:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[NH:13]2)(=[O:24])[CH3:2]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Agent: [Pd]
Product: COC(=O)c1cc2c(OC(C)=O)cccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 4-benzyloxyindole-2-carboxylate (48 g) in ethyl acetate (1 litre) at 50-60° C. was hydrogenated over 5%Pd-C catalyst (4.0 g) at 1 atmosphere pressure for 6 hours, until 3.7 litres of hydrogen was absorbed. The catalyst was filtered off and washed with warm ethyl acetate(100 ml). To the combined filtrates was added acetic anhydride (40 ml) and 4-dimethylaminopyridine (1.0 g), and the solution was stirred for 1 hour at 25° C. Ethanol (15 ml) was added and the solution reduced to halt volume by evaporation in vacuo, then hexane (1 litre) was added to cause crystallisation of the product as white needles (37 g, 93%). NMR d (CD3SOCD3) 2.34 (s, 3H), 3.85 (s, 3H), 6.80 (d, 1H), 7.06 (s, 1H), 7.23 (t, 1H), 7.29-7.35 (m, 1H), 12.1 (bs, 1H); M/z (−) 232 (M-H+).
Reaction SMILES: [Br:1][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:25].[Br:26]Br.O>CO>[Br:1][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH2:14][Br:26])[CH2:4][C@@H:3]1[OH:25]
Reactant: BrBr
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Br)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: CO
Solvent: O
Product: C[C@]12C[C@H](Br)[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A stirred solution of 2β-bromo-3α-hydroxy-5α-pregnane-11,20-dione (5.0 g.) in methanol (100 ml.) was treated at 0° with a solution of bromine (1 ml.) in methaol (30 ml.) at such a rate that the yellow colour disappeared before further addition of the bromine solution. The mixture was then poured into water and the precipitated solid was collected by filtration, washed with water and dried over P2O5 in vacuo. The resulting solid (5.0 g.) was purified by column chromatography (silica, EtOAc/ C6H6 1:2.5) to give crude 2β,21-dibromo-3α-hydroxy-5α-pregnane-11,20-dione (3,4 g.).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:21]1([C:27]([CH:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)O)=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C=O.ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: O=C(O)CCCOCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCCOCc1ccccc1)OC(C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.5 g of 4-benzyloxybutanoic acid are dissolved in 10 ml of anhydrous toluene in a reactor under a nitrogen atmosphere. 1.45 ml of 98% oxalyl chloride (2.1 eq.) and 4 drops of dimethylformamide, in order to catalyze the reaction, are subsequently added. The reaction mixture is left to react at room temperature for 1 hour. The solution is concentrated to dryness under vacuum. The orange oil obtained is dissolved in dichloromethane and then introduced dropwise into a reactor, placed under a nitrogen atmosphere, comprising a solution of 1.18 g (0.7 eq.) of benzoin and 1.58 g (2 eq.) of triethylamine in dichloromethane. An immediate evolution of gas is recorded. The reaction mixture is left stirring for 3 hours at room temperature. The reaction mixture is washed 3 times with water, dried over anhydrous sodium sulphate, filtered and finally brought to dryness. The esterified product is then isolated on a silica column (elutent:dichloromethane).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](Cl)=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4].[C-:30]#[N:31].[Na+].O>CN1CCCC1=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([C:30]#[N:31])=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(C)c(=O)c21
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(C#N)n(C)c(=O)c21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
176 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 2 ml of N-methylpyrrolidone, and 100 mg of sodium cyanide was added thereto. The mixture was stirred at 50° C. for 0.5 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated to give 170 mg of t-butyl 4-[7-(2-butynyl)-2-cyano-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate. 98 mg of this compound was dissolved in a mixture of 3 ml of tetrahydrofuran and 2 ml of methanol, and 0.5 ml of an aqueous solution of 20% ammonia and 0.5 ml of an aqueous solution of 30% hydrogen peroxide were added thereto. The mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 77 mg of the title compound was obtained from the fraction eluted with ethyl acetate-methanol.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[CH:15]=2)C(=O)O1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([C:14]2[C:15]3[C:6](=[O:8])[CH:5]=[CH:9][NH:10][C:11]=3[S:12][CH:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(-c2csc(NC=C3C(=O)OC(C)(C)OC3=O)c2)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cccc(-c2csc3[nH]ccc(=O)c23)c1
Temperature: 220 °C
Yield: 56.7 %

Procedure:
A mixture of 2,2-dimethyl-5-[({4-[3-(methyloxy)phenyl]-2-thienyl}amino)methylidene]-1,3-dioxane-4,6-dione (Description 41) (1.2 g, 3.34 mmol) and diphenyl ether (15 mL, 94 mmol) was heated at 220° C. for 1 h. After cooling to RT, the mixture was purified by chromatography on silica, eluting with a gradient of 0-100% ethyl acetate in DCM, to give the title compound (487 mg). LCMS (A) m/z: 258 [M+1]+, Rt 0.93 min (acidic).
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:14]([C:18]([OH:20])=O)=[CH:15][O:16][CH:17]=1)([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].CN(C)C=O.C(Cl)(=O)C([Cl:29])=O.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:14]([C:18]([Cl:29])=[O:20])=[CH:15][O:16][CH:17]=1)([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOP(=O)(OCC=C)OCc1cocc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOP(=O)(OCC=C)OCc1cocc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[[Bis(allyloxy)phosphoryl]oxymethyl]-3-furoic acid (500 mg, 1.65 mmol) obtained from Example 35-(5) was dissolved in dichloromethane (10 ml), and N,N-dimethylformamide (0.03 ml) and oxalyl chloride (0.7 g, 5.5 mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and toluene was added thereto, then the solvent was distilled off under reduced pressure to give crude 4-[[bis(allyloxy)phosphoryl]oxymethyl]-3-furoyl chloride.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([O:29]C(C4C=CC=CC=4)C4C=CC=CC=4)=[S:28])=[C:15]([C:18]4[S:19][CH:20]=[C:21]([CH2:23][C:24](=[S:26])[NH2:25])[N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([OH:29])=[S:28])=[C:15]([C:18]4[S:19][CH:20]=[C:21]([CH2:23][C:24](=[S:26])[NH2:25])[N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=S)Cc1csc(C2=C(C(=S)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)n1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: NC(=S)Cc1csc(C2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.7 %

Procedure:
To a mixture of benzhydryl 7β-(2-phenylacetamido)-3-(4-thiocarbamoylmethylthiazol-2-yl)thio-3-cephem-4-carboxylate (1.46 g), anisole (1.46 ml) and dichloromethane (4.38 ml) was added trifluoroacetic acid (2.92 ml) at 15° C. After stirring at room temperature for 1 hour, the solution was poured into diisopropyl ether. The resulting precipitate was collected by filtration, added to a mixture of tetrahydrofuran, ethyl acetate and water, and adjusted to pH 7.5 with an aqueous sodium hydrogen carbonate. The separated aqueous solution was washed with ethyl acetate, adjusted to pH 3.0 with 1N-hydrochloric acid and extracted with tetrahydrofuran. The tetrahydrofuran solution was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to preparative HPLC (eluent: pH 3 buffer/acetonitrile) to give 7β-(2-phenylacetamido)-3-(4-thiocarbamoylmethylthiazol-2-yl)thio-3-cephem-4-carboxylic acid (62 mg).