Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2](Cl)[C:3](=[O:5])[CH3:4].NN=CNC(N)=S.[C:14]([NH:17][C:18]([NH2:20])=[S:19])(=[NH:16])[NH2:15]>CC(C)=O>[ClH:1].[Cl:1][CH2:2][C:3]1([OH:5])[CH2:4][S:19][C:18]([N:17]=[C:14]([NH2:16])[NH2:15])=[N:20]1
Reactant: CC(=O)C(Cl)Cl
Reactant: N=C(N)NC(N)=S
Agent: NN=CNC(N)=S
Solvent: CC(C)=O
Product: Cl
Product: NC(N)=NC1=NC(O)(CCl)CS1
Reaction time: 120 h

Procedure:
60.0 kg of dichloroacetone is dissolved in 550 ml of acetone. After cooling the solution to -5°~-7° C., 55.8 kg of (aminoiminomethyl)thiourea [amidinothiourea] is added to the solution under cooling portionwise at one hour intervals each time in a 10 kg amount of amidinothiourea. The mixture is stirred continuously for 5 days below 0° C. The resultant precipitates are collected by filtration, and washed with 50 l of acetone to provide 111.6 kg of the desired compound. This material can be used as the starting material for the next process.
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH2:18][C:19]3[CH:20]=[C:21]([C:25]([OH:27])=O)[O:22][C:23]=3[CH3:24])[CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([NH2:39])(=[O:38])=[O:37].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.ClCCl.C(#N)C>[F:28][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH2:18][C:19]3[CH:20]=[C:21]([C:25]([NH:39][S:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH3:29])(=[O:37])=[O:38])=[O:27])[O:22][C:23]=3[CH3:24])[CH3:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: Cc1oc(C(=O)O)cc1CN(C)c1ccc(-c2ccc(OC(F)F)cc2)cc1
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1cc(CN(C)c2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.9 %

Procedure:
A stirred solution of 4-{[(4′-difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carboxylic acid (176) (21 mg, 0.054 mmoles), 2-methyl-benzenesulphonamide (19 mg, 0.108 mmoles) and 4-(N,N-dimethylamino)-pyridine (1 mg) in a mixture of dichloromethane (8 ml) and acetonitrile (2 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.4 mg, 0.060 mmoles). The mixture was stirred at room temperature for 18 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford compound 177 (2.9 mg) as a solid. LC/MS System D; Rt=11.21 mins, m/z (ES+)=541 (M+H for C28H26F2N2O5S).
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12.[NH2:29][C:30]1[S:31][CH:32]=[C:33](/[C:35](=[N:48]/[O:49][CH:50]([C:59]([O:61][CH:62]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[O:60])[C:51]2[CH:56]=[CH:55][C:54]([OH:57])=[C:53]([OH:58])[CH:52]=2)/[C:36](ON2C3C=CC=CC=3N=N2)=[O:37])[N:34]=1>C1COCC1.C(OCC)(=O)C>[NH2:29][C:30]1[S:31][CH:32]=[C:33](/[C:35](=[N:48]/[O:49][CH:50]([C:59]([O:61][CH:62]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)=[O:60])[C:51]2[CH:56]=[CH:55][C:54]([OH:57])=[C:53]([OH:58])[CH:52]=2)/[C:36]([NH:1][CH:2]2[C:27](=[O:28])[N:4]3[C:5]([C:11]([O:13][CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]23)=[O:37])[N:34]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: Nc1nc(/C(=N/OC(C(=O)OC(c2ccccc2)c2ccccc2)c2ccc(O)c(O)c2)C(=O)On2nnc3ccccc32)cs1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1nc(/C(=N/OC(C(=O)OC(c2ccccc2)c2ccccc2)c2ccc(O)c(O)c2)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.2 %

Procedure:
To a solution of diphenylmethyl 7-amino-3-chloromethyl3-cephem-4-carboxylate (VIa) (685 mg, 1.65 mmol) in THF (8.3 ml) was added benzotriazol-1-yl 2-(2-aminothiazol-4-yl)2-(Z)-(diphenylmethyloxycarbonyl-(3,4-dihydroxyphenyl) methyl]oxyiminoacetate (IIIa) (955 mg, 1.50 mmol) and the mixture was stirred for 5 hr at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water dried over MgSO4 and concentrated under reduced pressure. The crude product was chromatographed on a column of silica gel to afford 566 mg (41% yield) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:21])([F:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17].[CH3:22][P:23]([CH2:28][OH:29])(=[O:27])[O:24][CH2:25][CH3:26]>C1COCC1>[CH3:22][P:23]([CH2:28][O:29][S:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([F:8])([F:20])[F:21])(=[O:18])=[O:17])(=[O:27])[O:24][CH2:25][CH3:26]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CCOP(C)(=O)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)COS(=O)(=O)c1ccccc1C(F)(F)F
Reaction time: 8 h
Yield: 14.5 %

Procedure:
A solution of 8 ml of triethylamine diluted with 25 ml of THF was slowly added dropwise over two hours to a mixture of 11.2 g of 2-(trifluoromethyl)benzenesulfonyl chloride, 6.05 g of O-ethyl P-methyl(hydroxymethyl)phosphinate, (Example 22, Method B), and 60 ml of THF. A white precipitate began to form shortly after the addition of the triethylamine solution was begun. No significant exotherm occurred and the reaction was allowed to stir overnight. The reaction mixture was concentrated and the concentrate was partitioned between 220 ml of ethyl acetate and 50 ml of water. The organic phase was washed with an additional 50 ml of water, dried with magnesium sulfate, gravity filtered, and concentrated to yield an orange solid. The solid was flash chromatographed on silica gel using ethyl acetate to yield 2.2 g of the desired product, melting point 91°-92.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: C1=COCCC1
Reactant: O=Cc1cc(O)ccc1Br
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: O=Cc1cc(OC2CCCCO2)ccc1Br
Temperature: 25 °C
Reaction time: 21 h
Yield: 15.6 %

Procedure:
To a solution of 2-bromo-5-hydroxybenzaldehyde (10 g, 49.75 mmol) and 3,4 dihydro-2H-pyran (4.96 mL, 54.7 mmol) in CH2Cl2 (35 mL) was added camphorsulfonic acid (230 mg, 0.99 mmol), and the mixture was stirred at room temperature for 21 h. The reaction mixture was then quenched with equal volumes of 0.2 M NaOH and EtOAc (1:1, 70 mL) before the layers were separated. The water phase was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 2-bromo-5-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (2.22 g, 20%).
Reaction SMILES: NN.[CH3:3][O:4][C:5]1[C:27]([O:28][CH3:29])=[CH:26][C:8]([C:9]([N:11]2[CH2:15][C@H:14]([OH:16])[CH2:13][CH:12]2[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[O:10])=[C:7]([N+:30]([O-])=O)[CH:6]=1.O=[Al]O[Al]=O.C(Cl)(Cl)Cl.CO>CO.[Ni]>[NH2:30][C:7]1[CH:6]=[C:5]([O:4][CH3:3])[C:27]([O:28][CH3:29])=[CH:26][C:8]=1[C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[O:10]
Reactant: COc1cc(C(=O)N2C[C@H](O)CC2CO[Si](C)(C)C(C)(C)C)c([N+](=O)[O-])cc1OC
Agent: [Ni]
Agent: NN
Agent: O=[Al]O[Al]=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(N)c(C(=O)N2C[C@H](O)C[C@H]2CO[Si](C)(C)C(C)(C)C)cc1OC
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of hydrazine (6.59 g, 6.40 mL, 205.5 mmol) in MeOH (110 mL) was added dropwise to a solution of the nitro-compound 35 (18.1 g, 41.1 mmol), over anti-bumping granules and Raney Ni (2.6 g) in MeOH (325 mL) and heated at reflux. After 1 hour at reflux TLC (95% CHCl3/MeOH) revealed some amine formation. The reaction mixture was treated with further Raney Ni (2.6 g) and hydrazine (6.40 mL) in MeOH (50 mL) and was heated at reflux for an additional 30 minutes at which point TLC revealed reaction completion. The reaction mixture was then treated with sufficient Raney Ni to decompose any remaining hydrazine and heated at reflux for a further 1.5 h. Following cooling to room temperature the mixture was filtered through a sinter and the resulting filtrate evaporated in vacuo. The resulting residue was then treated with CH2Cl2 (300 mL), dried (MgSO4), filtered and evaporated in vacuo to provide the amine 36 as a green oil (16.03 g, 95%): [α]22D=−116.32 (c=0.31, CHCl3); 1H NMR (270 MHz, CDCl3) (Rotamers) δ 6.70 (s, 1H), 6.28 (s, 1H), 4.51-4.49 (m, 1H), 4.36-4.34 (m, 1H), 4.06-3.77 (m, 10H), 3.61-3.50 (m, 3H), 2.23-2.21 (m, 1H), 2.01-1.98 (m, 1H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (67.8 MHz, CDCl3) (Rotamers) δ 170.2, 151.5, 141.2, 140.5, 112.2, 112.0, 101.1, 70.4, 62.6, 59.0, 56.9, 56.6, 55.8, 35.7, 25.9 and 25.7, 18.2, −5.4 and −5.5; MS (EI), m/z (relative intensity) 412 (M+.+2, 3), 411 (M+.+1, 10), 410 (M+., 32), 354 (6), 353 (23), 263 (3), 212 (5), 181 (11), 180 (100), 179 (3), 165 (3), 164 (6), 152 (10), 137 (4), 136 (4), 125 (5), 120 (3), 100 (3), 94 (6), 75 (9), 73 (7), 57 (3); IR (CHCl3) 3353 (br), 2953, 2930, 2857, 1623, 1594, 1558, 1517, 1464, 1435, 1404, 1260, 1234, 1215, 1175, 1119, 1060, 1005, 915, 836, 777, 755, 666 cm−1, exact mass calcd for C20H34N2O5Si m/e 410.2237, obsd m/e 410.2281.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.[CH2:11]([I:13])[CH3:12]>>[I-:13].[CH2:11]([N:6]1[CH:7]=[CH:8][CH:9]=[C:4]2[O:3][CH:2]([CH3:1])[NH+:10]=[C:5]12)[CH3:12]
Reactant: Cc1nc2ncccc2o1
Reactant: CCI
Product: CCN1C=CC=C2OC(C)[NH+]=C21
Product: [I-]
Reaction time: 2 h
Yield: 86 %

Procedure:
This Example shows the preparation of exemplary compound Dye 9 and its physical properties. A mixture of 1.34 g (10 mmol) 2-methyl-oxazolo[4,5-b]pyridine and 2 ml ethyliodide in a closed system was kept 2 h at 110° C. The product was precipitated with acetone and filtered off. The yellow crystalline product was filtered off and washed with diethyl ether to provide 2.47 g (86%) 4-ethyl-2-methyl-oxazolo[4,5-b]pyridinium iodide, which was of sufficient purity to carry on to the next synthetic step.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH2:12][NH2:13].C(N(CC)CC)C>C(O)C.O>[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH2:12][NH:13][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Clc1ncccn1
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2ncccn2)c(OC)c1
Temperature: 120 °C
Yield: 72.7 %

Procedure:
A mixture of 2-chloropyrimidine (1.37 g, 12 mmol), 2,4-dimethoxybenzylamine (2.61 g, 15.6 mmol) and triethylamine (2.51 mL, 18 mmol) in ethanol (8 mL) was heated in a Biotage Initiator™ microwave at 120° C. for 15 minutes. The reaction mixture was diluted with water and extracted with dichloromethane (×3). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20-50% ethyl acetate in heptane gradient elution) to afford the title compound as a white solid (2.14 g, 72%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH:16]=[CH2:17])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH:16]=[CH2:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: C=CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
In a solution of THF/H2O (1:1, 35 mL) containing the product (IX) (1 g, 4.1 mmol) LiOH.H2O (432 mg, 10.3 mmol) is added in one portion. The mixture is stirred for 1 h at room temperature. The solvent is then evaporated and then a 5% H3PO4 solution in water is added until a pH=3 is obtained. The product is then extracted with EtOAc, dried (MgSO4), and then evaporated. After purification, the product (X) (840 mg, 89%) is isolated as a colorless lacquer.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:33][CH2:34][OH:35])[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]=2[N:32]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[CH3:43][S:44]([O:35][CH2:34][CH2:33][N:6]1[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([N:17]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:8]=2[N:32]=[C:5]1[CH2:1][CH2:2][CH2:3][CH3:4])(=[O:46])=[O:45]
Reactant: CCCCc1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2n1CCO)CCCC3
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2n1CCOS(C)(=O)=O)CCCC3
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, di(tert-butyl) 2-butyl-1-(2-hydroxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-ylimidodicarbonate (0.55 g, 1.13 mmol) and anhydrous dichloromethane (11 mL) under a nitrogen atmosphere. The resulting homogeneous solution was cooled to −10° C. in a methanol/ice bath. To the cooled solution was added triethylamine (0.23 g, 2.26 mmol) and methanesulfonyl chloride (0.19 g, 1.70 mmol). The reaction was judged to be complete after stirring at −10° C. for 15 minutes and was then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford 2-{4-[bis(tert-butoxycarbonyl)amino]-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl}ethyl methanesulfonate (0.61 g, 1.08 mmol) as a gummy yellow solid. The material was used without further purification. MS (CI) for C27H42N4O7S m/z 567 (MH+), 467, 367, 271.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1sc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C
Product: Cc1sc2nc(-n3cccn3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)=O.[C:23]1([SH:33])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:23]1([S:33][CH2:6][CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Sc1cccc2ccccc12
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1[nH]c2ccccc2c1CCCSc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 10A (42 mg), naphthalene thiol (45 mg), and potassium carbonate (36 mg) in acetonitrile (2 mL) was heated at 80° C. for 3 days. The reaction mixture was poured into water, extracted with dichloromethane and purified by flash chromatography on silica gel with 0-20% ethyl acetate in hexanes.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[H-].[Na+].C([Li])CCC.[C:16]1([CH2:22][CH2:23][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC.O1CCCC1>[C:26]1([C:24]2([CH2:23][CH2:22][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:25][C:1](=[O:6])[CH:2]=[CH:3][CH2:5]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CCc1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=CCC(CCc2ccccc2)(c2ccccc2)O1

Procedure:
The title compound was prepared as described in General Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6M n-butyl lithium in hexane, 25 mmol of 3-phenylpropiophenone and 70 mL of tetrahydrofuran. Upon concentrating the reaction a solid precipitated out which was triturated with ether and filtered (m.p. 130°-130.55,° C.). 1H NMR (CDCl3) δ 2.2-2.4 (m, 2 H), 2.4-2.6 (m, 1 H), 2.6-2.8 (m, 1 H), 2.9 (d, 1 H), 3.0 (d, 1 H), 3.3 (d, 1 H), 3.4 (d, 1 H), 7.0-7.5 (m, 15 H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:19])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=1)[CH2:2]2.[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)[CH3:21]>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:19])[NH:11][C:12]1[CH:13]=[C:14]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:20][CH3:21])[CH:15]=[CH:16][CH:17]=1)[CH2:2]2
Reactant: O=C(Nc1cccc(Br)c1)OC1CN2CCC1CC2
Reactant: CCc1ccccc1B(O)O
Product: CCc1ccccc1-c1cccc(NC(=O)OC2CN3CCC2CC3)c1
Yield: 78 %

Procedure:
Using general procedure E, quinuclidin-3-yl3-bromophenylcarbamate, 2-ethylphenylboronic acid and [PdCl2(pddf)]CH2Cl2 gave the title vcompound as a white solid (110 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 7.42-7.28 (m, 5H), 7.25-7.16 (m, 2H), 7.03-7.00 (m, 1H), 6.88 (br s, 1H), 4.83 (m, 1H), 3.27 (m, 1H), 2.98-2.70 (m, 5H), 2.61 (q, J=7.6 Hz, 2H), 2.08 (m, 1H), 1.92-1.80 (m, 1H), 1.75-1.65 (m, 1H), 1.63-1.55 (m, 1H), 1.46-1.37 (m, 1H), 1.10 (t, J=7.6 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 152.1, 141.7, 140.4, 139.9, 136.4, 128.6, 127.5, 127.4, 126.4, 124.3, 123.2, 118.4, 115.9, 71.0, 54.3, 46.2, 45.3, 25.0, 24.2, 23.4, 18.3, 14.5 ppm. Purity: 100% LCMS (214 nm & 254 nm); retention time 1.61 min; (M+1) 351.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH3:15])([CH3:14])[C:7](=O)[CH2:6][CH2:5]2.[NH:17]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23])N>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:8]([CH3:15])([CH3:14])[C:7]3[NH:17][C:19]4[C:26]([C:6]=3[CH2:5][C:4]=2[CH:3]=1)=[CH:25][CH:24]=[C:21]([C:22]#[N:23])[CH:20]=4
Reactant: COc1cc2c(cc1Br)CCC(=O)C2(C)C
Reactant: N#Cc1cccc(NN)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1Br)Cc1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
6-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound E1, 7.89 g, 27.85 mmol) and 3-hydrazino-benzonitrile (4.45 g, 1.2 eq.) were dissolved in TFA (250 mL), and stirred at 100° C. for 2 hours. TFA was removed by concentration under reduced pressure and the residues were added with saturated aqueous solution of NaHCO3 (500 mL), followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with ethyl acetate. After stirring at room temperature, the precipitated solid was separated by filtration (Compound E2-2). The filtrate was concentrated under reduced pressure to obtain the title compound as a mixture with E2-2 (yellowish white powder, 2.65 g).
Reaction SMILES: [C:1]([C:5]([C:7]1[N:12]2[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[CH:9]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[C:8]=1[CH3:26])=[O:6])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:34]([O:47][C:48](=[O:57])[C:49]1[CH:54]=[CH:53][C:52]([CH2:55]Br)=[CH:51][CH:50]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CS(C)=O.ClCCl>[CH:34]([O:47][C:48]([C:49]1[CH:50]=[CH:51][C:52]([CH2:55][C:9]2([C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[C:8]([CH3:26])=[C:7]([C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[O:6])[N:12]3[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]3[S:10]2(=[O:19])=[O:18])=[CH:53][CH:54]=1)=[O:57])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)c1ccc(CBr)cc1
Reactant: CO[C@H]1C(=S)N2C(C(=O)C(C)(C)C)=C(C)C(c3nnnn3C)S(=O)(=O)[C@H]12
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@H]1C(=S)N2C(C(=O)C(C)(C)C)=C(C)C(Cc3ccc(C(=O)OC(c4ccccc4)c4ccccc4)cc3)(c3nnnn3C)S(=O)(=O)[C@H]12
Reaction time: 1 h
Yield: 28.5 %

Procedure:
A solution of 4-tert-butylcarbonyl-7α-methoxy-3-methyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-3-cephem 1,1-dioxide (500 mg) in dimethyl sulphoxide (4 ml) was treated at room temperature with triethylamine (0.185 ml) and benzhydryl-4-bromomethylbenzoate (1.4 g). The solution was stirred for 1 hr, diluted with dichloromethane, washed with brine and eventually dried over Na2SO4. Removal of the solvent left a crude residue which afforded the title compound as a yellowish solid (250 mg) after flash chromatography.
Reaction SMILES: [C:1]([O:9][CH:10]([CH3:33])[CH2:11][CH:12]([CH2:15][S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:13][OH:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C.N(CC(NC(OC)=O)CSCCCCCCCCCCCCCCCC)=[N+]=[N-]>ClCCl>[CH3:34][S:35]([O:14][CH2:13][CH:12]([CH2:11][CH:10]([O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:33])[CH2:15][S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:37])=[O:36]
Reactant: CCCCCCCCCCCCCCCCSCC(CO)CC(C)OC(=O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CCCCCCCCCCCCCCCCSCC(CN=[N+]=[N-])NC(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCSCC(COS(C)(=O)=O)CC(C)OC(=O)c1ccccc1

Procedure:
A mixture of 1.268 g (2.65 mM) of 2-(2-benzoyloxypropan-1-yl)-3-n-hexadecylthiopropanol m12, 0.270 ml (3.45 mM) of methanesulfonyl chloride and 0.56 ml (3.98 mM) of triethylamine in 30 ml of dichloromethane is allowed to react by the same procedure as described in (52) and the crude product of the titled compound m12a is obtained.