Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl.[CH:23]([OH:26])([CH3:25])[CH3:24].[OH-].[Na+]>O>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:24][CH:23]3[O:26][CH2:25]3)=[CH:14][CH:15]=2)=[CH:6][CH:7]=1)[CH:20]1[O:22][CH2:21]1
Reactant: CC(=Cc1ccc(O)cc1)c1ccc(O)cc1
Reactant: ClCC1CO1
Reactant: CC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=Cc1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Temperature: 50 °C

Procedure:
4,4'-Dihydroxy-alpha-methylstilbene (452.5 grams, 4.0 hydroxyl equivalents) from A above, epichlorohydrin (1850.6 grams, 20.0 moles), deionized water (160.9 grams, 8.0 percent by weight of the epichlorohydrin used) and isopropanol (996.5 grams, 35 percent by weight of the epichlorohydrin used) are added to a reactor and heated to 50° C. with stirring under a nitrogen atmosphere. Once the 50° C. temperature is achieved, sodium hydroxide (144.0 grams, 3.60 moles) dissolved in deionized water (576.0 grams) is added dropwise to the reactor over a 45 minute period and so as to maintain the reaction temperature between 50° and 61° C. Ten minutes after completion of the aqueous sodium hydroxide addition, the stirring is stopped and the aqueous layer which separates from the reaction mixture is pipetted off and discarded. Stirring is resumed and after a total of 20 minutes following the completion of the initial aqueous sodium hydroxide addition, a second solution of aqueous sodium hydroxide (64.0 grams, 1.60 mole) dissolved in deionized water (256.0 grams) is added to the reactor over a 20 minute period with maintenance of the reaction temperature between 50° and 51° C. Fifteen minutes after completion of the aqueous sodium hydroxide, the recovered reaction mixture is added to a separatory funnel and washed with warm (60° to 70° C.) deionized water (1200 milliliters). The separated organic layer is washed a second time (1200 milliliters of warm deionized water), recovered and then rotary evaporated under vacuum using final conditions of 150° C. and one mm Hg vacuum for 2 hours. After removal from the rotary evaporator, the molten epoxy resin is vacuum filtered through a heated (175° C.) medium fritted glass funnel, then poured into an aluminum foil tray to solidify. The 4,4'-diglycidyloxy-alpha-methylstilbene is recovered (645.4 grams) as a crystalline white solid. Titration of portions of the diglycidyl ether product reveals an epoxide equivalent weight (EEW) of 181.15. Analysis of a portion of the diglycidyl ether product via microscopy under crosspolarized light is completed at 70× magnification using a microscope equipped with a programmable hot stage using a heating rate of 10° C. per minute and a range of 30° to 150° C., immediately followed by cooling. Isotropization is observed at 131° C., liquid crystallinity occurs at 92° C. and crystallization occurs at 55° C. The diglycidyl ether is a monotropic liquid crystal with a nematic texture.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O.[OH-].[Na+].[ClH:32]>C(Cl)Cl.C(Cl)Cl.CCOCC.CCOCC>[ClH:32].[ClH:32].[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)cc2F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Fc1ccc(CN2CCNCC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6.2 g (19.85 mmol) of the title A compound, t-butyl 4-(2,4-difluorobenzyl)piperazine-1-carboxylate in 50 mL of DCM at 0° C. is added 15 mL of trifluoroacetic acid. The reaction mixture is warmed to RT and stirred for 1 h, and 10 mL of 1 N aqueous sodium hydroxide (NaOH) are added. The mixture is extracted with 2×100 mL of DCM and the organic layer is washed with water, dried over anhydrous MgSO4 and evaporated to dryness in vacuo. The residue is dissolved in a mixture of DCM-Et2O and two equivalents of HCl in Et2O are added, the precipitate solid is collected by filtration and washed with acetone to afford 4-(2,4-difluorobenzyl)piperazine dihydrochloride as a white solid: m.p=237° C. LC/MS (M+1=213.1). 1H NMR (DMSO-d6, 400 MHz) δ 3.44 (m, 8H), 4.39 (s, 2H), 7.25 (dt, 1H, J=8.4 Hz and 1.6 Hz), 7.43 (dt, 1H, J=9.2 Hz and 2.0 Hz), 7.84 (dd, 1H, J=15.2 Hz and 8.4 Hz), 9.84 (br s, NH). Anal. calculated for (C11H14F2N2, 2HCl+0.25 H2O) C, 45.61; H, 5.74; Cl, 24.48; F, 13.12; N, 9.67; O, 1.38. Found C, 45.56; H, 5.90; N, 9.68.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][N:15]=2)=[O:13])[CH2:3]1.[CH3:23][C:24]1[S:25][C:26]([C:32]2[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=2)=[C:27]([C:29](O)=[O:30])[N:28]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:29]([C:27]3[N:28]=[C:24]([CH3:23])[S:25][C:26]=3[C:32]3[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=3)=[O:30])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][N:15]=2)=[O:13])[CH2:3]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: CC1C[C@H]2CN[C@H](CNC(=O)c3noc4ccccc34)[C@H]2C1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2noc3ccccc23)c1

Procedure:
prepared by reaction of benzo[d]isoxazole-3-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]N)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.C=O.[C:27]([BH3-])#[N:28].[Na+].[C:31](O)(=O)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:28]([CH3:27])[CH3:31])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Reactant: NCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 23 a solution of 8-chloro-1-(aminomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in acetonitrile is treated with formalin, sodium cyanoborohydride and acetic acid to give 8-chloro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[O:26])[CH:20]=3)[CH2:15]2)=[O:13])[CH2:7][CH2:6]1)(O)=[O:2].[NH:35]1[C:39]([NH2:40])=[N:38][N:37]=[N:36]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>Cl.CN(C=O)C>[NH:35]1[C:39]([NH:40][C:1]([CH2:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([O:11][C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:25]([NH:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[F:34])=[O:26])[CH:20]=4)[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)=[O:2])=[N:38][N:37]=[N:36]1
Reactant: O=C(O)C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1
Reactant: Nc1nnn[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1)Nc1nnn[nH]1

Procedure:
A DMF (4 mL) solution of trans-6-[3-(2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester (188 mg) obtained in Example 2, 1H-tetrazol-5-ylamine (54 mg), BOP reagent (212 mg), and diisopropylethylamine (0.10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with 1 N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was concentrated and vigorously stirred in water/isopropyl ether. The obtained solid was heated to reflux in methanol and collected by filtration. The title compound (99 mg, 46%) was obtained as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.C(OC([N:29]1[C:37]2[C:32](=[CH:33][C:34]([O:40][CH3:41])=[C:35]([O:38][CH3:39])[CH:36]=2)[C:31](B(O)O)=[CH:30]1)=O)(C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:41][O:40][C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][C:35]=1[O:38][CH3:39])[NH:29][CH:30]=[C:31]2[C:9]1[N:8]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=[C:2]([F:1])[CH:3]=[C:4]2[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3cc(F)cnc32)cc1
Reactant: COc1cc2c(B(O)O)cn(C(=O)OC(C)(C)C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2[nH]cc(-c3cc4cc(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Temperature: 110 °C
Yield: 76.7 %

Procedure:
A mixture of 3.1 g of 5-fluoro-2-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 2.4 g of 1-tert-butyloxycarbonyl-5,6-dimethoxy-1H-indole-3-boronic acid and 20.3 ml of a saturated aqueous sodium hydrogen carbonate solution in 100 ml of dimethylformamide is degassed with argon for approximately 15 minutes and then 0.43 g of tetrakis(triphenylphosphine)palladium is added. The mixture is heated at around 110° C. for approximately 2 hours and then concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 500 ml of water, and extracted with three times 250 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue is taken up with 100 ml of diisopropyl ether, filter-dried, washed with three times 20 ml of diisopropyl ether, and dried under reduced pressure (13 kPa) in the presence of potassium hydroxide chips at a temperature in the region of 20° C. 2.66 g of 2-(5,6-dimethoxy-1H-indol-3-yl)-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine are obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:32]=[CH:31][CH:30]=[CH:29][C:7]=1[CH2:8][C:9]1[S:10][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[C:16]=2[N:17]=1)=[CH2:5])C.Cl>C1COCC1.CCOC(C)=O>[F:27][C:25]([F:26])([F:28])[C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:15]2[C:16]3[N:17]=[C:9]([CH2:8][C:7]4[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=4[C:4](=[O:3])[CH3:5])[S:10][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:20][CH:21]=1
Reactant: C=C(OCC)c1ccccc1Cc1nc2c(Nc3ccc(C(F)(F)F)cc3)ncnc2s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccccc1Cc1nc2c(Nc3ccc(C(F)(F)F)cc3)ncnc2s1
Yield: 86.6 %

Procedure:
{2-[2-(1-Ethoxy-vinyl)-benzyl]-thiazolo[5,4-d]pyrimidin-7-yl}-(4-trifluoromethyl-phenyl)-amine (230 mg, 0.62 mmol) was dissolved in THF (5 mL) and 2 N HCl (2 mL) and the reaction mixture was stirred at rt for 1.5 h. The reaction mixture was diluted with EtOAc (20 mL), washed with satd. aq. NaCl (2×5 mL), dried (Na2SO4), and concentrated to provide a white solid (0.23 g, 69%). MS (ESI): mass calcd. for C21H15F3N4OS, 428.4; m/z found, 429.1 [M+H]+. 1H NMR (CDCl3): 8.61 (S, 1H), 8.08 (s, 1H), 7.98 (d, J=8.5 Hz, 2H), 7.91 (dd, J=8.0, 1.2 Hz, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.58-7.54 (m, 1H), 7.50-7.46 (m, 2H), 4.75 (s, 2H), 2.64 (s, 3H).
Reaction SMILES: C(O)C(O)C.[CH2:6]([O:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH3:35][N:36]([CH2:38][CH2:39][CH2:40][N:41]1[CH2:45][CH2:44][CH2:43][C:42]1=[O:46])[CH3:37]>>[S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)([O-:27])(=[O:26])=[O:24].[CH2:6]([N+:36]([CH3:35])([CH3:37])[CH2:38][CH2:39][CH2:40][N:41]1[CH2:45][CH2:44][CH2:43][C:42]1=[O:46])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CN(C)CCCN1CCCC1=O
Reactant: CCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Solvent: CC(O)CO
Product: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a 100 ml round bottom flask equipped with a thermometer and stirrer containing 167 g. of propylene glycol was added 50.7 g. of octadecyl-p-toluenesulfonate and 20.9 g. of [(dimethylamino)propyl]-2-pyrrolidone. The mixture was heated to 100° C. and stirred at that temperature for 6 hours after which it was cooled and recovered. Analysis by quaternary tetraphenyl boron indicated 22% activity corresponding to a 74% conversion.
Reaction SMILES: [NH2:1][C:2]1([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH2:23]([C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>C(Cl)Cl>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][C:2]1([NH:1][C:38]([NH:37][C:34]2[CH:35]=[CH:36][C:31]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:32][CH:33]=2)=[O:39])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:3]1)[CH3:22]
Reactant: CCCCCCCCc1ccc(N=C=O)cc1
Reactant: CCOC(=O)CC1(N)CCN(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CCN(C(=O)OCc3ccccc3)C2)cc1
Yield: 30.6 %

Procedure:
To a solution of benzyl 3-amino-3-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate (260 mg, 0.85 mmol) and p-octylphenylisocyanate (215 mg, 0.93 mmol) in CH2Cl2 (3 mL) was added triethylamine (0.35 mL, 2.55 mmol) to give the title compound as a brown solid (140 mg, 31%). MS ESI 538.2 [M+H]+, calcd for [C31H43N3O5+H] 538.32.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:22].[Mg+2]>CC(O)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N+:6]([O-:22])=[CH:7]2
Reactant: Brc1cccc2cnccc12
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CC(C)O
Solvent: O
Product: [O-][n+]1ccc2c(Br)cccc2c1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
3.1 A suspension of 6.24 g (30.0 mmol) of 5-bromoisoquinoline and 17.5 g (30 mmol) of magnesium monoperoxyphthalate hexahydrate (85%) in 120 ml of 2-propanol is stirred at room temperature for 50 hours. The reaction mixture is evaporated in vacuo, and saturated sodium chloride solution, saturated sodium hydrogencarbonate solution and dichloromethane are added. The organic phase is separated off and washed a number of times with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated. The residue is stirred with tert-butyl methyl ether, giving 5-bromoisoquinoline 2-oxide as colourless crystals; HPLC/MS: 1.51 min, [M+H] 224/226.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[C:15]2[C:6]([NH:7][C:8]3[C:9]([C:18]([OH:20])=[O:19])=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]2=O)=[CH:5][CH:4]=1)[CH3:2].C(N(CC)CC)C.[Al]>CCO.Cl[Hg]Cl>[CH2:1]([C:3]1[CH:16]=[C:15]2[C:6]([N:7]=[C:8]3[C:13](=[CH:14]2)[CH:12]=[CH:11][CH:10]=[C:9]3[C:18]([OH:20])=[O:19])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc2[nH]c3c(C(=O)O)cccc3c(=O)c2c1
Agent: Cl[Hg]Cl
Agent: [Al]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1ccc2nc3c(C(=O)O)cccc3cc2c1
Yield: 81.7 %

Procedure:
A suspension of the above acridone acid (1.00 g, 3.75 mmol) in 50% aqueous EtOH was stirred and heated, then sufficient triethylamine added to obtain a clear yellow solution. Portions of aluminium foil (0.83 g) were amalgamated in a solution of HgCl2 (3 g) in EtOH, then added to the above vigorously boiling solution over 30 min. After the reaction was observed to be complete by tlc, the reaction mixture was filtered and the solids collected were washed with a solution of KOH in aqueous EtOH. The filtrate was then strongly acidified with concentrated HCl and treated with FeCl3 under reflux for 45 min. The reaction mixture was concentrated under reduced pressure and sufficient potassium acetate added until the pH was neutral. Crystallization of the product occurred upon cooling and filtration and recrystallisation of the resulting brown solid gave 7-ethylacridine-4-carboxylic acid (0.77 g, 82%), mp (acetone) 210-211.5° C. 1H NMR [(CD3)2SO] δ 1.35 (t, J=7.5 Hz, 3 H, CH3), 2.91 (q, J=7.5 Hz, 2 H, CH2), 7.83 (dd, J=8.3, 7.2 Hz, 1 H, H-2), 7.97 (dd, J=9.0. 1.9 Hz, 1 H, H-6), 8.09 (br s, 1 H, H-8), 8.26 (d, J=9.0 Hz, 1 H, H-5), 8.54 (dd, J=8.4, 1.2 Hz, 1 H, H-1), 8.71 (br d, J=7.0 Hz, 1 H, H-3), 9.43 (s, 1 H, H-9), 17.09 (br s, 1 H, COOH). Anal. (C16H13NO2) C, H, N.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.C(N(CC)CC)C.[Cl:13][CH:14](Cl)[C:15]([NH:17][CH:18]1[C:36](=[O:37])[N:20]2[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH2:25][S:26][C:27]3[N:31]([CH3:32])[N:30]=[N:29][N:28]=3)[CH2:23][S:24][C@H:19]12)=[O:16]>C(Cl)(Cl)Cl>[CH3:1][Si:2]([O:35][C:33]([C:21]1[N:20]2[C:36](=[O:37])[CH:18]([NH:17][C:15](=[O:16])[CH2:14][Cl:13])[C@H:19]2[S:24][CH2:23][C:22]=1[CH2:25][S:26][C:27]1[N:31]([CH3:32])[N:30]=[N:29][N:28]=1)=[O:34])([CH3:5])[CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(Cl)Cl)[C@H]2SC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1nnnc1SCC1=C(C(=O)O[Si](C)(C)C)N2C(=O)C(NC(=O)CCl)[C@H]2SC1
Reaction time: 1.5 h

Procedure:
Trimethylchlorosilane(0.32 ml) and triethylamine (0.14 ml) were added to a solution of 7-dichloroacetamido-3-(1-methyl-1H-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid(374 mg) in chloroform(10 ml) and the reaction mixture was stirred at 5 - 7°C. for 1.5 hours to give 7-chloroacetamido-3-(1-methyl-1H-tetrazole-5-yl) thiomethyl-3-cephem-4-carboxylic acid trimethylsilyl ester. The resulting solution was added to a mixture of phosphorus pentachloride(176 mg), quinoline(0.12 ml) and chloroform(15 ml) at -50°C. The reaction mixture was stirred at -50°C for 3 hours and diluted with tetrahyrofuran(20 ml), which was cooled to -78°C. To this solution was added a methanol solution of lithium methoxide prepared from lithium(140 mg) and methanol (15 ml) at -78°C. The mixture was stirred at -78°C. for 30 minutes and treated with acetic acid(1.2 ml). The solution was poured into water and extracted with chloroform. The chloroform solution was washed with water, dried (Na2SO4) and evaporated to give a residue. The aqueous layer in the extraction of chloroform was again extracted with ethyl acetate. The extracts were washed with water, dried (Na2SO4) and the solvent was removed by distillation under reduced pressure to afford a residue. The residual fractions obtained above were combined and dissolved in a small amount of chloroform, to which was added excess hexane to precipitate the desired product. This precipitation process was repeated three times to give 200 mg of pure 7β-(2'-chloro-1'-methoxyethylidenimino)-7α-methoxy-3-(1-methyl-1H- tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid. NMR(CDCl3) δ ppm: 3.38 and 3.56(2H, AB-quartet, J=19 Hz), 3.46(3H, singlet), 3.78(3H, singlet), 3.82(3H, singlet), 4.20 and 4.55(2H, AB-quartet, J=12 Hz), 4.47(2H, singlet), 5.07(1H, singlet).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1)(=O)=O.[Cl:26][C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[N:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([O:33][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:7][N:6]=2)[CH:30]=[N:31][CH:32]=1
Reactant: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: Oc1cncc(Cl)c1
Product: Clc1ccc(-c2cnc(Oc3cncc(Cl)c3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylsulfonyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine from Reference Example 3 was reacted with 5-chloro-3-hydroxypyridine according to the procedure described in Example 74 to afford 2-(5-chloro-3-pyridyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine: HPLC/MS: m/e=462 (M++1); Rt=4.40 min; 1H-NMR 400 MHz (CDCl3): δ 7.05. (d, J=9 Hz, 2H), 7.21 (d, J=10 Hz, 1H), 7.25-7.31 (m, 3H), 7.41 (s, 1H), 7.75 (s, 1H), 8.50 (s, 1H), 8.55 (s, 1H), 8.62 (s, 1H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=O.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:46]([O:48][C:49](=[O:59])[CH2:50][C:51](=[O:58])[N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)[CH3:47]>CN(C=O)C.O>[CH2:46]([O:48][C:49](=[O:59])[CH2:50][C:51](=[O:58])[N:52]1[CH2:57][CH2:56][N:55]([C:24](=[O:26])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[C:21]([F:20])([F:32])[F:31])[CH2:54][CH2:53]1)[CH3:47]
Reactant: O=C(O)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)CC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
HOBt (1.38 g, 10.2 mmol) and DIPEA (3.68 mL, 21.3 mmol) were added to a stirred solution of 2-trifluoromethyl-benzoic acid (1.62 g, 8.5 mmol) in DMF (5 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (1.96 g, 10.2 mmol) followed by 3-oxo-3-piperazin-1-yl-propionic acid ethyl ester hydrochloride (2 g, 8.5 mmol) were added. The reaction mixture was stirred at the room temperature overnight, then diluted with water and the product extracted with Ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4 and evaporated to dryness. The residue was purified by column chromatography using silica gel 60-120 mesh (50% ethyl acetate in hexane) to afford 1.5 g (48%) of 3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionic acid ethyl ester. LCMS: 373.13 (M+1)+, 90%
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3Cl)[CH:14]=2)=[N:11][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+:29]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)([O-:31])=[O:30]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:38][C:35]3[CH:36]=[CH:37][C:32]([N+:29]([O-:31])=[O:30])=[CH:33][C:34]=3[F:39])[CH:14]=2)=[N:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ccnc2cc(-c3ccc(C4OCCCO4)cn3)sc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
To a suspension of 29 (22.48 g, 67.5 mmol) in phenyl ether (65 mL) was added sodium carbonate (14.32 g, 135 mmol) and 2-fluoro-4-nitrophenol (3) (15.92 g, 101 mmol). The reaction mixture was heated at 180° C. for 2 h, cooled down to 40° C., diluted with DCM (300 mL), stirred at r.t. for 15 min and filtered. The filtrate was collected and concentrated to a minimal volume; Et2O (200 mL) was added and the formed suspension was stirred for 30 min. The solid material was collected by filtration, to afford intermediate 30 (25.20 g, 55.6 mmol, 82% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d) δ (ppm): 8.63-8.62 (m, 2H), 8.48 (dd, J=10.6, 2.6 Hz, 1H), 8.43 (s, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.21 (dt, J=8.8, 1.2 Hz, 1H), 7.94 (dd, J=8.4, 2.0 Hz, 1H), 7.71 (t, J=8.6 Hz, 1H), 6.98 (d, J=5.2 Hz, 1H), 5.67 (s, 1H), 4.19 (dd, J=10.8, 5.2 Hz, 2H), 3.98 (td, J=12.0, 2.0 Hz, 2H), 2.08-1.99 (m, 1H), 1.46 (d, J=13.6 Hz, 1H). MS (m/z): 454.2 (M+H).