Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:16][C:17]1[O:21][C:20]([C:22]([OH:24])=O)=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH2:25](OC1OC(C(O)=O)=CC=1)CCCCCCCCCCCCC>>[CH2:1]([O:16][C:17]1[O:21][C:20]([C:22]([CH3:25])=[O:24])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCC/C=C\CCCCCCCCOc1ccc(C(=O)O)o1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Product: CCCCC/C=C\CCCCCCCCOc1ccc(C(C)=O)o1

Procedure:
When in the procedure of Example 1(B) an appropriate amount of 5-(cis-9-pentadecenyloxy)-2-furoic acid is substituted for 5-(tetradecyloxy)furoic acid, methyl 5-(cis-9-pentadecenyloxy)-2-furyl ketone is obtained.
Reaction SMILES: ClC[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:7][C:6]=1[CH3:21])=[O:4].ClCC(C1C=CC(C)=CC=1NC(=O)C1C=CC=CC=1C)=[O:25].Cl>C1(C)C=CC=CC=1>[CH3:21][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:25]
Reactant: Cc1cc(NC(=O)c2ccccc2C)ccc1C(=O)CCl
Reactant: Cc1ccc(C(=O)CCl)c(NC(=O)c2ccccc2C)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)c2ccccc2C)ccc1C(=O)O
Yield: 86 %

Procedure:
A toluene solution of a mixture of 2-chloro-2′-methyl-4′-(2-methylbenzoylamino)acetophenone and 2-chloro-4′-methyl-2′-(2-methylbenzoylamino)acetophenone obtained in the above Reference Example 5 is concentrated and to the residue is added isopropyl alcohol (twice volume). To the mixture is added dropwise an aqueous sodium hypochlorite solution (twice molar amount) at 10-20° C. After completion of the reaction (30 minutes to one hour), the reaction mixture is acidified with hydrochloric acid, and the precipitated crystals are separated by filtration to give a crude product of 2-methyl-4-(2-methylbenzoylamino)benzoic acid in a yield of 86-100%. This crude product is recrystallized from methanol to give the desired product (yield 57%, purity by HPLC 99.3%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([N:17]([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.CC(O)=O.N.[N+:29]([CH3:32])([O-:31])=[O:30]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10](/[CH:11]=[CH:32]\[N+:29]([O-:31])=[O:30])=[CH:13][CH:14]=[CH:15][C:16]=1[N:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: CN(C)c1cccc(C=O)c1OCc1ccccc1
Agent: N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(C)c1cccc(/C=C\[N+](=O)[O-])c1OCc1ccccc1
Temperature: 105 °C
Reaction time: 8 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(benzyloxy)-3-(dimethylamino)benzaldehyde (5 g, 19.58 mmol, 1.00 equiv), acetic acid (40 mL), acetic acid amine (750 mg, 9.73 mmol, 0.50 equiv) and nitromethane (11.96 g, 195.94 mmol, 10.01 equiv). The resulting solution was stirred overnight at 105° C. in an oil bath. The resulting solution was diluted with 200 mL of ethyl acetate. The mixture was washed with NaOH (5 mol/L) until pH=7. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). This resulted in 3.5 g (60%) of 2-(benzyloxy)-N,N-dimethyl-3-[(Z)-2-nitroethenyl]aniline as a dark red solid. MS (ESI) m/z 299 ([M+H]+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:15][CH2:14][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][CH:7]=1)=O)C.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[CH2:13]1[C:9]2([CH2:14][CH2:15][C:6]([CH2:4][OH:3])=[CH:7][CH2:8]2)[CH2:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)C1=CCC2(CCCC2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCC1=CCC2(CCCC2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of spiro[4.5]dec-7-ene-8-carboxylic acid ethyl ester (2.8 g) obtained in Step 3 in tetrahydrofuran (40 mL) was added dropwise a toluene solution of diisobutylaluminum hydride (0.99 M, 41 mL) under argon atmosphere at −78° C., followed by stirring the reaction mixture at −78° C. for 1 hour. Then, after adding 2N aqueous hydrochloric acid solution and raising the temperature to room temperature, the reaction mixture was extracted with ethyl acetate twice. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:4) to give spiro[4.5]dec-7-en-8-yl-methanol (1.95 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7](O)[CH3:8])[CH2:3][CH2:2]1.[OH:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([O:16]CC)=[O:15]>>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:10][C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=2)[C:14]([OH:16])=[O:15])[CH2:3][CH2:2]1
Reactant: CC(O)C1CCOCC1
Reactant: CCOC(=O)c1cccc(O)c1
Product: O=C(O)c1cccc(OCCC2CCOCC2)c1

Procedure:
Prepared from tetrahydro-2H-pyran-4-yl-ethanol and ethyl 3-hydroxybenzoate.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].Cl[C:10]1[C:11]2[CH:18]=[C:17]([CH2:19][CH3:20])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[N:13]=[CH:14][N:15]=1.CCCCCCC.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:8][O:7][C:3](=[O:6])[CH2:4][O:5][C:10]1[C:11]2[CH:18]=[C:17]([CH2:19][CH3:20])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COC(=O)CO
Reactant: CCc1cc2c(Cl)ncnc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: c1ccccc1
Product: CCc1cc2c(OCC(=O)OC)ncnc2n1Cc1ccccc1
Temperature: 60 °C
Yield: 70.1 %

Procedure:
To a suspension of 165 mg (6.84 mmol) of sodium hydride in 12 mL of benzene was added 530 mg (5.93 mmol) of methyl glycolate and 1.24 g (4.56 mmol) of 4-chloro-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine. The mixture was heated at 60° C. and monitored by TLC (silica, 7:3 heptane-ethyl acetate) for conversion to product. After 5 days the reaction was cooled to ambient temperature and partitioned by the addition of 10 mL of 2 M sodium hydrogen sulfate and 30 mL of ethyl acetate. The aqueous phase was extracted with 10 mL of ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated to 1.5 g of white solid. The solid was purified by flash chromatography (75 g silica, 3:2 heptane-ethyl acetate) to provide 1.04 g (70%) of [[6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a white solid. nmr (500 MHz, CDCl3) δ1.28 (t, J=7.4 Hz, 3H), 2.63 (q, J=7.4 Hz, 2H), 3.81 (s, 3H), 5.10 (s, 2H), 5.47 (s, 2H), 6.41 (s, 1H), 7.03 (d, J=7.0 Hz, 2H), 7.27 (m, 3H), 8.39 (s, 1H)
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:5][C:6]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[N:7][C:8]=1[CH:9]([CH3:11])[CH3:10].C1(C)C=CC=CC=1.[C:32]1([PH2:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:39]CC)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O>[C:32]1([P:38](=[O:39])([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:2][C:3]2[C:4]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:5][C:6]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[N:7][C:8]=2[CH:9]([CH3:11])[CH3:10])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCO[PH2](c1ccccc1)c1ccccc1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CBr
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CP(=O)(c1ccccc1)c1ccccc1
Reaction time: 9 h
Yield: 72.8 %

Procedure:
N-[5-bromomethyl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (10.0 g), toluene (100.0 mL), and diphenyl(ethoxy)phosphorane (6.2 g) were added to a reactor. The reaction mixture was stirred at 90˜100° C. for 9 hours and then water (80.0 mL) was added thereto. The separated organic layer was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1:1) to obtain diphenyl[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-ylmethyl]phosphine oxide as a white solid (9.4 g, yield 73%).
Reaction SMILES: [Cl:1][C:2]1[C:20]([N+:21]([O-])=O)=[CH:19][C:5]2[N:6]([CH:16]([CH3:18])[CH3:17])[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.N>Cl.[Zn]>[NH2:21][C:20]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[N:6]([CH:16]([CH3:18])[CH3:17])[C:5]=2[CH:19]=1
Reactant: CC(C)n1c(N2CCN(C)CC2)nc2cc(Cl)c([N+](=O)[O-])cc21
Agent: Cl
Agent: N
Agent: [Zn]
Product: CC(C)n1c(N2CCN(C)CC2)nc2cc(Cl)c(N)cc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
5-Chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)-6-nitrobenzimidazole (1.2 g) was dissolved in 2.5N hydrochloric acid (20 ml) and thereto was added zinc powder (1.5 g) in portions and the mixture was stirred at 80° C. for 4 hours. The reaction mixture was made basic with an aqueous ammonia and extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The residue was recrystallized from acetonitrile to give 6-amino-5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)benzimidazole (0.6 g) as colorless crystal.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([O:25]CC)=[O:24])[C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([OH:25])=[O:24])[C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1cnn2CCNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCn1ncc2c(C(=O)O)cc(C3CC3)nc21
Reaction time: 16 h

Procedure:
The title compound was prepared in the same manner as described for intermediate 46 using ethyl 6-cyclopropyl-1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (110 mg, 0.294 mmol), sodium hydroxide (1 mL, 0.294 mmol), and ethanol (10 mL) wherein the stir time was 16 h. The final product was collected as 0.060 g (59%). LCMS E-S (M+H)=347.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.13 (m, 4 H) 1.27 (s, 9 H) 2.33-2.43 (m, 1 H) 3.37 (q, J=5.81 Hz, 2 H) 4.44 (t, J=5.94 Hz, 2 H) 6.84 (t, J=5.81 Hz, 1 H) 7.62 (s, 5 H) 8.24 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[O:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:4]=2[N:3]=1.Br[C:18]1[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=1>>[CH3:1][CH:2]1[O:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7]([C:18]3[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=3)[CH:8]=[CH:9][C:4]=2[NH:3]1
Reactant: N#Cc1cc(Br)cs1
Reactant: CC1=Nc2ccc(Br)cc2C2(CCCC2)O1
Product: CC1Nc2ccc(-c3csc(C#N)c3)cc2C2(CCCC2)O1

Procedure:
Prepared according to the procedure for Example 13 from 2-methyl-6-bromospiro[4H-3,1-benzoxazine-4,1′-cyclopentane] and 4-bromo-2-thiophenecarbonitrile. An off-white solid: mp 103-104° C.
Reaction SMILES: C(OC([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=O)C.[CH2:23]([O:25][C:26](C1C(C2C=CC(CBr)=CC=2)=CC=CC=1)=[O:27])[CH3:24].SCCO.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:23]([O:25][C:26]([C:7]1[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][S:19][CH2:20][CH2:21][OH:22])=[CH:16][CH:17]=2)=[CH:9][CH:10]=[CH:11][CH:6]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCO)cc2)c1
Agent: O=C([O-])[O-]
Agent: OCCS
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1-c1ccc(CSCCO)cc1
Yield: 42 %

Procedure:
4′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester was prepared as described for 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 4′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester (4.1 g, 12.84 mmol, 1 eq.) in anhydrous DMF was treated with 2-mercaptoethanol (1.2 g, 15.41 mmol, 1.2 eq.) and potassium carbonate (5.32 g, 38.52 mmol, 3 eq.). When complete, the reaction was worked up and purified as described for 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid ethyl ester to leave 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester (3.05 g, 42% yield) as a light yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[OH:32])(=[O:23])=[O:22])C1C=CC=CC=1>C(O)C.[Pd]>[C:30]([C:28]1[CH:27]=[CH:26][C:25]([OH:32])=[C:24]([S:21]([NH:20][CH2:19][CH2:18][C:10]2[CH:11]=[CH:12][C:13]([CH:15]([CH3:17])[CH3:16])=[CH:14][C:9]=2[OH:8])(=[O:23])=[O:22])[CH:29]=1)#[N:31]
Reactant: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(O)c1
Reaction time: 3 h
Yield: 88.1 %

Procedure:
To a stirred solution of 0.203 g of N-[2-(2-benzyloxy-4-isopropylphenyl)ethyl]-5-cyano-2-hydroxybenzenesulfonamide in ethanol was added 0.04 g of 10% palladium on carbon, and the mixture was stirred under a hydrogen atmosphere and ordinary pressure for 3 hours. After the insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure to give 0.143 g of 5-cyano-2-hydroxy-N-[2-(2-hydroxy-4-isopropylphenyl)ethyl]benzenesulfonamide.
Reaction SMILES: C1(=O)[N:5]([C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)C(=O)C2=CC=CC=C12.[H][H].O.NN>CO.CCOCC.[Pt]=O>[Cl:18][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH2:5])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C1c2ccccc2C(=O)N1C#CCCCCc1cccc(Cl)c1
Reactant: [H][H]
Agent: O=[Pt]
Agent: NN
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: NCCCCCCc1cccc(Cl)c1
Temperature: 5 °C
Reaction time: 72 h

Procedure:
A suspension of 1-(phthalimido)-6-(3-chlorophenyl)hex-1-yne (10 g, 30 mmol) in methanol (100 ml) was treated with platinum oxide (250 mg) and the mixture hydrogenated at 50 psi for 72 h. Further quantities of catalyst were added at intervals and when the theoretical uptake of hydrogen was complete, the mixture was filtered and the filtrate evaporated to a brown oil (9.5 g, 96%). This was dissolved in IMS 99 (100 ml) and treated with hydrazine hydrate (2.8 g, 56 mmol) under reflux for 16 h. The mixture was cooled to 5° C. and the precipitated solid removed by filtration. Evaporation of the filtrate gave an oil which was taken up in ether, washed with water, dried (Na2SO4) and evaporated to a brown oil (5.8 g, 98%)
Reaction SMILES: ClC1C(N)=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1.C(O)=O.[Cl:18][C:19]1[C:27]2[NH:26][CH:25]=[N:24][C:23]=2[CH:22]=[C:21]([NH:28]C=O)[CH:20]=1.C(N)=O>C(OC(=O)C)(=O)C.Cl.[Pd].CCO>[Cl:18][C:19]1[C:27]2[NH:26][CH:25]=[N:24][C:23]=2[CH:22]=[C:21]([NH2:28])[CH:20]=1
Reactant: O=CNc1cc(Cl)c2[nH]cnc2c1
Agent: [Pd]
Agent: Cl
Agent: Nc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCO
Solvent: O=CO
Solvent: NC=O
Product: Nc1cc(Cl)c2[nH]cnc2c1

Procedure:
Methanolic solution of 6-chloro-2,4-dinitroaniline (2.4 g, 11 mmol) was stirred overnight with 100 mg of 10% Pd/C under H2. Reaction mixture was filtered and concentrated in vacuo to provide an oil which was dissolved in 10 ml of acetic anhydride and 10 ml of formic acid and stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, yielding a brown oil which was characterized as 4-chloro-6-foramidylbenzimidazole in NMR analysis. The formamide was dissolved in 20 ml of HCl sat'd EtOH and stirred for 3h at 25° C. The reaction mixture was purified in column chromatography (5% MeOH/EtOAc) to provide 0.89 g (5.3 mmol, 48% overall) of the desired product.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH2:9][CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:17]([SH:19])[CH3:18].C[O-].[Na+]>CO>[CH2:17]([S:19][C:2]1[C:3]([O:8][CH2:9][CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=1)[CH3:18]
Reactant: CC(C)NCC(O)COc1nccnc1Cl
Reactant: CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCSc1nccnc1OCC(O)CNC(C)C

Procedure:
Analogously to the description in Example 8, 7.5 g (0.03 mol) of 3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine, 2.8 g (0.045 mol) of ethyl-mercaptan and 2.4 g (0.045 mol) of sodium methylate in 150 ml of methanol, when refluxed for 30 hours, give the crude base 3-ethylthio-2-(3'-isopropylamino-2'-hydroxypropoxy)-pyrazine, and this is converted, with 1.74 g of fumaric acid, into the fumarate of melting point 158°-160° C. when crystallised from methanol-ether.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][N:7]([S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:11])=[O:10])[CH2:6][CH2:5][N:4]1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.[O:30]1[CH2:33][C:32](=O)[CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:25][C:24]([F:26])([F:27])[C:23]([C:20]1[CH:19]=[CH:18][C:17]([N:4]2[CH2:5][CH2:6][N:7]([S:9]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)(=[O:10])=[O:11])[CH2:8][C@@H:3]2[CH2:2][NH:1][CH:32]2[CH2:33][O:30][CH2:31]2)=[CH:22][CH:21]=1)([OH:29])[CH3:28]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN)cc1)C(F)(F)F
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CNC2COC2)cc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a solution of 2-(4-((2S)-2-(aminomethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.300 g, 0.667 mmol, Example 192, Step 1) in CH2Cl2 (5.0 mL) was added 3-oxetanone (0.050 mL, 0.67 mmol, Aldrich, St. Louis, Mo.), 4 molecular sieves (75 mg), and acetic acid (0.01 mL, 0.1 mmol). After stirred for 30 min, sodium triacetoxyborohydride (0.425 g, 2.01 mmol) was added and the reaction mixture was continued to stir at room temperature for 1 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (2×15 mL) and the combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (80 g of silica gel, 2 to 5% 2M NH3 in MeOH/CH2Cl2) to afford 1,1,1-trifluoro-2-(4-((2S)-2-((3-oxetanylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.235 g) as a mixture of two isomers:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.CN1CCOCC1.[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O>C(Cl)Cl>[C:15]([N:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:14]
Reactant: C1=CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=CCC1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To 1.66 g of 1,2,5,6-tetrahydropyridine in 25 ml of CH2Cl2, 2.02 g of N-methylmorpholine are added, the mixture obtained is treated with a solution of 4.36 g (BOC)2O in 30 ml of CH2Cl2 and the mixture obtained is stirred for ca. 36 hours at RT. N-BOC-1,2,5,6-tetrahydropyridine is obtained. 1H-NMR: 5.82(m,1H,HIV), 5.64(m,1H,HIII), 3.86(b,2H,HII), 3.47(t,2H,HVI), 2.12(b,1H,HV), 1.46(m,9H,(CH3)3).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[H-].[Na+].[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([CH3:29])=[CH:24][N:23]=1>CN(C=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:24]3[C:25]([CH3:29])=[CH:26][N:27]=[C:22]([Cl:21])[N:23]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3nc(Cl)ncc3C)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
To a solution of 1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamine (40.3 mg, 0.15 mmol, 1.2 equiv; intermediate A2) in dry DMF (1.5 mL) was added sodium hydride (6.6 mg, 0.15 mmol, 1.2 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt under Ar. After 2 h, 2,4-dichloro-5-methyl-pyrimidine (20.4 mg, 0.125 mmol, 1.0 equiv; commercially available) was added and the mixture heated to 120° C. for 48 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 3.7 mg (8%) of the title compound. MS (ISP): 395.2 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.CN(C=O)C.[F:17][C:18]1[C:23]([OH:24])=[C:22]([CH:25]=[O:26])[CH:21]=[CH:20][C:19]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>O>[Br:1][C:20]1[C:19]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[C:18]([F:17])[C:23]([OH:24])=[C:22]([CH:25]=[O:26])[CH:21]=1
Reactant: O=Cc1ccc(-c2ccc(F)cc2)c(F)c1O
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c(-c2ccc(F)cc2)c(F)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 181.8 %

Procedure:
Dibromoisocyanuric acid (8.87 g) was added at room temperature to a DMF (75 mL) solution of 2,4′-difluoro-3-hydroxybiphenyl-4-carbaldehyde (12.7 g), and the mixture was stirred at room temperature for 30 minutes. Water (50 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The resulting solid was collected by filtration, then washed with DMF-water, and dried to obtain the title compound (17.6 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[OH-].[Mg+2:27].[OH-]>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Mg+2:27].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Agent: [Mg+2]
Agent: [OH-]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
7-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.15 g.) was added to a suspension of magnesium hydroxide (0.088 g.) in water (100 ml.), and the mixture was stirred at 70° C. for 30 minutes to give a solution. After the resultant solution was filtered, the filtrate was lyophilized to give magnesium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 1.1 g.).