Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[CH3:11][S-:12].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:10][C:4]1[CH:3]=[C:2]([S:12][CH3:11])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Cc1cc(Br)ccc1C#N
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(C#N)c(C)c1

Procedure:
A solution of 500 mg of 4-bromo-2-methylbenzonitrile and 268 mg of sodium thiomethoxide in 3 mL of DMF was stirred for 1 h. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated to afford 2-methyl-4-(methylthio)benzonitrile. 400 mg of 2-methyl-4-(methylthio)benzonitrile was reacted via Procedure T to give 2-methyl-4-(methylthio)benzoic acid. 430 mg of 2-methyl-4-(methylthio)benzoic acid was reacted via Procedure R to yield 2-methyl-4-(methylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-methyl-4-(methylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-(methylsulfonyl)benzamide. MS (Q1) 401.0 (M)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[Br:11]P(Br)Br>ClCCl>[Br:11][CH2:9][C:8]1[C:3]([CH2:1][CH3:2])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ncccc1CO
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCc1ncccc1CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (2-ethylpyridin-3-yl)methanol (3.0 g, 21.9 mmol) in anhydrous dichloromethane (150 mL) was added tribromophosphane (2.3 mL, 24.2 mmol). The mixture was stirred at room temperature overnight. Dichloromethane was evaporated. The residue was dried in vacuo, affording 3-(bromomethyl)-2-ethylpyridine, which was used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:5]=[CH:4]1)[CH3:2].Cl[CH2:16][P:17](=[O:20])([CH3:19])[CH3:18]>>[CH2:1]([N:3]1[C:11]2[C:10](=[O:12])[N:9]([CH2:16][P:17](=[O:20])([CH3:19])[CH3:18])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:5]=[CH:4]1)[CH3:2]
Reactant: CP(C)(=O)CCl
Reactant: CCn1cnc2c1c(=O)[nH]c(=O)n2C
Product: CCn1cnc2c1c(=O)n(CP(C)(C)=O)c(=O)n2C

Procedure:
The title substance was prepared from 5 g (0.0258 mol) of 7-ethyl-3-methylxanthine and 3.91 g (0.031 mol) of chloromethyl-dimethylphosphine oxide analogously to Example 67.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[O:13][C:12]([C:14](=[O:31])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:19][CH:18]=3)=[N:11][CH:10]=2)[N:4]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+]>CC(O)C.O.[Br-].[Zn+2].[Br-]>[NH:32]1[C:1]([C:3]2[N:4]=[C:5]([C:9]3[O:13][C:12]([C:14](=[O:31])[CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:19][CH:18]=4)=[N:11][CH:10]=3)[CH:6]=[CH:7][CH:8]=2)=[N:2][N:34]=[N:33]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(-c2cnc(C(=O)CCc3ccc(COc4ccccc4)cc3)o2)n1
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CC(C)O
Solvent: O
Product: O=C(CCc1ccc(COc2ccccc2)cc1)c1ncc(-c2cccc(-c3nnn[nH]3)n2)o1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
2-Cyano-6-(2-(3-(4-(phenoxymethyl)phenyl)propanoyl)oxazol-5-yl)pyridine (98 mg, 0.24 mmol), sodium azide (31 mg, 0.48 mmol), and zinc bromide (27 mg, 0.12 mmol) were dissolved in i-PrOH/H2O (1:2, 2.1 mL) and warmed at reflux for 24 h. The reaction solution was allowed to cool to ambient temperature and was quenched with aqueous 1 N HCl. The solution was diluted with EtOAc and the organic phase was washed with saturated aqueous NaCl, dried over Na2SO4, and the solvent was removed in vacuo. The crude product was purified by tritration in 3% CH2Cl2/ether to provide 1-(5-(6-(1H-tetrazol-5-yl)pyridin-2-yl)oxazol-2-yl)-3-(4-(phenoxymethyl)phenyl)propan-1-one as a pale yellow solid (60 mg, 55%): NMR (DMSO-d6, 600 MHz) δ 8.25-8.24 (m, 3H), 8.08-8.05 (m, 1H), 7.38 (d, 2H, J=8.0 Hz), 7.31-7.27 (m, 4H), 6.99 (d, 2H, J=8.7 Hz), 6.92 (t, 1H, J=7.3 Hz), 3.47 (t, 2H, J=7.5 Hz), 3.02 (t, 2H, J=7.5 Hz); 13C NMR (DMSO-d6, 150 MHz) δ 207.8, 188.3, 159.7, 158.7, 153.0, 147.3, 141.6, 141.2, 136.2, 130.8, 129.7, 129.6, 129.2, 124.1, 123.3, 122.0, 116.1, 70.2, 32.0, 30.0; HR ESI-TOF m/z 453.1681 (M+H+, C25H20N6O3, requires 453.1670).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]5[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=5)=[O:35])=[C:29]([F:44])[CH:28]=4)=[CH:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[C:45]#[N:46])[CH2:10][CH2:9]1)=O)(C)(C)C.O.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[F:44][C:29]1[CH:28]=[C:27]([O:26][C:20]2[C:19]3[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[C:17]([C:45]#[N:46])[CH:18]=3)[N:23]=[CH:22][CH:21]=2)[CH:32]=[CH:31][C:30]=1[NH:33][C:34]([NH:36][C:37]1[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(NC(=O)Nc5ccc(F)cc5)c(F)c4)c3cc2C#N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
After dissolving 4-(6-cyano-4-{3-fluoro-4-[3-(4-fluorophenyl)ureido]phenoxy}quinolin-7-yloxymethyl)piperidine-1-carboxylic acid tert-butyl ester (395 mg) in trifluoroacetic acid (2 ml), the solution was stirred for 10 minutes at room temperature. Water (20 ml) was added, the mixture was neutralized with sodium bicarbonate, and the precipitated crystals were filtered out to obtain the title compound (260 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH3:17])[C:8]([CH3:19])([CH3:18])[CH2:7][CH2:6][C:5]2([CH3:21])[CH3:20].[Li]CCCC.[C:27](=[O:29])=[O:28]>O1CCCC1>[CH:12](/[C:11]1[C:2]([C:27]([OH:29])=[O:28])=[CH:3][C:4]2[C:5]([CH3:20])([CH3:21])[CH2:6][CH2:7][C:8]([CH3:19])([CH3:18])[C:9]=2[CH:10]=1)=[CH:13]/[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCC/C=C\c1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC/C=C\c1cc2c(cc1C(=O)O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.72 g of (Z)-6-bromo-7-hex-1-enyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene (75% pure) were placed in 25 ml of abs. tetrahydrofuran and treated at -75° with 8.25 ml of 1.55M n-BuLi (hexane) (1.2 eq.). After 1/2 h., a CO2 stream was conducted vigorously through the solution for 30 min., with the temperature rising to -60° in spite of constant cooling. The mixture was left to warm to room temperature, poured on to ice/HCl solution, extracted with diethyl ether, washed with H2O, dried over Na2SO4 and the solvent was removed in a vacuum. Two-fold flash chromatography on SiO2 (hexane/ethyl acetate=85/15, then 9/1) yielded 1.06 g of (Z)-3-hex-1-enyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid as colorless crystals.
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/[CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.P(Br)(Br)[Br:18]>C(OCC)C>[Br:18][CH2:9]/[CH:8]=[CH:7]/[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC/C=C/C1CCCCC1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: BrC/C=C/C1CCCCC1
Reaction time: 16 h
Yield: 61 %

Procedure:
To a stirred solution of (E)-3-cyclohexyl-2-propen-1-ol (A. G. M. Barrett et al, Tetrahedron, 1996, 52, 15325), (1.47 g, 10.5 mmol) in diethyl ether (20 ml) and pyridine (1 ml) was added phosphorus tribromide (1.40 ml, 15 mmol) dropwise at room temperature under an atmosphere of nitrogen. After 16 h, the reaction mixture was carefully poured onto ice water (100 ml) and extracted with diethyl ether (100 ml). The extract was washed with saturated aqueous sodium hydrogen carbonate solution (100 ml), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by silica (20 g) column chromatography eluting with hexane:ethyl acetate (4:1) to give the title compound as a colourless oil (1.3 g, 61%).
Reaction SMILES: [P:1]([O-:29])([O:25][CH2:26][CH2:27]Br)([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O: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][CH2:23][CH3:24])=[O:2].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[P:1]([O-:29])([O:25][CH2:26][CH2:27][N+:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O: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][CH2:23][CH3:24])=[O:2]
Reactant: CCCCCCCCCCCCCCCOCCOCCOP(=O)([O-])OCCBr
Reactant: c1ccncc1
Product: CCCCCCCCCCCCCCCOCCOCCOP(=O)([O-])OCC[n+]1ccccc1

Procedure:
In the same manner as above, 2-[2-(pentadecyloxy)ethoxy]ethyl 2-bromoethyl phosphate is reacted with pyridine to give the title compound.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:4]#[N:5].[O:21]([CH2:28][CH2:29][NH2:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[O:21]([CH2:28][CH2:29][NH:30][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:4]#[N:5])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)c(C#N)c(Cl)n2)n[nH]1
Reactant: NCCOc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(C(F)(F)F)c(C#N)c(NCCOc3ccccc3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h

Procedure:
Compound F (300 mg, 1.00 mmol), 2-phenoxyethylamine (261 μl) and sodium hydrogencarbonate (837 mg) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction system was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-phenoxyethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-trifluoromethylnicotinonitrile (80 mg).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5](Br)=[O:6].[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14]>CCCCCCC>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:6]
Reactant: Cc1cccc(CBr)c1C(=O)Br
Reactant: CC(C)(C)O
Solvent: CCCCCCC
Product: Cc1cccc(CBr)c1C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 1 h

Procedure:
20 g (24 mmol) of 2-bromomethyl-6-methylbenzoyl bromide solution (35% solution in heptane) are added to a mixture of 15 ml of n-heptane and 25 ml of tert-butanol. After stirring at 40° C. for one hour, 400 ml of n-heptane are added. The solution is washed successively with 60 ml of sat. sodium hydrogencarbonate solution and washed four times with 20 ml each time of water. Subsequently, the solvent is removed fully under reduced pressure. When the conversion is quantitative, tert-butyl 2-bromomethyl-6-methylbenzoate is obtained as a virtually colorless oil having 93% purity and having a molecular weight of 284.04 (C13H17BrO2); MS (ESI): 302.1 [M+NH4]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH3:50])[C:11](=[O:49])[CH2:12][N:13]([C:36]2[CH:41]=[C:40]([C:42]3[N:46]=[C:45]([CH3:47])[O:44][N:43]=3)[CH:39]=[CH:38][C:37]=2[CH3:48])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([CH:33]([CH3:35])[CH3:34])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)=[O:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1(S)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.ClCCl>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([CH3:50])[C:11](=[O:49])[CH2:12][N:13]([C:36]2[CH:41]=[C:40]([C:42]3[N:46]=[C:45]([CH3:47])[O:44][N:43]=3)[CH:39]=[CH:38][C:37]=2[CH3:48])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][NH:20][CH:33]([CH3:35])[CH3:34])=[O:16])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(C)C(=O)CN(CC(=O)NCCN(C(C)C)S(=O)(=O)c2ccccc2[N+](=O)[O-])c2cc(-c3noc(C)n3)ccc2C)CC1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)N1CCC(N(C)C(=O)CN(CC(=O)NCCNC(C)C)c2cc(-c3noc(C)n3)ccc2C)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 83.6 %

Procedure:
The compound (260 mg, 0.365 mmol) obtained in step D was dissolved in acetonitrile (3 ml). Then, benzenethiol (0.057 ml, 0.547 mmol) and cesium carbonate (594 mg, 1.82 mmol) were added, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with dichloromethane, and the organic layer was washed with diluted aqueous sodium hydroxide solution, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (NH silica gel use, methanol-dichloromethane) to give the title compound (161 mg, yield 84%) as a pale-yellow amorphous solid. This was directly used for the next step.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].C(Cl)(=O)C([Cl:14])=O>C(#N)C.CN(C=O)C>[ClH:14].[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7]([Cl:1])=[O:8]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN(C)C/C=C/C(=O)Cl
Temperature: 60 °C

Procedure:
To (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (110 mg, 0.664 mmol) in acetonitrile (1.5 mL) was added oxalyl dichloride (75.9 mg, 0.598 mmol) followed by one drop of DMF. After heating to 60° C. for 30 minutes, the mixture was cooled to room temperature and concentrated to 0.5 mL total volume. The resulting solution was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]([C:13]2[N:14]=[N:15][S:16][C:17]=2[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])SC)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:30][OH:31]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[N:14]=[N:15][S:16][C:17]=2[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[N:30][OH:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NO
Reactant: CSC(=Nc1ccc(F)c(Cl)c1)c1nnsc1CO[Si](C(C)C)(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)[Si](OCc1snnc1C(=NO)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Methyl N-(3-chloro-4-fluorophenyl)-5-[(triisopropylsilyl)oxy]methyl-1,2,3-thiadiazole-4-carbimidothioate (90 mg, 0.0002 mol) was dissolved in EtOH (2 mL) followed by addition of hydroxylamine (116 μL, 0.00190 mol) (50% by wt, 99.9% in water solution). The reaction was stirred at 60° C. for 4 h and overnight at room temperature. The reaction was evaporated and purified by flash chromatography to give the desired product (85 mg, 98%). 1H NMR (400 MHz, CDCl3): δ 7.32 (s, 1H), 7.25 (s, 1H), 6.90 (m, 2H), 6.62 (m, 2H), 5.17 (s, 2H), 1.05 (m, 21H). MF=C19H28ClFN4O2SSi; LCMS calculated for C19H29ClFN4O2SSi (M+H)+: m/z=459.2.
Reaction SMILES: [NH2:1][CH:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH2:20][OH:21])[N:19]=[C:15]4[N:14]=[C:13]([CH3:22])[CH:12]=3)[CH2:7][S:8][C@H:3]12.[OH-].[Na+].[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36](Cl)=[O:37]>O.CCOCC>[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36]([NH:1][CH:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH2:20][OH:21])[N:19]=[C:15]4[N:14]=[C:13]([CH3:22])[CH:12]=3)[CH2:7][S:8][C@H:3]12)=[O:37]
Reactant: O=C(Cl)Cc1cccs1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n2nc(CO)nc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)n2nc(CO)nc2n1
Yield: 80.2 %

Procedure:
In 100 ml of water was suspended 4.6 g of 7-amino-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylic acid obtained in Example 2, and a 2N aqueous sodium hydroxide solution was added to the suspension and the mixture was dissolved at a pH 7. To this solution was while stirring under ice-cooling added dropwise a solution of 1.93 g of 2-thienyl acetyl chloride in 20 ml of ether over one hour. During this time, a pH of the mixture was maintained to 7 to 7.5 by addition of a 2N aqueous sodium hydroxide. After stirring for further one hour, the reaction mixture was washed with ethyl acetate. The reaction mixture was adjusted to pH 2.5 with a 2N hydrochloric acid under ice-cooling and stirring, and precipitated crystals were collected by filtration, washed with water and dried to obtain 4.81 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[C:5]([CH3:12])=[C:4]([CH:13]2[CH2:15][O:14]2)[CH:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[N:16]1([CH2:15][CH:13]([C:4]2[CH:3]=[C:2]([F:1])[C:7]3[C:8](=[O:11])[O:9][CH2:10][C:6]=3[C:5]=2[CH3:12])[OH:14])[CH2:21][CH2:20][N:19]([CH2:15][CH:13]([C:4]2[CH:3]=[C:2]([F:1])[C:7]3[C:8](=[O:11])[O:9][CH2:10][C:6]=3[C:5]=2[CH3:12])[OH:14])[CH2:18][CH2:17]1
Reactant: Cc1c(C2CO2)cc(F)c2c1COC2=O
Reactant: C1CNCCN1
Product: Cc1c(C(O)CN2CCN(CC(O)c3cc(F)c4c(c3C)COC4=O)CC2)cc(F)c2c1COC2=O

Procedure:
5,5′-[piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl)]bis(7-fluoro-4-methyl-2-benzofuran-1(3H)-one) was prepared in a similar fashion to that described for the synthesis of EXAMPLE 2 starting from 7-Fluoro-4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one and piperazine.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C([O:12][C:13]([CH:15]=[C:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=O)C.CO>C1(C)C=CC=CC=1>[OH:12][CH2:13][CH:15]=[C:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)C=C1CCNCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: OCC=C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
A solution of 15 ml of DIBAL (1.5 M solution in toluene) in 20 ml of toluene is added dropwise with 0.976 g of 4-(ethoxycarbonylmethylidene)piperidine, dissolved in few milliliter of toluene. The reaction mixture is stirred at room temperature for 2 hours, then it is cooled to 0-5° C. and added dropwise with methanol, until the gaz development is seen. The mixture is concentrated to a little volume and diethyl ether is added: a white solid separates, which is filtered off. The organic phase is concentrated to dryness, redissolved in diethyl ether and again filtered. The clear solution is concentrated to dryness to give 500 mg of the product.
Reaction SMILES: [OH-].[K+].[C:3]([NH:13][C@@H:14]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:15]([OH:18])[CH2:16]Cl)([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]>C(O)C>[CH2:6]([O:5][C:3]([NH:13][C@@H:14]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:15]1[O:18][CH2:16]1)=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1

Procedure:
To a solution of 1.2 equiv. of potassium hydroxide in 968 mL of absolute ethanol at room temperature, is added 0.097 mol of N-CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol. After stirring for fifteen minutes, the solvent is removed under reduced pressure and the solids are dissolved in methylene chloride. After washing with water, drying over magnesium sulfate, filtering and stripping, one obtains a white solid. Recrystallization from hot ethyl acetate and hexane will afford N-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:32][C@@H:33]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=1)[O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([C:29]([OH:31])=O)=[CH:22][N:23]3[CH:26]([CH3:28])[CH3:27])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:60][S:61]([NH2:64])(=[O:63])=[O:62].C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O>[Cl:47][C:43]1[CH:42]=[C:41]([C@@H:33]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH2:32][N:8]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]([C:29]([NH:64][S:61]([CH3:60])(=[O:63])=[O:62])=[O:31])=[CH:22][N:23]4[CH:26]([CH3:28])[CH3:27])=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)n1cc(C(=O)O)c2ccc(-c3ccc(CCN(C[C@H](OC4CCCCO4)c4cccc(Cl)c4)C(=O)OC(C)(C)C)cc3)cc21
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)NS(C)(=O)=O)c2ccc(-c3ccc(CCN(C[C@H](OC4CCCCO4)c4cccc(Cl)c4)C(=O)OC(C)(C)C)cc3)cc21
Reaction time: 2.5 h
Yield: 91.6 %

Procedure:
To a solution of 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-amino]ethyl]phenyl]-1-isopropyl-1H-indole-3-carboxylic acid (131 mg) in N,N-dimethylformamide (2 mL) was added 1,1′-carbonyldiimidazole (35 mg) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 2.5 hours. To this one were added methanesulfonamide (46 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (72 mg) at room temperature, and the mixture was stirred at 60° C. for 10 hours. The resulting mixture was poured into 0.1N hydrochloric acid and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with 0.1N hydrochloric acid three times and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol=200/1 to 100/1) to give tert-butyl [(2R)-2-(3-chlorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)ethyl][2-[4-[1-isopropyl-3-[[(methylsulfonyl)amino]-carbonyl]-1H-indol-6-yl]phenyl]ethyl]carbamate (134 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:42]([OH:44])=O)=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[C:6]=1[CH3:7].[CH2:45]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([I:56])=[CH:52][CH:51]=1)[CH2:46][CH2:47][CH3:48]>>[CH2:45]([N:49]([C:50]1[CH:51]=[CH:52][C:53]([I:56])=[CH:54][CH:55]=1)[C:42]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[N:4]=1)=[O:44])[CH2:46][CH2:47][CH3:48]
Reactant: CCCCNc1ccc(I)cc1
Reactant: Cc1c(Cl)c(C(=O)O)nn1-c1ccc(C(=O)NS(=O)(=O)c2ccc3ccccc3c2)cc1C(=O)N1CCc2ccccc2C1
Product: CCCCN(C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl)c1ccc(I)cc1
Yield: 4.4 %

Procedure:
Following a procedure analogous to that for the synthesis Intermediate 122G, 4-chloro-5-methyl-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxylic acid (Intermediate 122F, 116 mg, 0.18 mmol) and N-butyl-4-iodoaniline (Okano, K. et al., Org. Lett., 5:4987-4990 (2003)) (59 mg, 0.22 mmol) were converted to the title compound (7 mg, 41%). 1H NMR (MeOD, 1:1 mixture of amide rotamers) δ 8.65 (s, 1H), 8.15-8.07 (m, 1.5H), 8.05-8.00 (m, 3.5H), 7.95 (d, J=8.0 Hz, 1H), 7.69-7.54 (m, 3H), 7.45-7.31 (m, 2H), 7.20-7.17 (m, 4H), 7.03-7.00 (m, 0.5H), 6.97-6.96 (m, 0.5H), 6.70 (d, J=8.6 Hz, 1H), 6.43 (br s, 1H), 4.93 (br s, 0.5H), 4.68 (br s, 0.5H), 4.48 (br s, 0.5H), 4.35 (br s, 0.5H), 3.83 (br s, 1H), 3.71 (br s, 1H), 3.61-3.45 (m, 2H), 3.11-3.01 (m, 1H), 2.92-2.78 (m, 1H), 2.16 (s, 3H), 1.41-1.22 (m, 4H), 0.91-0.80 (m, 3H); MS(ESI+) m/z 886.8 (M+H)+.