Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH:10]([NH2:30])[C:11]2[N:16]([CH3:17])[C:15]([C:18](O)=[O:19])=[C:14]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:29])[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:31][NH:32][C:18]([C:15]1[N:16]([CH3:17])[C:11]([CH:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[NH2:30])=[CH:12][C:13](=[O:29])[C:14]=1[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:19]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a stirred solution of 6-(benzene sulfonyl amino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01) (400.0 mg, 0.935 mmol) in dimethylformamide (10 mL) were added HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (426.17 mg, 1.12 mmol) and diisopropylethylamine (1.08 mL, 6.54 mmol). The mixture was stirred for 30 min., thenmethylamine hydrochloride salt (189.31 mg, 2.80 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was quenched with ice cold water and the reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. It was then purified using normal column chromatography to get 6-(benzene sulfonyl amino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methyl amide (15-01) (180.0 mg, 43.62%) as a white solid.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([CH2:9][C:10]([NH2:12])=[O:11])#[N:8].[CH3:13][C:14](=O)/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH3:19]>CS(C)=O>[CH3:13][C:14]1[NH:12][C:10](=[O:11])[C:9]([C:7]#[N:8])=[C:16]([CH2:17][CH2:18][CH3:19])[CH:15]=1
Reactant: N#CCC(N)=O
Reactant: CCC/C=C/C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCc1cc(C)[nH]c(=O)c1C#N
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
To a stirred solution of t-BuOK (20.0 g, 179 mmol) and cyanoacetamide (16.5 g, 196 mmol) in DMSO (300 mL) was added (3E)-3-hepten-2-one (20.0 g, 178 mmol). The reaction mixture was stirred at 23° C. for 30 minutes and then additional t-BuOK (60.0 g, 712 mmol) was added to the reaction mixture. The reaction mixture was placed under oxygen atmosphere and stirred for 16 h. The reaction mixture was then purged with argon and was cooled to 0° C. The mixture was diluted with aq. HCl and the resulting precipitate was collected. The solid was washed with water and dried to give 6-methyl-2-oxo-4-propyl-1,2-dihydropyridine-3-carbonitrile (15.0 g, 47% yield).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]O)=[CH:8][C:7](=[O:27])[CH2:6][CH2:5]1.C(Cl)(Cl)(Cl)[Cl:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Cl:29][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:11]1[CH2:10][C:9]2[C@H:4]([CH2:5][CH2:6][C:7](=[O:27])[CH:8]=2)[C@@H:3]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][C@@H:2]2[F:1])([CH3:18])[C:16](=[O:20])[CH2:15][CH2:14]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O

Procedure:
A solution of 78.7 g of 11β-fluoro-7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione (Example 12e) in 1.41 of carbon tetrachloride and 475 ml of acetonitrile is stirred with 71 g of triphenylphosphine for 8.5 hours at room temperature. Then, it is extracted with water, aqueous sodium bicarbonate and common salt solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 48.0 g of 7α-(5-chloropentyl)-11β-fluoro-estr-4-ene-3,17-dione is obtained as crystals with a melting point of 51°-53° C. [α]D22 =+78.5°(c=0.5% in chloroform).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[C:5]([CH3:8])([CH3:7])[CH3:6].[S-:10][C:11]#[N:12].[K+]>O>[C:5]([C:4]1[N:12]=[C:11]([SH:10])[NH:2][CH:3]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)C(=O)CN
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1c[nH]c(S)n1

Procedure:
35.2 g. 1-Amino-3,3-dimethylbutan-2-one hydrochloride and 30 g. potassium thiocyanate in 50 ml. water was warmed on the steam bath for 2 hours. After cooling, the solid formed was collected, washed with water, dried and recrystallised from industrial methylated spirit to give 4-tert.butylimidazole-2-thiol, melting point 232° - 234° C. A solution/suspension of this in industrial methylated spirit was added to a solution of 4.5 g. sodium hydroxide in 100 ml. water. 17.6 g. Ethyl iodide was added forming a lower layer and the mixture was shaken for two minutes whilst the ethyl iodide reacted and dispersed. After 20 minutes the alkali was neutralised by passing in carbon dioxide and the methylated spirit removed by evaporation. The solid was collected, washed with water, dried and on recrystallisation from toluene gave 2-ethylthio-4-tert.butylimidazole, melting point 116.5° - 120° C.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(Cl)Cl>[C:1]1([C:7]#[C:8][C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([C:8]#[C:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[C:1]([C:7]#[C:8][C:11]4[CH:10]=[CH:9][CH:14]=[CH:13][CH:12]=4)[CH:2]=3)[CH:14]=[CH:13][C:12]=2[C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: CCCCCC
Solvent: ClCCl
Product: C(#Cc1ccc(-c2ccc(C#Cc3ccccc3)c(C#Cc3ccccc3)c2)cc1C#Cc1ccccc1)c1ccccc1
Temperature: 85 °C

Procedure:
Analysis of the crude reaction mixture by LC at this point indicated a significant amount of unreacted starting material and products of intermediate conversion. An additional 10 g of phenylacetylene and 1 g of catalyst were added and the reaction mixture was heated at 85° C. for one hour. At this time, the LC indicated conversion was complete. The cooled reaction mixture was diluted with 500 mL of CH2Cl2 and washed with three 1-L portions of 10 percent HCl. The CH2Cl2 solution was isolated and evaporated to provide a crude solid product which was suspended in hexane. The solid was collected by filtration and purified by washing excessively with hot CCL4. This wash removed discoloration and many of the by-products, but it was not sufficiently effective at removing the residual Pd (II) catalyst from the monomer. The monomer was further purified by chromatography over neutral alumina using tetrahydrofuran as an eluent. The resulting monomer was isolated (32.0 g, 58 percent yield) as a light yellow solid with an m.p. of 172° C. to 174° C. with properties:
Reaction SMILES: [I-:1].[Na+].Br[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6]>CC(C)=O>[I:1][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(CBr)OCc1ccc([N+](=O)[O-])cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CI)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2.25 h
Yield: 89.6 %

Procedure:
Sodium iodide (3.5 g) was slowly added to a stirred solution of 4-nitrobenzyl bromoacetate (5.0 g) in acetone (50 ml) at room temperature over 5 minutes, and the solution was stirred at the same temperature for 2.25 hours. The resultant mixture was evaporated in vacuo, and the residue was dissolved in a mixture of ethyl acetate (40 ml) and water (15 ml). The organic layer was separated, washed with a saturated aqueous solution of sodium chloride and an aqueous solution of sodium thiosulfate in turn, and then dried over anhydrous magnesium sulfate. After the solution was evaporated in vacuo, the residue was allowed to stand in a refrigerator overnight, and triturated with methanol (10 ml) to give crystals (5.25 g) of 4-nitrobenzyl iodoacetate, mp 62.5° to 63.5° C.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([C:7]2[N:8]=[CH:9][C:10]([NH:13][C:14](=[O:38])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[C:31]([F:32])=[CH:30][CH:29]=[C:28]([O:33][CH2:34][CH3:35])[C:27]=4[F:36])=[CH:22][C:21]3=[O:37])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:11][CH:12]=2)[CH2:4][O:3]1.Cl>O1CCCC1.C(OCC)(=O)C>[OH:6][C@@H:5]([C:7]1[N:8]=[CH:9][C:10]([NH:13][C:14](=[O:38])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[C:31]([F:32])=[CH:30][CH:29]=[C:28]([O:33][CH2:34][CH3:35])[C:27]=3[F:36])=[CH:22][C:21]2=[O:37])[CH2:16][CH:17]([CH3:18])[CH3:19])=[N:11][CH:12]=1)[CH2:4][OH:3]
Reactant: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3cnc([C@H]4COC(C)(C)O4)cn3)C2)c1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3cnc([C@H](O)CO)cn3)C2)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.1 %

Procedure:
A solution of (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-amide (prepared in Example 152, 0.251 g, 0.46 mmol) in tetrahydrofuran (25 mL) was treated with 1N aqueous hydrochloric acid (10 mL). The reaction mixture was stirred for 20 h at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 10% to 100% (9:1 dichloromethane:methanol)/hexanes) to afford (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-amide (0.210 g, 90%) as a fluffy white solid: HR-ES-MS m/z calculated for C24H28F2N4O6, [M+H]+ 507.2050 observed 507.2051; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.9 Hz, 3H), 0.95 (d, J=6.9 Hz, 3H), 1.35 (t, J=6.9 Hz, 3H), 1.40-1.56 (m, 1H), 1.56-1.73 (m, 1H), 1.75-1.93 (m, 1H), 3.42-3.62 (m, 1H), 3.61-3.74 (m, 1H), 4.13 (q, J=6.9 Hz, 2H), 4.31 (d, J=18.7 Hz, 1H), 4.51-4.69 (m, 2H), 4.73 (t, J=5.7 Hz, 1H). 5.02 (dd, J=10.6, 4.2 Hz, 1H), 5.08 (s, 1H), 5.55 (d, J=5.1 Hz, 1H), 7.12-7.23 (m, 1H), 7.23-7.33 (m, 1H), 8.45 (s, 1H), 9.17 (s, 1H), 11.16 (s, 1H).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:13]=[CH:12][N:11]=1)=O)(C)(C)C.[C:26](O)(C(F)(F)F)=O.C=O>C(Cl)Cl.O>[CH3:26][N:8]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)[CH:13]=[CH:12][N:11]=1)[CH3:6]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1ccc(-c2ccnc(CNC(=O)OC(C)(C)C)c2)cc1
Agent: C=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(-c2ccnc(CN(C)C)c2)cc1
Reaction time: 1.5 h

Procedure:
To a solution of Methyl 4-(2-[t-butyloxycarbonylamino-methyl]-pyridin-4-yl)-benzoate (reference example 56) (520 mg, 1.5 mmol) in CH2Cl2 (5 mL) is added TFA (1.5 mL) and 2 drops of water (approx. 100 mL). The resulting solution is stirred for 90 minutes, then concentrated under reduced pressure. The residue is dissolved in THF (4 mL) then NaBH4 added (222 mg, 6 mmol) followed by paraformaldehyde (360 mg, 12 mmol). To this mixture is added TFA (4 mL) dropwise. The resulting mixture is stirred for 6 hours then concentrated. The residue is brought to pH 8 with aqueous NaOH (1M) and sat NaHCO3. The mixture is then extracted with ethyl acetate then ethyl acetate methanol (9/1). The combined organic extracts are washed with brine dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 10% methanol in CH2Cl2) to give 329 mg of the title compound. 1H NMR (CD3OD) δ 3.00 (s, 6H), 3.94 (s, 3H), 4.56 (s, 2H), 7.74 (d, J=5 Hz, 1H), 7.83 (s, 1H), 7.88 (d, J=8 Hz, 2H), 8.17 (d, J=8 Hz, 2H), 8.76 (d, J=5 Hz, 1H). MS (ion spray) m/z 271 (M+H).
Reaction SMILES: CN(C)[CH2:3][CH2:4][NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1.[CH3:19][O:20]CCN>>[CH3:19][O:20][CH2:3][CH2:4][NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CN(C)CCNc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: COCCN
Product: COCCNc1nc2ccc([N+](=O)[O-])cc2s1

Procedure:
The title compound was prepared following the procedure for N,N-dimethyl-N′-(6-nitrobenzothiazol-2-yl)-ethane-1,2-diamine, using 6.78 eq of 2-methoxyethylamine. 1H NMR (400 MHz, CDCl3): δ=3.42 (s, 3H), 3.65 (td, J=4.4, 0.8 Hz, 2H), 3.70 (t, br, J=4.4 Hz, 2H), 5.92 (s, br, —NH), 7.53 (d, J=8.8 Hz, 1H), 8.21 (dd, J=9.2, 2.4 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H). MS (ES+): m/z 254.10 (100) [MH+]. HPLC: tR=2.89 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:18]1[C:26]2[O:25][CH2:24][C:23](=[O:27])[C:22]=2[CH:21]=[CH:20][C:19]=1[O:28][CH3:29]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:29][O:28][C:19]1[CH:20]=[CH:21][C:22]2[C:23](=[O:27])[CH2:24][O:25][C:26]=2[C:18]=1[C:3]#[C:2][CH2:1][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc2c(c1I)OCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1C#CCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 61.2 %

Procedure:
A solution of tert-butyl 4-(prop-2-ynyl)piperazine-1-carboxylate (0.449 g, 2.00 mmol) in triethylamine (12 mL) was added with 7-iodo-6-methoxybenzofuran-3(2H)-one (0.580 g, 2.00 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.141 g, 0.200 mmol) and copper(I) iodide (0.0381 g, 0.200 mmol), and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was concentrated, then the solid was suspended in a mixed solvent of 50% ethyl acetate in hexane, and the suspension was filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)prop-2-ynyl]piperazine-1-carboxylate (0.473 g, 61%).
Reaction SMILES: C[N:2]([CH3:20])/[CH:3]=[C:4](/[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:12]=1[F:18])\[C:5]([O:7][CH2:8][CH3:9])=[O:6].NC[CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C(O)C.C(OCC)C>[F:18][C:12]1[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:11]=1[C:10]([C:4](=[CH:3][NH:2][CH2:20][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:19]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Reactant: NCCN1CCOCC1
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=CNCCN1CCOCC1)C(=O)c1cc(I)ccc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
A suspension of ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate (WO2006/010733, 294 mg, 0.75 mmol) in ethanol (2.500 mL) and diethyl ether (5 mL) was cooled 0° C. and 4-(2-aminoethyl)morpholine (103 mg, 0.79 mmol) was added dropwise. The reaction mixture was stirred for 3 h, then concentrated under reduced pressure to give the desired product (358 mg). MS (ESP): 477 (M+H+) for C18H22FIN2O4.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:32]/[OH:33])/[C:8]([NH:10][CH:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([O-:29])=[S:28])=[C:15]([CH2:18][CH:19]4[CH2:24][CH2:23][O:22][C:21]([CH3:26])([CH3:25])[O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:32]/[OH:33])/[C:8]([NH:10][CH:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([O:29][CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[S:28])=[C:15]([CH2:18][CH:19]4[CH2:24][CH2:23][O:22][C:21]([CH3:26])([CH3:25])[O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC1(C)OCCC(CC2=C(C([O-])=S)N3C(=O)C(NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)O1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Product: CC1(C)OCCC(CC2=C(C(=S)OCOC(=O)C(C)(C)C)N3C(=O)C(NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)O1
Yield: 59.7 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(2,2-dimethyl-1,3-dioxan-4-yl)methylthio-3-cephem-4-carboxylate (60 mg) was reacted with iodomethyl pivalate (40 mg),followed by purifying the reaction product in accordance with the procedure of Example 4, yielding the titled compound (42 mg; 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[CH:24])[CH2:18][C@@H:17]1[C:25]([O:27][CH3:28])=[O:26].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1I.C(N(CC)CC)C>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[C:24][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[F:29])[CH2:18][C@@H:17]1[C:25]([O:27][CH3:28])=[O:26]
Reactant: Fc1ccccc1I
Reactant: C#CCN1CC[C@@H](CCCc2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@H]1CN(CC#Cc2ccccc2F)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 20 h

Procedure:
0.041 g of tetrakis(triphenylphosphine)palladium and 0.070 g of cuprous iodide were added, at a temperature in the region of 20° C. and under an inert atmosphere, to a stirred solution of 0.7 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylate in 14 cm3 of acetonitrile. 0.32 cm3 of 1-fluoro-2-iodobenzene and 0.51 cm3 of triethylamine were subsequently added. The mixture was stirred at a temperature in the region of 20° C. for 20 hours. The reaction mixture was filtered and the cake was washed with 3 times 10 cm3 of acetonitrile. The combined filtrates were taken up with stirring in a mixture of 100 cm3 of dichloromethane and 100 cm3 of water. The organic phase was separated by settling, washed with 3 times 50 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, and then, after filtration, concentrated under reduced pressure (2 kPa) at a temperature in the region of 35° C. The residue obtained was purified by chromatography under argon pressure (50 kPa) on a column of silica gel (particle size 40-63 μm; diameter 4 cm; height 14 cm), elution was carried out with ethyl acetate, and 2-cm3 fractions were collected. Fractions 33 to 160 were combined and then evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.56 g of methyl (3R,4R)-4-(3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2-fluorophenyl)prop-2-ynyl]piperidine-3-carboxylate was obtained in the form of an oil with a light brown color.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].FC(F)(F)C(O)=O>ClCCl>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Example 1013 (8.2 g, 28.5 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (30 mL) at about 0° C. The mixture was stirred at room temperature for about 4 h and was then concentrated under vacuum. The residue was basified with sodium carbonate and was extracted with dichloromethane. The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum to provide the desired product. 1H NMR (300 MHz, CDCL3): δ 2.80 (s, 3H), 3.00 (t, J=7.0 Hz, 4H), 3.21 (t, J=7.0 Hz, 4H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=1.Cl[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[NH:24][CH:23]=[CH:22][N:21]=2)=[CH:8][N:7]=[C:6]([CH2:5][NH:4][CH2:3][CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[N:11]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: O=[N+]([O-])c1ccc(NCCNCc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
Using the procedure described above in Example 139, reaction of (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methylamine and 2-chloro-5-nitropyridine were reacted to afford [4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methyl {2-[(5-nitro(2-pyridyl))amino]ethyl}amine (73174).
Reaction SMILES: [CH3:1][NH:2][CH3:3].ClCCl.Cl[S:8]([C:11]1[CH:26]=[CH:25][C:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]>O1CCCC1>[CH3:1][N:2]([CH3:3])[S:8]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[CH:25][CH:26]=1)(=[O:9])=[O:10]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of dimethylamine in tetrahydrofuran (2M, excess) was added 4-(4-chlorosulfonylbenzyl)-nitrobenzene dichloromethane hemisolvate (354 mg, 1 mmol) dissolved in tetrahydrofuran (5 mL). The mixture was stirred for 1 hour and extracted with a solution of diethyl ether and dilute potassium carbonate. The organic layer was separated and solvents evaporated. The residue was recrystallized from acetone/hexanes to give 4-(4-dimethylaminosulfonylbenzyl)-nitrobenzene (311 mg, 98%).
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[C:22]([S:24]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1[CH3:33])(C)(C)C>CCCCC.C(OCC)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:34])=[O:5])=[C:10]([C:16]#[C:17][C:18]2[CH:23]=[C:22]([S:24]([N:27]([CH2:29][CH:30]([CH3:31])[CH3:32])[CH3:28])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=2[CH3:33])[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: Cc1ccc(S(=O)(=O)N(C)CC(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)O
Yield: 77 %

Procedure:
Following the general method as outlined in Example 15, starting from tert-butyl{4-chloro-2-[(5-{[isobutyl(methyl)amino]sulfonyl}-2-methylphenyl)ethynyl]phenoxy}acetate (Intermediate 160), the title compound was obtained as a beige solid in 77% yield after tituration in pentane/diethyl ether.