Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[NH:2])=[CH:12][CH:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: N#Cc1ccccn1
Product: N=C(Nc1ccc(F)cc1)c1ccccn1

Procedure:
The title compound was prepared from 2-cyanopyridine (0.94 g, 9 mmol) and 4-fluoroaniline (1 g, 9 mmol) by following the procedure described in preparation 10 (1.1 g, yield 56.81%). 1H-NMR (CDCl3):δ 6.98-7.09 (m, 2H), 7.26 (s, 2H), 7.39-7.42 (d, 1H), 7.82-7.84 (m, 1H), 8.38-8.4 (d, 1H), 8.57-8.58 (s, 1H). MS m/z: 216.3 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[S:5][C:6]=1[C:7](=[O:16])[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15].[NH2:27][CH2:28][C:29]1([N:34]([CH3:36])[CH3:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([NH:27][CH2:28][C:29]3([N:34]([CH3:36])[CH3:35])[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:24])=[CH:25][CH:26]=2)[S:5][C:6]=1[C:7](=[O:16])[C:8]1[C:9]([F:15])=[CH:10][CH:11]=[CH:12][C:13]=1[F:14]
Reactant: CN(C)C1(CN)CCCC1
Reactant: Nc1nc(Nc2ccc(C(=O)O)cc2)sc1C(=O)c1c(F)cccc1F
Product: CN(C)C1(CNC(=O)c2ccc(Nc3nc(N)c(C(=O)c4c(F)cccc4F)s3)cc2)CCCC1
Yield: 62 %

Procedure:
The title compound was prepared in a manner similar to Step 3 in Method A; from coupling 4-[4-amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid (3) and 1-(aminomethyl)-N,N-dimethylcyclopentanamine (Yang et al., Eur. J. Med. Chem. 31, 231-239 (1996)) to afford a yellow amorphous powder in 62% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][CH2:14][C:15]([NH2:17])=[O:16])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[CH2:19][C:20]([NH2:22])=[O:21]>CN(C)C=O>[C:15]([CH2:14][N:13]([S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:11])[CH2:19][C:20]([NH2:22])=[O:21])(=[O:16])[NH2:17]
Reactant: NC(=O)CCl
Reactant: NC(=O)CNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: NC(=O)CN(CC(N)=O)S(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
reacting 2-(3-Nitro-benzenesulfonylamino)-acetamide with ClCH2CONH2 in the presence of N,N-Dimethylformamide and a base to provide 2-[Carbamoylmethyl-(3-nitro-benzenesulfonyl)-amino]acetamide;
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].Cl[C:6]1[C:7]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=[CH:14][C:8]=2[S:9][C:10]=1[C:11]([NH2:13])=[O:12].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.O>CN(C=O)C>[CH3:1][CH:2]([S:4][C:6]1[C:7]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=[CH:14][C:8]=2[S:9][C:10]=1[C:11]([NH2:13])=[O:12])[CH3:3]
Reactant: NC(=O)c1sc2ccc(OCc3ccccc3)cc2c1Cl
Reactant: CC(C)S
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Sc1c(C(N)=O)sc2ccc(OCc3ccccc3)cc12
Temperature: 55 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
2-Propanethiol (0.8 mL, 8 mmol) is added to a solution of 3-chloro-5-(phenylmethoxy)benzo[b]thiophene-2-carboxamide (1.0 g, 3 mmol) and diazabicycloundecene (DBU) (2.6 mL, 17 mmol) in 10 mL of DMF and the mixture is warmed to 55° C. for 1 hour. The reaction mixture is allowed to cool and then poured into water and stirred. After 1 hour, the precipitate is filtered off, washed with water, and dried to provide 3-[(1-methylethyl)thio]-5-(phenylmethoxy)benzo[b]thiophene-2-carboxamide in 98% yield; mp=150°-152° C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH2:19][Cl:20])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:21])=[N+]=[N-].Cl>CO.[Pd].C(O)C>[ClH:20].[NH2:1][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH2:19][Cl:20])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:21]
Reactant: [N-]=[N+]=NC[C@H]1O[C@@H](n2cc(CCCl)c(=O)[nH]c2=O)C[C@@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: NC[C@H]1O[C@@H](n2cc(CCCl)c(=O)[nH]c2=O)C[C@@H]1O
Reaction time: 2 h
Yield: 157.3 %

Procedure:
0.16 g of 5'-azido-2',5'-dideoxy-5-(2-chloroethyl)uridine was dissolved in 100 ml of methanol and 1.9 ml of a 0.27M solution of hydrogen chloride in methanol was added. A slurry of 25 mg of 5% palladium-on-charcoal catalyst in 10 ml of ethanol was added under a nitrogen atmosphere and the mixture was hydrogenated at room temperature and under atmospheric pressure for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated to give a solid which, after crystallization from a mixture of 15 ml of methanol and 30 ml of diethyl ether, gave 0.13 g of 5'-amino-5-(2-chloroethyl)-2',5'-dideoxyuridine hydrochloride of melting point 229°-230° C. (decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH2:22].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C.CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([NH:22][C@H:21]([C:20]([O:19][CH3:18])=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Temperature: 50 °C

Procedure:
A solution of 8.92 g. of Nα -benzyloxycarbonyl-D-alanine, 7.28 g. of leucine methyl ester hydrochloride and 5.4 g. of 1-hydroxybenztriazole in 100 ml. of dimethylformamide is cooled to -10° C. with stirring and is treated with 5.6 ml. of triethylamine. The mixture is stirred for ten minutes at -10° C. and is treated with 8.6 g. of dicyclohexylcarbodiimide. The reaction is then stirred at -10° C. for fifteen minutes, brought to 0° C. and stirred to 10° during two hours following which it is stirred overnight at 20° C. The mixture is warmed to 50° C. and stirred for two hours.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:7][N:6]1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])(=[O:10])=[O:9])=[O:4].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I-].[Na+]>>[CH3:1][O:2][C:3]([CH:5]1[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])(=[O:9])=[O:10])[C:28](=[O:29])[N:27]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:4]
Reactant: COC(=O)C1CN1S(=O)(=O)c1ccccc1C(F)(F)F
Reactant: O=C=Nc1ccccc1
Agent: [I-]
Agent: [Na+]
Product: COC(=O)C1CN(S(=O)(=O)c2ccccc2C(F)(F)F)C(=O)N1c1ccccc1

Procedure:
In analogy to example 1, (RS)-1-(2-trifluoromethyl-benzenesulfonyl)-aziridine-2-carboxylic acid methyl ester was reacted with phenylisocyanate and sodiumiodide to give (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C@@H:16]([CH3:19])[CH:17]=[O:18])[C:9](=[O:15])OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1.Br[C:21]([F:28])([F:27])C(OCC)=O.S([O-])(O)(=O)=O.[K+].C(N(C(C)C)CC)(C)C>O1CCCC1.[Zn].O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@H:16]([CH3:19])[C@H:17]([OH:18])[C:21]([F:28])([F:27])[C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C[C@@H](C=O)N(C(=O)OC(C)(C)C)c1cccc(Cl)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1[C@H](O)C(F)(F)C(=O)N1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
tert-Butyl (3-chlorophenyl)[(1S)-1-methyl-2-oxoethyl]carbamate (19.5 g) and ethyl bromodifluoroacetate (41.3 g) were dissolved in tetrahydrofuran (110 mL), and to a suspension of a zinc powder (13.6 g) in tetrahydrofuran (25 mL) was added dropwise the solution at room temperature. After heating under reflux for 1 hr, the mixture was cooled to room temperature, 1 mol/L aqueous potassium hydrogen sulfate solution (300 mL) was added, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→10%), the obtained oil was dissolved in 4 mol/L hydrogen chloride/ethyl acetate solution (100 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, tetrahydrofuran (275 mL) and diisopropylethylamine (21.3 mL, 119 mmol) were added, and the mixture was heated under reflux for 12 hr. The reaction solution was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=10→40%) to give the title compound as a yellow oil (yield: 3.76 g, 21%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH3:18])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>O>[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH3:18])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[C:27]([O:28][CH3:29])[CH:26]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Cn1cnc2cc(Br)cc(OCc3ccccc3)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cc(OCc3ccccc3)c3c(c2)ncn3C)cc1OC
Temperature: 110 °C

Procedure:
To a mixture 7-(benzyloxy)-5-bromo-1-methyl-1H-benzo[d]imidazole 2.51 (105 mg, 0.33 mmol), 3,4-dimethoxy phenyl boronic acid (72 mg, 0.39 mmol), Cs2CO3 (294 mg, 0.90 mmol) and PEPPSI″-IPr catalyst (10.2 mg, 0.015 mmol) was added DME and water (1:1, 3 mL) and the reaction was heated to 110° C. for 1 hr. The reaction mixture was concentrated and purified by flash chromatography (SiO2, 0% MeOH/EtOAc to 20% MeOHEtOAc/MeOH) to afford 7-(benzyloxy)-5-(3,4-dimethoxyphenyl)-1-methyl-1H-benzo[d]imidazole 2.52.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][C:6](=O)[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].CC(O)=O.[CH2:18]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:26]([N:25]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:6]1[CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]([CH2:1][CH3:2])[CH2:7]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1CC(=O)CC1CC
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1CC
Temperature: 0 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
A round bottom flask was charged with ethyl 2-ethyl-4-oxocyclopentanecarboxylate (95.9 g, 521 mmol) and DCE (1.8 L). The solution was cooled to about 0° C. and AcOH (45 mL, 780 mmol) and dibenzylamine (120 mL, 625 mmol) were added dropwise, resulting in the formation of a thick suspension. The reaction mixture was warmed to about 10° C. and additional DCE (500 mL) was added. Sodium triacetoxyborohydride (166 g, 781 mmol) was added portionwise and the reaction mixture was stirred at ambient temperature for about 20 h. The reaction mixture was slowly poured into stirred saturated aqueous NaHCO3 (1.5 L), followed by the portionwise addition of solid NaHCO3 (175 g). The mixture was stirred for about 2 h and the organic layer was separated, dried over anhydrous Na2SO4, and coned under reduced pressure. The crude yellow oil was purified by silica gel chromatography eluting with 0-20% EtOAc in heptane to yield ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (136.6 g, 72%) as a white solid: LC/MS (Table 1, Method a) Rt=3.26 min; MS m/z: 366 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:6]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[N:33]1([C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[NH:45][C:44](=[O:49])[CH:43]=[CH:42]3)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C(N(CC)CC)C.CN(C)C=O>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:36]2[CH2:37][CH2:38][N:33]([C:39]3[CH:40]=[C:41]4[C:46](=[CH:47][CH:48]=3)[NH:45][C:44](=[O:49])[CH:43]=[CH:42]4)[CH2:34][CH2:35]2)=[O:10])[N:6]=1
Reactant: O=c1ccc2cc(N3CCNCC3)ccc2[nH]1
Reactant: Cc1nc(CC(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(CC(=O)N2CCN(c3ccc4[nH]c(=O)ccc4c3)CC2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A mixture of 2-(2-methyl-4-thiazolyl)acetic acid (628 mg), 1-hydroxybenzotriazole (648 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (917 mg) and N,N-dimethylformamide (25 ml) was stirred for 1 hour at ambient temperature. 6-(1-Piperazinyl)-2(1H)-quinolinone (687 mg) and triethylamine (1 ml) were added thereto, and the mixture was stirred for 3 hours at the same temperature. After the reaction mixture was concentrated in vacuo, to the residue were added ethyl acetate (10 ml) and water (10 ml) and the mixture was stirred. The resulting oil was separated by decantation and dissolved in tetrahydrofuran. The solution was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to a column chromatography on silica gel (80 g) and eluted with 3% solution of methanol in chloroform. The fractions containing the desired compound were collected and concentrated to give a residue, which was crystallized from ethyl acetate-diethyl ether to give 6-[4-{2-(2-methyl- 4-thiazolyl)acetyl}-1-piperazinyl]-2(1H)-quinolinone (0.74 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][C:9]=1[F:15])(=[O:3])[CH3:2].[CH3:28][C:29]1[C:33](B(O)O)=[C:32]([CH3:37])[O:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:33]2[C:29]([CH3:28])=[N:30][O:31][C:32]=2[CH3:37])=[CH:10][C:9]=1[F:15])(=[O:3])[CH3:2]
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)cc1F
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2c(C)noc2C)cc1F
Yield: 59 %

Procedure:
By carrying out the operation analogously to example 3, starting from 4-bromo-2-fluorophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to preparation VI, and 3,5-dimethyl-4-isoxazoleboronic acid, the expected compound is obtained in the form of a white solid with a yield of 59%.
Reaction SMILES: [Na+].[CH3:2][O:3][N:4]=[C:5]([C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:11]2[C:12]([C:24]([O-:26])=[O:25])=[C:13]([CH:16]=[CH:17][C:18]3[S:22][CH:21]=[N:20][C:19]=3[CH3:23])[CH2:14][S:15][C@H:10]12)=[O:7].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].C(OCC)(=O)C>CN(C)C=O>[C:35]([O:41][CH2:42][O:25][C:24]([C:12]1[N:11]2[C:27](=[O:28])[CH:9]([NH:8][C:6](=[O:7])[C:5](=[N:4][O:3][CH3:2])[C:29]3[N:30]=[C:31]([NH2:34])[S:32][CH:33]=3)[C@H:10]2[S:15][CH2:14][C:13]=1[CH:16]=[CH:17][C:18]1[S:22][CH:21]=[N:20][C:19]=1[CH3:23])=[O:26])(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)C(=O)OCI
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=Cc3scnc3C)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(C=Cc3scnc3C)CS[C@H]12)c1csc(N)n1
Temperature: 0 °C

Procedure:
7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid sodium salt (syn-isomer, trans-isomer) (0.03 g, 0.06 mmol) was dissolved in dimethylformamide (3 ml). To the resultant solution was added a solution in dimethylformamide (1 ml) of iodomethyl pivalate (as prepared by reacting chloromethyl pivalate (0.090 g, 0.60 mmol) with sodium iodide (0.090 g, 0.06 mmol) in acetone) under ice-cooling, followed by stirring the resultant mixture for 10 minutes. The reaction solution as obtained were admixed with ice-water (20 ml) and ethyl acetate (20 ml), stirred thoroughly and then allowed to stand until the mixture separated into aqueous phase and organic phase. The organic phase was separated from the aqueous phase and washed twice with water (10 ml) and then with aqueous saturated NaCl solution (10 ml). The organic phase as washed was subsequently dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified chromatographically on a column of silica-gel (Wako-gel C-300) (5 g) as developed with ethyl acetate. The titled compound was thus obtained (yield 0.025 g, 67%).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:20])([F:19])[C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.[N+:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[C-:22]>C1COCC1>[F:8][C:9]([F:20])([F:19])[C:10]1[CH:18]=[CH:17][C:13]([C:14]2[O:15][CH:22]=[N:21][C:23]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ncoc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
Triethylamine (10.0 mL, 71.9 mmol) was added to a solution of 4-(trifluoromethyl)benzoyl chloride (5.0 g, 24.0 mmol) in THF (50 mL) at 0° C. Ethyl 2-isocyanoacetate (2.9 mL, 26.4 mmol) was added dropwise and the mixture was warmed to ambient temperature. After 3.5 days the reaction mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The separated aqueous phase was extracted with EtOAc, and the combined organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography on silica gel (Analogix® Intelliflash 280™; SF40-150 g column; 20% to 50% EtOAc/hexanes eluant, 30 min) yielded 4.30 g (63%) of the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.18 (d, J=8.2, 2H), 7.92 (d, J=8.3, 2H), 4.31 (q, J=7.1, 2H), 1.28 (t, J=7.0, 3H). MS (DCI+) m/z 286 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].CN1CCCC1=O.[CH2:21]([NH:24][CH2:25][CH:26]=[CH2:27])[CH:22]=[CH2:23].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:21]([N:24]([CH2:25][CH:26]=[CH2:27])[C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH:22]=[CH2:23]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: C=CCNCC=C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C=CCN(CC=C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 111 %

Procedure:
A mixture of 2,4-dinitrofluorobenzene (9.3 g), N-methylpyrrolidinone (NMP, 50 mL), diallylamine (5.82 g) and potassium carbonate (6.9 g) was stirred at ambient temperature for 1 h. The mixture was poured into water and extracted with ethyl ether. The extract was washed twice with water, once with saturated brine solution, and dried over magnesium sulfate. Concentration of the extract gave N,N-diallyl-2,4-dinitrobenzenamine as a yellow oil (14.6 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH3:22][O:23][CH2:24][CH2:25][NH2:26]>>[CH3:22][O:23][CH2:24][CH2:25][NH:26][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21]
Reactant: COCCN
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: COCCNc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 36 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (20 mg, 0.0628 mmol) is reacted with 2-methoxy-ethylamine according to the GPA affording 8.5 mg (36%) of a red powder. Rt=3.84 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>>[CH3:36][O:35][C:33]([C:32]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=3)=[O:11])=[CH:6][CH:7]=2)=[CH:28][C:27]=1[F:26])=[O:34]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Product: COC(=O)c1ccc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)cc1F

Procedure:
In analogy to example 74, step 6, from 3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and 3-fluoro-4-methoxycarbonylphenyl boronic acid was prepared the title compound as a yellow oil, MS (ESI+): m/z=468.1977 ([M+H]+).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[N:37]1([CH2:43][C:44]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[O:45])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[N:46]1([C:44](=[O:45])[CH2:43][N:37]2[CH2:38][CH2:39][N:40]([CH2:6][C:7]3[N:12]=[CH:11][C:10]4[N:13]=[CH:14][N:15]([C:16]5[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=6[C:30]([F:33])([F:31])[F:32])[CH3:23])[CH:20]=5)[C:9]=4[CH:8]=3)[CH2:41][CH2:42]2)[CH2:47][CH2:48][O:49][CH2:50][CH2:51]1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4CCN(CC(=O)N5CCOCC5)CC4)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 58, 108 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 213.3 mg of 4-(piperazin-1-ylacetyl)morpholine in 2.5 ml dichloromethane give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C

Procedure:
The mixture of (4-aminomethyl-benzyl)-carbamic acid tert-butyl ester (4.06 g, 17.2 mmol), 1,5-dibromo-pentane (2.60 mL, 19.1 mmol) and potassium carbonate (8.96 g, 65.1 mmol) in acetonitrile (160 mL) was refluxed overnight under N2. The reaction was cooled to r.t. and filtered. The filtrate was concentrated in vacuo and chomatographed on silica (CH2Cl2→CH2Cl2/MeOH with 2N NH3=25/1) to yield the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([O:16][C:17]1[CH:18]=[CH:19][C:20]([NH:21][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:22][CH:23]=1)[CH2:13][CH2:14][CH3:15]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CCCCOc1ccc(N)cc1
Product: CCCCOc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-butoxyaniline to yield 2-[(4-butoxyphenyl)amino]phenylacetic acid.