Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[CH3:42][NH:43][S:44]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(=[O:46])=[O:45].ClCCCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[CH:28][CH:27]=[C:23]([C:24](=[O:26])[N:43]([CH3:42])[S:44]([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)(=[O:46])=[O:45])[CH:22]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNS(=O)(=O)c1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)N(C)S(=O)(=O)c4ccccc4)c3)cc12
Yield: 55.3 %

Procedure:
In a 1 dram vial with stir bar were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (35 mg, 0.090 mmol), DMAP (33 mg, 0.27 mmol), EDC hydrochloride (26 mg, 0.14 mmol), and N-methylbenzenesulfonamide (50 μL, 0.26 mmol). 1,2-Dichloroethane (0.5 mL) and DMF (0.5 mL) were added, the vial was capped, and the reaction was stirred at r.t. overnight. The reaction was filtered, purified by prep HPLC, and concentrated on a speedvac to give 27 mg (55% yield) of the title compound as a white powder. 1H NMR (500 MHz, CDCl3) δ ppm 7.91-8.02 (m, 5H) 7.75-7.82 (m, 2H) 7.65 (t, J=7.48 Hz, 1H) 7.47-7.60 (m, 6H) 7.15-7.24 (m, 2H) 5.91 (d, J=4.27 Hz, 1H) 3.36 (s, 3H) 3.04 (d, J=4.88 Hz, 3H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, Solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.89 min, (ES+) m/z (MH+)=543. Analytical HPLC were performed using a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: solvent A=5% CH3OH/95% H2O/10 mM NH4HCO3, solvent B=95% CH3OH/5% H2O/10 mM NH4HCO3, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Phenomenex Gemini C18, 4.6 mm, 3 μam, Rt=17.42 min, purity=92%; column: Waters Xbridge Phenyl 4.6×150 mm, 3.5 μm, Rt=17.86 min, purity >90%.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]=[C:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1.O>C1C=CC=CC=1>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]([C:34]([CH:31]3[CH2:33][CH2:32]3)=[O:35])[C:8]([CH3:21])=[CH:7][C:6]=2[CH:22]=1
Reactant: COc1cc2c(cc1Br)CC(C)=NN=C2c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: COc1cc2c(cc1Br)C=C(C)N(C(=O)C1CC1)N=C2c1ccc([N+](=O)[O-])cc1

Procedure:
0.5 g of 7-bromo-1-(4-nitrophenyl)-4-methyl-8-methoxy-5H-2,3-benzodiazepine (Example 3, Step C) is suspended in 15 ml of benzene, mixed with 0.53 g of potassium carbonate and 0.17 ml of cyclopropylcarboxylic acid chloride and then refluxed for 5 hours. Then, the mixture is stirred with water, the organic phase is separated, washed in succession with soda solution and water, dried, filtered and concentrated by evaporation. The residue is purified by absorptive precipitation in ethanol, and 0.38 g of 7-bromo-3-cyclopropylcarbonyl-1-(4-nitrophenyl)-4-methyl-8-methoxy-3H-2,3-benzodiazepine of the title compound with a melting point of 231-223° C. is obtained.
Reaction SMILES: C1(C)C=CC=CC=1.Cl[CH2:9][CH2:10][CH:11]1[N:24]([CH3:25])[C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[C:14](=[O:26])[N:13]([CH3:27])[CH2:12]1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:31][CH:30]=1>C(N(CC)CC)C>[F:48][C:45]1[CH:46]=[CH:47][C:42]([CH:35]([C:32]2[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=2)[CH:36]2[CH2:41][CH2:40][N:39]([CH2:9][CH2:10][CH:11]3[N:24]([CH3:25])[C:16]4=[N:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[N:15]4[C:14](=[O:26])[N:13]([CH3:27])[CH2:12]3)[CH2:38][CH2:37]2)=[CH:43][CH:44]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: CN1CC(CCCl)N(C)c2nc3ccccc3n2C1=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1CC(CCN2CCC(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)N(C)c2nc3ccccc3n2C1=O
Reaction time: 24 h

Procedure:
To a solution of 50 mL of toluene containing 4.0 g (0.04 mol) of triethylamine was added 3.0 g (0.01 mol) of 2-(2-chloroethyl)-3,4-dihydro-1,4-dimethyl-1H-[1,3,5]triazepino[3,2-a]benzimidazol-5(2H)-one and 4.0 g (0.014 mol) of 4-[bis(4-fluorophenyl)methyl]piperidine. The mixture was heated to reflux for 3 days after which time 1.0 g (0.003 mL) of 4-[bis(4-fluorophenyl)methyl]piperidine and 1.0 g (0.01 mol) of triethylamine was added. Heating under reflux was continued for 24 hr. The solvent was removed by rotary evaporation and the residue dissolved in 100 mL of CH2Cl2. The organic phase was washed with 2×100 mL of 1N NaOH, dried over Na2SO4, filtered, and concentrated by rotary evaporation. The residue was subjected to preparative HPLC using silica gel as the stationary phase and eluting with ethanol. Combination of like fractions afforded 3.1 g (57%) of analytically pure material as a glass.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[S:13]1[CH:17]=[C:16]([S:18][C:19]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:20]=2[C:21](O)=[O:22])[C:15]2[CH:29]=[CH:30][CH:31]=[CH:32][C:14]1=2.CN.C(OCC)(=O)C>C1COCC1>[S:13]1[CH:17]=[C:16]([S:18][C:19]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:20]=2[C:21]([NH:3][CH3:1])=[O:22])[C:15]2[CH:29]=[CH:30][CH:31]=[CH:32][C:14]1=2
Reactant: Cc1ccc(Sc2csc3ccccc23)c(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C)ccc1Sc1csc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carbonyldiimidazole (324 mg, 2 mmol) is added to 2-(benzo[b]thiophen-3-ylsulfanyl)-5-methyl-benzoic acid (300 mg, 1 mmol) in mL dry THF and stirred for 2 hours at room temperature. 2.5 mL methyl amine (2M in THF, 5 mmol) is added and the reaction mixture is stirred for 16 hours at room temperature. Ethyl acetate is added and the organic phase is washed with 1 N HCl (aq) and brine, dried with MgSO4 and concentrated in vacuo to give the title compound, which is used in the next step without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]([S:17]([CH3:20])(=[O:19])=[O:18])([CH3:16])[CH3:15])[N:11]=[C:10]([C:21]2[S:25][C:24]([NH2:26])=[N:23][CH:22]=2)[N:9]=1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29].C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]([S:17]([CH3:20])(=[O:19])=[O:18])([CH3:15])[CH3:16])[N:11]=[C:10]([C:21]2[S:25][C:24]([NH:26][C:28](=[O:29])[O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:23][CH:22]=2)[N:9]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2cnc(N)s2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2cnc(NC(=O)Oc3ccccc3)s2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
A mixture of 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidin-2-yl]-1,3-thiazol-2-amine (1.05 g, 2.6 mmol), phenyl chloroformate (618 mg, 3.9 mmol) and sodium hydrogen carbonate (311 mg, 3.9 mmol) in dioxane (10 mL) was stirred at RT for 2 hours then diluted with ethyl acetate and washed with water (150 mL) and brine (100 mL). The organics were dried over magnesium sulphate and concentrated in vacuo. The residue was recrystallised from diethyl ether and hexane to give the desired product as a beige solid (1 g).
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].[C:17]([O:21][CH2:22][CH2:23]O)(=[O:20])[CH:18]=[CH2:19].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:17]([O:21][CH2:22][CH2:23][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)(=[O:20])[CH:18]=[CH2:19]
Reactant: C=CC(=O)OCCO
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: C=CC(=O)OCCC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Yield: 17.8 %

Procedure:
At room temperature, 500 mg of biotin (Compound i, product of Merck & Co., Inc.), 200 mg of 2-hydroxyethyl acrylate, 20 ml of thionyl chloride and 20 ml of toluene were mixed. The resulting mixture was refluxed for 2 hours. The solvent was then distilled off under reduced pressure. The residue was subjected to column chromatography by using a chloroform-methanol solvent mixture. By removal of the solvent, 100 mg of 2-biotinylethyl acrylate (Compound A) was obtained as a powdery substance (yield: 14%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:15]C1C=CC(S(O)(=O)=O)=CC=1>CO>[OH:1][C:2]1[CH:3]=[C:4]([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1(c2ccc(O)c(O)c2)CC1
Solvent: CO
Product: COC(=O)C1(c2ccc(O)c(O)c2)CC1
Temperature: 80 °C
Yield: 912.5 %

Procedure:
To a solution of 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid (190 mg, 1.0 mmol) in MeOH (3 mL) was added 4-methylbenzenesulfonic acid (19 mg, 0.10 mmol). The mixture was heated at 80° C. overnight. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc twice and the combined organic layers were washed with sat. NaHCO3 and brine and dried over MgSO4. After the removal of solvent, the residue was dried in vacuo to yield methyl 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylate (190 mg, 91%) that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 6.76-6.71 (m, 2H), 6.66 (d, J=7.9 Hz, 1H), 3.56 (s, 3H), 1.50 (q, J=3.6 Hz, 2H), 1.08 (q, J=3.6 Hz, 2H).
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1([CH3:14])[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[OH-:15].[Ca+2].[OH-]>O>[C:10]([NH:11][C@:7]([CH3:14])([C:8]([OH:15])=[O:13])[CH2:6][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:12])[NH2:9]
Reactant: CC(C)(C)SCC1(C)NC(=O)NC1=O
Reactant: [OH-]
Agent: [Ca+2]
Solvent: O
Product: CC(C)(C)SC[C@](C)(NC(N)=O)C(=O)O
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 25 %

Procedure:
First, 5-tert-butylthiomethyl-5-methylhydantoin (purity content 10.82 g, 50.0 mmol) was mixed with calcium hydroxide (3.70 g, 50.0 mmol), and water (60 g), and the mixture was heated to 100° C. and stirred for 3.5 hours. The HPLC analysis of the reaction solution showed the production of the title compound in a reaction yield of 25%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:21]([OH:24])(=[O:23])=[O:22])[C:5]([CH:8]=[CH:9][C:10]2[C:11]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1.[N:25]1[C:32]([Cl:33])=[N:31][C:29]([Cl:30])=[N:28][C:26]=1Cl.[OH-].[Na+:35]>CC(C)=O>[Cl:30][C:29]1[N:31]=[C:32]([Cl:33])[N:25]=[C:26]([NH:1][C:2]2[CH:3]=[C:4]([S:21]([O-:24])(=[O:23])=[O:22])[C:5]([CH:8]=[CH:9][C:10]3[C:11]([S:17]([O-:20])(=[O:19])=[O:18])=[CH:12][C:13]([NH:16][C:26]4[N:25]=[C:32]([Cl:33])[N:31]=[C:29]([Cl:30])[N:28]=4)=[CH:14][CH:15]=3)=[CH:6][CH:7]=2)[N:28]=1.[Na+:35].[Na+:35]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(C=Cc2ccc(N)cc2S(=O)(=O)O)c(S(=O)(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=S(=O)([O-])c1cc(Nc2nc(Cl)nc(Cl)n2)ccc1C=Cc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1S(=O)(=O)[O-]
Temperature: 0 °C

Procedure:
Disodium 4,4'-bis(4,6-dichloro-s-triazin-2-ylamino)-2,2'-stilbenedisulfonate was prepared by interaction of 500 pounds of 4,4'-diamino-2,2'-stilbenedisulfonic acid with a solution of 500 pounds of cyanuric chloride in 2100 pounds of acetone in an aqueous reaction medium at pH 7-8 prepared by mixing 3200 pounds of crushed ice and approximately 2100 pounds of 10 percent aqueous sodium hydroxide solution. The disodium 4,4'-bis(4,6-dichloro-s-triazin-2-ylamino)-2,2'-stilbenedisulfonate thus obtained was mixed with 270 pounds of disodium phosphate and interacted at 15°-50° C. with 625 pounds of aniline for thrity minutes and then the pH of the reaction mixture was adjusted to 6.7-6.8 by adding approximately 600 pounds of 10 percent aqueous sodium hydroxide solution during a period of one hour.
Reaction SMILES: [S:1]([CH2:11][N+:12]#[C-:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:14][S:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.[C-]#N.[Na+]>>[CH3:14][S:15][C:16]1[CH:23]=[CH:22][C:19]([C@@H:20]2[O:21][CH:13]=[N:12][C@@H:11]2[S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])=[CH:18][CH:17]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CSc1ccc(C=O)cc1
Agent: [C-]#N
Agent: [Na+]
Product: CSc1ccc([C@@H]2OC=N[C@@H]2S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
In a manner analogous to Preparation 1, tosylmethylisocyanide (0.23 g, 1.20 mmol), 4-(methylthio)benzaldehyde (0.19 g, 1.26 mmol), and NaCN (5.9 mg, 0.12 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 348.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([SH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].CI.[C:20]([O-])(O)=O.[Na+]>CO>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10][CH3:20])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: O=C([O-])O
Reactant: COC(=O)[C@@H]1C[C@@H](S)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: COC(=O)[C@@H]1C[C@@H](SC)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.9 %

Procedure:
To a solution of (2S,4R)-4-mercapto-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (9.5 g, 35.4 mmol) in MeOH (300 ml) were added methyl iodide (24 ml, 363.5 mmol) and NaHCO3 (3.4 g, 39.98 mmol). The reaction mixture was stirred for 12 h at 25° C. After complete consumption of the starting material, the solvent was removed under reduced pressure to get the crude material that was purified by column chromatography over silica gel (25-40% EtOAc/hexane) to obtain the title compound as white solid (6.9 g, 24.4 mmol; 69%). MS (ESI): m/z=276.4 [M+H]+.
Reaction SMILES: CN(C)C=O.[F:6][C:7](I)([F:9])[F:8].[CH2:11]([N:15]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH:25]=[O:26])[N:17]=[C:16]1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[C:12]#[C:13][CH3:14].[Cl-].[NH4+]>[Zn].C(OCC)(=O)C>[CH2:11]([N:15]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH:25]([OH:26])[C:7]([F:9])([F:8])[F:6])[N:17]=[C:16]1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:29][CH2:28]1)[C:12]#[C:13][CH3:14]
Reactant: FC(F)(F)I
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(O)C(F)(F)F)c1C(=O)OCC
Reaction time: 0.5 h
Yield: 7.1 %

Procedure:
0.065 g of zinc and a 2 ml N,N-dimethylformamide solution of 0.200 g of trifluoromethyl iodide were added to a 3 ml N,N-dimethylformamide solution of 0.155 g of t-butyl 4-[1-(2-butynyl)-5-ethoxycarbonyl-4-formyl-1H-imidazol-2-yl]piperazine-1-carboxylate under a nitrogen atmosphere, and the mixture was stirred under sonication for 30 minutes. 30 ml of ethyl acetate and 30 ml of a 5% ammonium chloride solution were added to the mixture. The organic layer was washed twice with 20 ml of water and then with 20 ml of a saturated sodium chloride solution, and dried over magnesium sulfate. The organic liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.013 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1:9).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O)([O-:14])=[O:13]>C(O)C>[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[N:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)([O-:14])=[O:13]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1C=Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
A mixture of 4-(trifluoromethyl)aniline (5 g) and 2-nitrobenzaldehyde (5.2 g) in anhydrous ethanol was heated to reflux for 3 h; the reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The residue was washed with diethyl ether and petro-ether to give N-(2-nitrobenzylidene)-4-(trifluoromethyl)aniline as yellow solid (6.6 g, yield 72.3%). LC/MS m/e obsd. (ESI+) [(M+H)+] 295.1.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=[O:5].[CH3:17][CH2:18][Mg+].[Br-].O>CCOCC>[O:10]1[C:9]2([CH2:8][CH2:7][CH:6]([C:4](=[O:5])[CH2:17][CH3:18])[CH2:15][CH2:14]2)[O:13][CH2:12][CH2:11]1
Reactant: CC[Mg+]
Reactant: CON(C)C(=O)C1CCC2(CC1)OCCO2
Agent: [Br-]
Solvent: CCOCC
Solvent: O
Product: CCC(=O)C1CCC2(CC1)OCCO2
Yield: 30.4 %

Procedure:
To a solution of N-methoxy-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide (1 g, 0.0043 mol) in anhydrous Et2O (20 mL) was added EtMgBr (9 g, 0.043 mol). The reaction mixture was refluxed overnight, and then 200 mL water was added. The mixture was extracted with ethyl acetate. The extract was concentrated and purified by silica gel column chromatography (CH2Cl2:MeOH=150:1) to give the desired product (0.259 g, 26% yield).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[OH:10])=[N+:2]=[N-:3].N1C=CC=CC=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18]>C(Cl)Cl>[N:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[O:10][S:26]([C:23]1[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=1)(=[O:27])=[O:28])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1CCCC[C@H]1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: [N-]=[N+]=N[C@@H]1CCCC[C@H]1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.8 %

Procedure:
A solution of (±)-trans-2-azidocyclohexan-1-ol (11.3 g, 80.0 mmol) (Zhang, Z. da; Scheffold, R. Helv. Chim. Acta 1993, 76, 2602] in CH2Cl2 (110 mL) at 0° C. was treated successively with pyridine (14.2 mL, 176 mmol) and 4-nitro-benzenesulfonyl chloride (35.6 g, 160 mmol), allowed to warm to room temperature slowly, stirred for 4 d, and partitioned between CH2Cl2 and 1 N HCl. The aqueous phase was extracted with CH2Cl2 and the extracts were washed with saturated NaHCO3, dried and concentrated. Chromatography of the residue with 10:1–1:1 hexanes:EtOAc gave the product (19 g, 72%) as a cream solid: 1H NMR δ 1.19–1.39 (m, 3H), 1.53–1.82 (m, 3H), 2.00–2.10 (m, 1H), 2.26 (m, 1H), 3.36 (m, 1H), 4.35 (ddd, J=4.7, 9.2, 10.8 Hz, 1H), 8.17 (m, 2H), 8.41 (m, 2H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[C:39]([O:43][C:44]([NH:46][CH2:47][CH2:48][C:49](O)=[O:50])=[O:45])([CH3:42])([CH3:41])[CH3:40]>ClCCl>[O:50]=[C:49]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:48][CH2:47][NH:46][C:44](=[O:45])[O:43][C:39]([CH3:41])([CH3:40])[CH3:42]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.4 %

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (5.9 g, 15.4 mmol), pyrrolidine (3.2 g, 16.8 mmol) and diisopropylethylamine (5.4 mL, 42.2 mmol) was added to a suspension of 3-((tert-butoxycarbonyl)amino)propanoic acid (1.0 g, 14.0 mmol) in dichloromethane (20 mL) and the resulting mixture was stirred at ambient temperature for 6 hours. TLC analysis showed no acid remaining so the mixture was diluted with dichloromethane and washed with water and brine. The organic layer was separated, dried (Na2SO4), filtered and the solvent was removed to afford a solid. The crude material was purified by silica gel chromatography using a 70:30 mixture of hexane and ethyl acetate as eluent to afford the title product as a solid (3.0 g, 88% yield). MS m/z: 243.26 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)=O)[CH3:2].[CH:16]1([O:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[CH2:1]([O:3][C:4](=[O:15])/[C:5](=[N:22]/[O:21][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)/[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(Cl)c(Cl)c1
Reactant: NOC1CCCC1
Solvent: CCO
Product: CCOC(=O)/C(=N/OC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
(3,4-Dichloro-phenyl)-oxo-acetic acid ethyl ester (1.08 g, 4.37 mmol) was stirred in ethanol (9.7 mL) and warmed in a 70° C. oil bath. O-Cyclopentyl-hydroxylamine (prepared as in Example 1, 722 mg, 5.25 mmol) was added. After 2 h, the reaction mixture was allowed to cool and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 33% methylene chloride/hexanes) afforded (E)-cyclopentyloxyimino-(3,4-dichloro-phenyl)-acetic acid ethyl ester (371 mg, 26%) as a clear, colorless oil: H1-NMR (400 MHz, CDCl3) δ=1.37 (3H, t, J=7.1 Hz), 1.63 (4H, m), 1.85 (4H, m), 4.36 (2H, q, J=7.1 Hz), 4.94 (1H, m), 7.26 (1H, dd, J=8.3 Hz, J=1.9 Hz), 7.46 (1H, d, J=8.3 Hz), 7.54 (1H, d, J=1.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[O-]CC.[Na+].[C:25]([CH2:27][C:28](OCC)=[O:29])#[N:26]>C(O)C>[NH2:26][C:25]1[N:10]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[S:12][C:11]2=[N:20][C:28](=[O:29])[CH:27]=1
Reactant: COc1ccc(-c2nc(N)sc2-c2ccncc2)cc1
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2c(-c3ccncc3)sc3nc(=O)cc(N)n23)cc1
Yield: 42.1 %

Procedure:
To a suspension of [4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (1.0 g) in ethanol were added in turn a 20% solution of sodium ethoxide in ethanol (1.4 mL) and ethyl cyanoacetate (0.40 g). The resultant mixture was heated under reflux for 8 hours. After distilling off the solvent, water was added to the residue, the mixture was neutralized with acetic acid and the precipitate formed was filtered off. The remaining crude crystals were recrystallized from ethanol to obtain the title compound (0.52 g, yield 42%).