Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH:23]([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][C:18](B5OC(C)(C)C(C)(C)O5)=[CH:19][CH:20]=4)[CH2:15]3)[N:11]=[C:10]([NH2:34])[N:9]=2)[CH2:4][CH2:3]1.Br[C:36]1[N:37]=[C:38]([CH3:41])[S:39][CH:40]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O>[CH3:24][CH:23]1[CH2:22][C:21]2[C:16](=[CH:17][C:18]([C:36]3[N:37]=[C:38]([CH3:41])[S:39][CH:40]=3)=[CH:19][CH:20]=2)[CH2:15][N:14]1[C:12]1[CH:13]=[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:9]=[C:10]([NH2:34])[N:11]=1
Reactant: Cc1nc(Br)cs1
Reactant: CC1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1nc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cs1
Temperature: 120 °C

Procedure:
A mixture of 4-(4-methylpiperazin-1-yl)-6-[3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine (0.0464 g, 0.100 mmol), 4-bromo-2-methyl-1,3-thiazole (0.0231 g, 0.130 mmol, Frontier, Cat. No. B4559) in 1,4-dioxane (1.0 mL) was stirred at r.t. for 10 min. Potassium carbonate (63.0 mg, 0.456 mmol) in water (0.50 mL) was added to give a deep red solution. The mixture was degassed and refilled with nitrogen three times. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (5.0 mg, 0.0061 mmol) was added and the mixture was degassed and refilled with nitrogen three times and then heated at 120° C.) (oil bath temperature) for 3 h. After cooling, the mixture was diluted with methanol, and filtered. The filtrate was purified on RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=436.1.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17](O)=[O:18])[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:34][C:35]1[S:36][CH:37]=[CH:38][N:39]=1)[CH3:33].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:21][C:2]([CH3:1])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([N:34]([CH2:32][CH3:33])[C:35]2[S:36][CH:37]=[CH:38][N:39]=2)=[O:18])[N:6]=1)=[O:4]
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Reactant: CCNc1nccs1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCN(C(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21)c1nccs1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
Weigh 29.0 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid, 23.0 mg HOBt, and 38.3 mg EDC into a 13×100 mm screw cap tube. Add 19.2 mg N-ethyl-1,3-thiazol-2-amine followed by 1 mL DMF and 45.2 mg DIEA in that order. The mixture was stirred at 45° C. for two hours and purified by RP-HPLC using 50-90% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound as a white solid. LC-MS: 3.96 min. (m/Z=423.2, 245.1, 273.1, 401.2).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]([CH:12]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]3[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:15]=3N(C)C2=O)=[O:11])[CH2:3][CH2:2]1.CN(C)C=O.[H-].[Na+].O>C(#N)C>[ClH:29].[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]([C:12]2[NH:18][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:16]3[C:15]=2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25]3)=[O:11])[CH2:5][CH2:6]1
Reactant: CN1C(=O)C(C(=O)OCCN2CCOCC2)N=C(c2ccccc2)c2cc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: Cl
Product: O=C(OCCN1CCOCC1)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 19.7 g. of 7-chloro-2,3-dihydro-1methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid 2-morpholinoethyl ester in 200 ml. of dimethylformamide is treated under an atmosphere of argon at 0° C. with 0.10 mol of sodium hydride (4.4 g. of a 55% dispersion in mineral oil) and the mixture is stirred at room temperature for 30 minutes. The mixture is then warmed to 100° C. over a period of about 30 minutes and then stirred at this temperature for 1 hour. After cooling, 12 ml. of water are added dropwise and the mixture is poured on to 600 ml. of ice-water. After the addition of 30 g. of sodium chloride, the separated product is extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate and concentrated to dryness. For purification, the solid residue obtained is boiled for about 10 minutes in 50 ml. of acetonitrile and then cooled in an ice-bath. The crude base is removed by filtration, taken up in methylene chloride and treated with excess ethereal hydrochloric acid. After the addition of diethyl ether, there is obtained 5-chloro-3-phenylisoindole-1-carboxylic acid 2-morpholinoethyl ester hydrochloride in the form of greenish crystals which melt at 240°-242° C. (decomposition). Recrystallization from methanol/diethyl ether does not increase the melting point.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:12]N1C(=O)CCC1=O>O1CCOCC1.COCCO>[CH2:1]([C:5]1[NH:6][C:7]([CH2:10][OH:11])=[C:8]([Cl:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CO)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CCCCc1nc(Cl)c(CO)[nH]1
Temperature: 40 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
In a mixture of 70 ml of dioxane and 60 ml of methyl cellosolve was dissolved 4 g of 2-butyl-5-hydroxymethylimidazole, and 3.9 g of N-chlorosuccinimide was added to the solution, followed by stirring at 40° C. for 1 hour. The reaction solution was evaporated to dryness under reduced pressure, and 100 ml each of water and ethyl acetate were added to the residue to shake for mixing. The ethyl acetate layer was evaporated to dryness under reduced pressure, and the residue was dissolved in 50 ml of ether. The solution was allowed to cool, thereby yielding 2.4 g of 2-butyl-4-chloro-5-hydroxymethylimidazole deposited as colorless prisms, m.p. 147°-148° C.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC>C1COCC1>[CH2:1]([OH:6])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CCCCO
Reactant: C=CCCCCCCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCC/C=C\CCCO
Temperature: 35 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
In a glovebox, a 20 mL vial was charged with 4-pentenol (410 μL, 3.98 mmol), 1-dodecene (4.4 mL), and THF (2.7 mL). A solution of 1 (0.025 g, 1 mol %) in THF (0.5 mL) was added, and the mixture was stirred in an open vial for 6 hours at 35° C. The vial was removed from the glovebox, the reaction was quenched with excess ethyl vinyl ether, and the solvent was removed in vacuo. Flash chromatography of the residue (SiO2, using a gradient of hexanes to 8% EtOAc in hexanes) provided 21 (0.56 g, 62% yield, 84% Z as determined by 13C-NMR) as a colorless oil; 1H NMR (CDCl3): δ 5.38 (2H, m), 3.65 (2H, m), 1.95-2.14 (4H, m), 1.63 (2H, m), 1.52 (1H, s), 1.25 (16H, m), 0.87 (3H, t, J=6.9 Hz); 13C NMR (100 Hz, CDCl3): δ 131.0, 128.9, 62.8, 32.8, 32.1, 29.9, 29.8, 29.7 (2C), 29.5 (2C), 29.3, 23.7, 22.8, 14.2; HRMS (FAB): 227.2372, [C15H30O+H]+ requires 227.2369.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O=[CH:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.O>ClCCl>[Br:2][C:1]([Br:5])=[CH:26][CH2:27][CH:28]1[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC=C(Br)Br)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Carbon tetrabromide (46.7 g, 141 mmol) was dissolved in 200 mL dichloromethane. The solution was cooled in an ice-water bath and triphenylphosphine (73.9 g, 282 mmol) in 200 mL dichloromethane was introduced via an addition funnel over 20 min. The reaction mixture was stirred at 0° C. for 10 min and a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (16 g, 70.4 mmol) in 100 mL dichloromethane was added via an addition funnel. The solution was stirred at 0° C. for 1 hour. Water (250 mL) was added and aqueous layer was extracted 3 times with 100 mL dichloromethane. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. 300 mL ether was added to the residue, and the resulting suspension was filtered. The solid was washed 3 times with 150 mL ether. The combined filtrate was concentrated and passed through a plug of silica gel, washed thoroughly with 10% acetone/hexanes to afford yellow oil which was used without further purification.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)=O.CC(C)=O.[H-].[Na+].[C:32](N1C=CN=C1)(N1C=CN=C1)=[S:33]>O1CCCC1>[S:33]=[C:32]1[N:12]2[C:13]3[N:14]([C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH3:2])[CH:4]=4)=[CH:10][CH2:11]2)[N:15]=[CH:16][C:17]=3[C:18](=[O:19])[NH:20]1
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(C2=CCn3c(=S)[nH]c(=O)c4cnn2c43)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1.00 g of 4,5-dihydro-7-(3-methyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (prepared as described in Example 4) in dry tetrahydrofuran cooled to -78° C. (dry ice-acetone) is added sodium hydride (60% dispersion in mineral oil). The reaction mixture is stirred at -78° C. for 30 minutes then 1,1'-thiocarbonyldiimidazole is added. The mixture is allowed to slowly warm to room temperature and is stirred for 36 hours. Then reaction mixture is quenched with water, neutralized with 5% aqueous hydrochloric acid and extracted with chloroform. Evaporation of the solvent in vacuo gives 4,5-dihydro-5-thioxo-8-(3-methylphenyl)-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3]S.[NH2:8][C@H:9]([C:15]([OH:17])=O)CS(=O)(O)=[O:12].[CH:18]([O:20]O)=[O:19]>Cl>[NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:12].[NH2:8][C@H:9]([C:18]([OH:20])=[O:19])[C@@H:15]([CH3:2])[OH:17]
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=COO
Reactant: N[C@@H](CS(=O)(=O)O)C(=O)O
Agent: Cl
Product: C[C@@H](O)[C@H](N)C(=O)O
Product: N[C@@H](CO)C(=O)O

Procedure:
This analysis was conducted after the mutein was hydrolyzed in 6N hydrochloric acid containing 4% thioglycolic acid at 110° C. for 24 hours and 48 hours. Cysteine was quantitated as cysteic acid after performic acid oxidation. The values for serine and threonine were obtained by extrapolating the 0-hour value from the 24- and 48-hour values.
Reaction SMILES: Cl.CN[C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[C:22]1([N:32]=[C:33]=[O:34])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.[CH:35]([N:38](C(C)C)[CH2:39]C)(C)C>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:35][N:38]([CH3:39])[C:33]([NH:32][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)=[O:34])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: CCN(C(C)C)C(C)C
Reactant: CNc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Product: CN(Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O)C(=O)Nc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a suspension of 3-(4-methylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.60 g, 1.86 mmol) and 1-naphthyl isocyanate (0.32 mL, 2.23 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with MeOH and filtered. The resulting solid was rinsed with CH2Cl2 (5 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-naphthalen-1-yl-urea (0.76 g, 89%): mp 292-294° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.65 (99%); 1H NMR (DMSO-d6): δ 2.00-2.05 (m, 1H), 2.29-2.35 (m, 1H), 2.56-2.62 (m, 1H), 2.87-2.97 (m, 1H), 3.09 (s, 3H), 4.40 (d, J=17.3 Hz, 1H), 4.47 (d, J=17.4 Hz, 1H), 4.72 (s, 2H), 5.13-5.19 (dd, J=5.1, 13.3 Hz, 1H), 7.47-7.93 (m, 10H), 8.57 (s, 1H), 11.04 (s, 1H). 13C NMR (DMSO-d6) δ: 22.62, 31.14, 34.78, 46.20, 48.55, 51.52, 121.70, 123.30, 123.38, 125.46, 125.48, 125.74, 127.87, 128.42, 129.63, 129.91, 131.95, 133.71, 133.99, 135.39, 140.17, 156.71, 168.02, 170.99, 172.81. Anal Calcd for C26H24N4O4: C, 68.41; H, 5.30; N, 12.27. Found: C, 68.54; H, 5.12; N, 11.87.
Reaction SMILES: [C:1]([C:3](=[C:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH3:18])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1)#[N:2]>C(O)C.[Pt].[H][H]>[C:1]([C:3](=[C:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH3:18])[C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1)#[N:2]
Reactant: [H][H]
Reactant: CN1CCCC1=C(C#N)c1ccc([N+](=O)[O-])cc1
Agent: [Pt]
Solvent: CCO
Product: CN1CCCC1=C(C#N)c1ccc(N)cc1
Yield: 62.7 %

Procedure:
Dissolve 10 g of 2-(α-cyano-4-nitrobenzylidene)-1-methylpyrrolidine in ethanol and then reduce it with platinum/hydrogen. After completion of hydrogen uptake, filter the catalyst from the hydrogenated product, distil off the solvent and recrystallize the residue from 50 ml of ethanol to obtain 5.5 g of the title compound as light-brown crystals of m.p. 116° to 118°.
Reaction SMILES: [C:1]([F:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].C([O-])(=O)C.[K+:13]>>[F-:4].[F-:4].[K+:13].[C:5]([O:8][C:1](=[O:3])[CH3:2])(=[O:7])[CH3:6]
Reactant: CC(=O)F
Reactant: CC(=O)[O-]
Agent: [K+]
Product: CC(=O)OC(C)=O
Product: [F-]

Procedure:
The reaction of the by-product acetyl fluoride with metal acetate such as potassium acetate is carried out under suitable reaction conditions of time, temperature and pressure which are sufficient to produce a metal fluoride such as potassium fluoride and acetic anhydride. Preferably, a pressure is maintained which is sufficient to maintain the acetyl fluoride essentially in the liquid phase at a temperature in a broad range of 20° to 200° C and more preferably in a temperature range of 80° to 150° C. The time required for the reaction is approximately 10 minutes to 24 hours and, more preferably, in a range of 1 to 8 hours. The produced potassium acetate and acetic anhydride are suitably separated such as by flash distilling, recovering the acetic anhydride as an overhead product which can be recycled for equilibration with additional hexafluoroacetone-HF complex. The remaining potassium fluoride which is produced in this reaction is transferred to a suitable reactor for contacting with acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.[CH2:18](Br)[CH2:19][CH3:20].[H-].[Na+]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH2:18][CH2:19][CH3:20])[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: Clc1cnccc1Nn1ccc2ccccc21
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCN(c1ccncc1Cl)n1ccc2ccccc21
Product: Cl

Procedure:
The title compound was prepared from N-(3-chloro-4-pyridinyl)-1H-indol-1-amine and propyl bromide with the aid of sodium hydride in substantially the same manner as in Example 20, m.p. 202° C. (dec.).
Reaction SMILES: [CH:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[NH:14])=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+:18]([C:21]1[CH:32]=[CH:31][C:24]([CH:25]=[CH:26][S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([CH:25]=[CH:26][S:27]([NH:14][C:13](=[NH:15])[C:12]2[CH:11]=[CH:10][C:9]([CH:1]=[CH:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:17][CH:16]=2)(=[O:29])=[O:28])=[CH:31][CH:32]=1)([O-:20])=[O:19]
Reactant: N=C(N)c1ccc(C=Cc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(C=CS(=O)(=O)Cl)cc1
Product: N=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccc(C=Cc2ccccc2)cc1

Procedure:
Reaction of 4-styrylbenzamidine with 4-nitrostyrylsulfonyl chloride according to the procedure of Example 29 (a) provides N-(4-NITROSTYRYLSULFONYL)-4-STYRYLBENZAMIDINE.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.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>[F:22][C:16]1[CH:15]=[CH:14][C:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:18][C:17]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Yield: 76.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.8 g) was added to a mixture of 5 g 3-methoxyphenylboronic acid, 5 g 5-bromo-2-fluoro-nitrobenzene and 11 mL of 2 M sodium carbonate solution in 100 ML of toluene. The mixture was refluxed for 2 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate was washed with saturated sodium bicarbonate and brine and then dried and concentrated to give an oily solid. The solid was chromatographed on silica gel (ethyl acetate:hexane (1:6)) to give 4.3 g (77% yield) of 4-fluoro-3′-methoxy-3-nitrobiphenyl.
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][Br:6].ClC(Cl)(Cl)C(=N)O[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1CCCCC1.FC(F)(F)S(O)(=O)=O>ClCCl>[Br:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[O:7][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(O)CCCBr
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(CCCBr)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of 1-methyl-4-bromo-1-butanol (9.0 g, 0.05384 mol) and benzyl 2,2,2-trichloroacetimidate (16.3 g,) in a mixture of anhydrous cyclohexane (100 ml) and anhydrous dichloromethane (50 ml) cooled to 0° C., trifluoromethanesulfonic acid (1.0 ml) was added, and the mixture was stirred overnight at room temperature under argon. The mixture was filtered, washed with a saturated solution of NaHCO3 (250 ml) and deionized water (250 ml), and dried with anhydrous Na2SO4. The solvents were removed by distillation under reduced pressure. The crude product (9.2 g) was subjected to vacuum distillation, giving 7.2 g of colorless viscous liquid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[O:8](C(OC(C)(C)C)=O)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O>C(Cl)Cl>[C:12]([O:11][C:9]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:8])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C1CNCCN1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reaction time: 3 h

Procedure:
To a mixture of piperazine-2-one (1.037 g, 10.4 mmol) in 52 mL of CH2Cl2, was added BOC2O (2.5 g, 11.4 mmol). The reaction became homogeneous after 3 hours when the starting material was completely consumed. The reaction was diluted with CH2Cl2 and the organic layer was washed with water. The solvent was removed in vacuo to yield quantitative amount of product 33 as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.48 (s, 9H), 3.35-3.44 (m, 2H), 3.64 (t, 2H, J=5 Hz), 4.10 (s, 2H), 6.41 (br s, 1H).
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11](=[C:14]1[CH:19]=[C:18]([CH3:20])[C:17](=[N:21]O)[CH:16]=[C:15]1[Cl:23])[C:12]#[N:13]>[Fe].CC1C=CC=CC=1>[ClH:3].[NH2:21][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([CH:11]([C:5]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=2[Cl:3])[C:12]#[N:13])=[C:15]([Cl:23])[CH:16]=1
Reactant: CC1=CC(=C(C#N)c2ccc(Cl)cc2Cl)C(Cl)=CC1=NO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Cc1cc(C(C#N)c2ccc(Cl)cc2Cl)c(Cl)cc1N
Product: Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
370 parts of ammonium chloride solution 0.78N are stirred and heated to reflux. Then there are added 37 parts of iron-powder, followed by the dropwise addition of a solution of 37 parts of 2,4-dichloro-α-[2-chloro-4-(hydroxyimino)-5-methyl-2,5-cyclohexandien-1-ylidene]benzeneacetonitrile in 333 parts of methylbenzene. Upon completion, stirring at reflux is continued overnight. The reaction mixture is cooled to 60° C, filtered and the filter-cake is washed with tetrahydrofuran. The filtrate is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2,2'-oxybispropane and 2-propanol, yielding 4-amino-2-chloro-α-(2,4-dichlorophenyl)-5-methylbenzeneacetonitrile hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1.N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl.C(Cl)(Cl)Cl>[CH2:12]([C:9]1[N:7]2[N:8]=[C:3]([CH2:2][NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=3)[C:6]2=[CH:11][CH:10]=1)[CH3:13]
Reactant: CCOC(=O)CCCCc1c(CN)nn2c(CC)ccc2c1-c1cncc(C)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCCc1c(CNS(C)(=O)=O)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a solution of ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (80 mg) and pyridine (1 mL) in dichloromethane (2 mL) was added methanesulfonyl chloride (34.8 mg) under ice-water cooling and the mixture was stirred at ambient temperature for 1 hour. The solution was diluted with chloroform, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(methylsulfonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate as yellow oil (62.8 mg)