Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:39])[CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]3[O:27][N:39]=[C:31]([CH2:32][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[N:30]=3)[CH2:10]2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: NC(CN1CCOCC1)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(CN3CCOCC3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 35 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2-morpholin-4-ylethanimidamide were reacted according to the General Method 1. Yield: 28 mg (26% of theory)
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:16][NH2:17].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:16][NH:17][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(F)cc1NCc1cc(Cl)cc(Cl)c1
Yield: 46 %

Procedure:
A mixture of 2,4-difluoronitrobenzene (5.0 mmol), 3,5-dichlorobenzylamine (5.0 mmol), N,N-diisopropylethylamine (10.0 mmol) and acetonitrile (25 mL) was heated at reflux for 18 h, cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 5% ethyl acetate in hexanes as eluent to yield the title compound as a yellowish solid (46%). 1H NMR (400 MHz, CDCl3): δ 9.28 (br s, 1 H), 7.88 (m, 1 H), 7.34 (s, 1 H), 7.22 (s, 2 H), 6.44 (m, 1 H), 6.30 (dd, 1 H), 4.43 (d, 2 H).
Reaction SMILES: FC(F)(F)[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]([CH:16]([CH3:18])[CH3:17])[CH:6]=1)=[O:4].[OH-:21].[Na+]>>[CH:16]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([C:3]([OH:4])=[O:21])=[CH:6]1)([CH3:18])[CH3:17]
Reactant: COc1ccc2c(C(=O)C(F)(F)F)cn(C(C)C)c2c1
Reactant: [OH-]
Agent: [Na+]
Product: COc1ccc2c(C(=O)O)cn(C(C)C)c2c1
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 2,2,2-trifluoro-1-(1-isopropyl-6-methoxy-1H-indol-3-yl)-ethanone (950 mg, 3.33 mmol) in a 20% aqueous sodium hydroxide solution (12 mL) was heated at 105° C. for 18 h. At this time, the reaction was cooled to 25° C., partitioned between water (50 mL) and ethyl acetate (50 mL), and treated with a 1N aqueous hydrochloric acid solution (35 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solids were collected by filtration, washed with petroleum ether, and dried in vacuo to afford 1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid (553 mg, 71%) as orange needles: mp 162-163° C.; EI-HRMS m/e calcd for C13H15NO3 (M+) 233.1052, found 233.1056.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)(=[O:18])[CH3:17].C(N(CC)CC)C.Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([NH:15][S:26]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:16](=[O:18])[CH3:17])=[CH:25][CH:24]=3)(=[O:28])=[O:27])=[CH:14][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCN1CCc2ccc(N)cc2CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCN1CCc2ccc(NS(=O)(=O)c3ccc(NC(C)=O)cc3)cc2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
400 mg (1.96 mmol) of 3-propyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-amine and 1.86 mmol of 4-acetylaminobenzenesulfonyl chloride were dissolved in 20 ml of tetrahydrofuran at room temperature, 0.82 ml (5.87 mmol) of triethylamine was added dropwise, and the mixture was stirred at room temperature overnight. After the solvent had been evaporated off, 20 ml of water were added, and the mixture was acidified with 1 mol of hydrochloric acid and extracted with 50 ml of diethyl ether. The aqueous phase was made basic at pH 9-10 with 1 mol of sodium hydroxide solution and then extracted with diethyl ether. The residue obtained after drying with sodium sulfate and after removal of the solvent was converted into the hydrochloride with ethereal hydrochloric acid. Yield: 280 mg (35% of theory)
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(N(CC)CC)C.[C:11]([O:15][C:16](=[O:26])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)([CH3:14])([CH3:13])[CH3:12]>C(O)C>[OH:2][N:3]=[C:24]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:16](=[O:26])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:23][CH:22]=1)[NH2:25]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(C(N)=NO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At RT, 1.40 g (20.16 mmol, 2.2 eq.) of hydroxylammonium chloride and 2.81 ml (20.16 mmol, 2.2 eq.) of triethylamine were added to a solution of 2.0 g (9.16 mmol) of tert-butyl-(4-cyanophenyl)carbamate in 45 ml of ethanol. The reaction mixture was heated under reflux for 4 h and concentrated under reduced pressure. The residue was stirred with 100 ml of water at RT for 1 h. The reaction mixture was filtered and the filter cake was washed with water. The residue was dissolved in ethyl acetate. The aqueous phase that remained was separated off and the organic phase was dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was used for the next step without purification. Yield: 2.10 g (purity 95%, 87% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]=1[NH:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])([O-:3])=[O:2].C(=O)(O)[O-].[Na+].Br[C:33]1[CH:38]=[N:37][CH:36]=[CH:35][N:34]=1>[Pd]>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:33]2[CH:38]=[N:37][CH:36]=[CH:35][N:34]=2)=[CH:6][C:5]=1[NH:19][C:20]([N:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1)=[O:21])([O-:3])=[O:2]
Reactant: Brc1cnccn1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])c(NC(=O)N3CCCC3)c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(Nc1cc(-c2cnccn2)ccc1[N+](=O)[O-])N1CCCC1
Yield: 69.6 %

Procedure:
To a solution of N-(2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-1-carboxamide (0.20 g, 0.55 mmol) was added at room temperature sodium bicarbonate (0.09 g, 0.80 mmol, 1.45 equiv.), 2-bromopyrazine (0.14 g, 0.89 mmol, 1.6 equiv.) and palladium (0.07 g, 0.06 mmol, 0.1 equiv). The reaction was refluexed for fourteen hours. The crude reaction was filtered and concentrated. The residue was diluted into water and washed with ethyl acetate, the concentrated. The obtained was purified through column chromatography by eluting ethyl acetate and hexane to allow N-(2-nitro-5-(pyrazin-2-yl)phenyl)pyrrolidine-1-carboxamide (0.12 g, 70% yield).
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:4]=2[O:3]1.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15]C([O-])=O>>[F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:15][C:14]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][C:4]=2[O:3]1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: CCOC(=O)CC(=O)[O-]
Product: CCOC(=O)C=Cc1ccc2c(c1)OC(F)(F)O2
Yield: 81.3 %

Procedure:
2,2-difluoro-1,3-benzodioxole-5-carboxaldehyde (5.0 g, 26.9 mmol) and mono-ethyl malonate (4.1 ml, 34.9 mmol) were reacted as described under General Procedure A to furnish the title compound (5.6 g, 82%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.61 (d, J=16.0 Hz, 1H), 7.26-7.22 (m, 2H), 7.06 (d, J=7.9 Hz, 1H), 6.33 (d, J=16.0 Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([CH2:5][CH2:6][N:7]([CH3:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O:3][CH3:4])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)(=[O:23])[C:20](Cl)=[O:21]>O>[C:1]([CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][C:11]([C:20]([C:19]([C:11]2[CH:10]=[CH:9][C:8]([N:7]([CH3:14])[CH2:6][CH2:5][C:1]([O:3][CH3:4])=[O:2])=[CH:13][CH:12]=2)=[O:23])=[O:21])=[CH:10][CH:9]=1)[CH3:14])([O:3][CH3:4])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)CCN(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COC(=O)CCN(C)c1ccc(C(=O)C(=O)c2ccc(N(C)CCC(=O)OC)cc2)cc1

Procedure:
4,4'-bis(N-2-carbomethoxyethyl-N-methylamino)benzil was prepared according to the procedure of Tuzun, et al. (Org. Syn., 41, 1 (1961)). Charges were 86.4 g of N-2-carbomethoxyethyl-N-methylaniline (prepared according to the procedure in Example 1), 41.7 g of anhydrous aluminum chloride and 6.7 ml of oxalyl chloride. After the addition of 157 ml of water the reaction mixture was extracted three times with 100 ml portions of chloroform. The chloroform extract was washed with water, dried over anhydrous sodium sulfate and filtered. The solvent was removed on a steam bath and the dark brown residue was chromatographed on Activity I basic alumina (the most active and dried form, in terms of absorbing power, of chromatographic grade alumina) using a 1:1 mixture of ethyl acetate and heptane. Fractions containing a new product which appeared to be free of starting material by TLC (thin layer chromatography) were combined and concentrated to a brown gum. The combined chromatography fractions were dissolved in 50 ml of 10 percent methanolic sodium hydroxide and refluxed overnight. A tan solid separated which was isolated by filtration, washed with methanol and dried. This material in water had λmax=382 nm and εmax=14,650. This is only one third the extinction coefficient reported for 4,4'-bis(dimethylamino)benzil. No further purification was attempted.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.S(Cl)(Cl)=O.[CH3:16]O>>[NH2:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:16])=[O:10])[CH2:7][CH2:8]1
Reactant: CO
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](CN)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of trans-4-(aminomethyl)cyclohexanecarboxylic acid (2 g, 12.7 mmol) in MeOH (64 mL) was added dropwise thionyl chloride (0.93 mL, 12.7 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo to dryness to give trans-methyl 4-(aminomethyl)cyclohexanecarboxylate (2.5 g, 115%) as HCl salts.
Reaction SMILES: [OH-:1].[Na+].[OH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](OC)[CH:12]=2)[O:7][C:6](=[O:16])[C:5]=1[N+]([O-])=O>O>[OH2:3].[OH:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([OH:1])=[CH:11][CH:12]=2)[O:7][C:6](=[O:16])[CH:5]=1
Reactant: [OH-]
Reactant: COc1ccc2oc(=O)c([N+](=O)[O-])c(O)c2c1
Agent: [Na+]
Solvent: O
Product: O=c1cc(O)c2ccc(O)cc2o1

Procedure:
Dilute sodium hydroxide solution was added to a suspension of 4-hydroxy-6-methoxy-3-nitrocoumarin (2.0g) in water (40 ml) till the pH of the solution reached 14. Filtration gave the product m.p. 277°-8°(d); (C10H6NO6Na requires C, 46.35; H, 2.33; N, 5.41; Na, 8.87. Found: C, 46.32; H, 2.44; N, 5.50; Na, 8.34) after washing briefly with water and drying under vacuum.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9](C2C=CC=C(C(F)(F)F)C=2)=[CH:10][CH:11]=1)=[O:5].[CH3:27][O:28][C:29]([C:31]1[CH:32]=[CH:33][C:34]([CH3:40])=[C:35](B(O)O)[CH:36]=1)=[O:30]>>[CH3:27][O:28][C:29](=[O:30])[C:31]1[CH:32]=[CH:33][C:34]([CH3:40])=[C:35]([C:9]2[S:8][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:25][CH:24]=[CH:23][C:22]=3[F:26])=[CH:11][CH:10]=2)[CH:36]=1
Reactant: COC(=O)c1ccc(C)c(B(O)O)c1
Reactant: O=C(Nc1ccc(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Product: COC(=O)c1ccc(C)c(-c2ccc(NC(=O)c3c(F)cccc3F)s2)c1

Procedure:
Compound 118 was synthesized in an analogous fashion as described for Compound 117 except that 5-methoxycarbonyl-2-methylbenzeneboronic acid was used instead of 3-trifluoromethylbenzeneboronic acid in the final step.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[C:21]3[O:20][C:19]([F:23])([F:22])[O:18][C:17]=3[CH:16]=[CH:15][CH:14]=2)[N:5]=1)(=[O:3])[CH3:2].CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>>[F:23][C:19]1([F:22])[O:18][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([N:6]3[CH:7]=[C:8]([O:11][CH3:12])[C:9](=[O:10])[C:4]([C:1](=[O:3])[CH:2]=[CH:26][N:27]([CH3:29])[CH3:28])=[N:5]3)[C:21]=2[O:20]1
Reactant: COC(OC)N(C)C
Reactant: COc1cn(-c2cccc3c2OC(F)(F)O3)nc(C(C)=O)c1=O
Product: COc1cn(-c2cccc3c2OC(F)(F)O3)nc(C(=O)C=CN(C)C)c1=O
Yield: 74 %

Procedure:
A solution of 3-acetyl-1-(2,2-difluoro-1,3-benzodioxol-4-yl)-5-methoxypyridazin-4(1H)-one (2.3 g, 7.1 mmol) in N,N-dimethylformamide dimethyl acetal (75 mL) was refluxed for 3 h. The mixture was concentrated under reduced pressure. The brown crystals were washed with AcOEt/hexane (1/1) to give the title compound (2.0 g, 74% yield) as yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 2.91 (3H, s), 3.14 (3H, s), 3.94 (3H, s), 5.78 (1H, d, J=11.7 Hz), 7.10 (1H, dd, J=8.3, 1.1 Hz), 7.23 (1H, t, J=8.3 Hz), 7.63 (1H, d, J=8.7 Hz), 7.79 (1H, brs), 8.03 (1H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][SH:12])[CH:2]=1.[N+:13]([CH:16]=[C:17](SC)SC)([O-:15])=[O:14]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][S:12][C:17]2=[CH:16][N+:13]([O-:15])=[O:14])[CH:2]=1
Reactant: SCCCNCc1cccnc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: O=[N+]([O-])C=C1SCCCN1Cc1cccnc1
Yield: 48.4 %

Procedure:
A mixture of N-(3-pyridylmethyl)3-aminopropanethiol (1.8 g), 1-nitro-2,2-bis(methylthio)ethylene (1.7 g) and ethanol (40 ml) was heated under reflux for 5 hours under a nitrogen stream. After the reaction, about 2/3 by volume of ethanol was distilled off under reduced pressure. Ether was added little by little to the reaction mixture to precipitate crystals. The crystals were collected by filtration, and washed with a mixture of ethanol and ether to give the desired 3-(3-pyridylmethyl)2-nitromethylenetetrahydro-2H-1,3-thiazine (1.2 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1.[NH:42]1[CH:46]=[C:45]([C:47]2[CH:48]=[C:49]([OH:53])[CH:50]=[CH:51][CH:52]=2)[N:44]=[CH:43]1>>[NH:42]1[CH:46]=[C:45]([C:47]2[CH:48]=[C:49]([CH:50]=[CH:51][CH:52]=2)[O:53][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:16])[CH2:11][CH:10]3[O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]4[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=4[CH:41]=3)=[CH:5][CH:4]=2)[N:44]=[CH:43]1
Reactant: Oc1cccc(-c2c[nH]cn2)c1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CCl)cc3)cc21
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(COc4cccc(-c5c[nH]cn5)c4)cc3)cc21

Procedure:
Analogously to Method I, 0.107 g of benzyl 4-(4-chloromethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270b) and 0.0444 g of 3-(1H-imidazol-4-yl)phenol are reacted. The title compound is obtained as an orange oil. Rf=0.19 (200:10:1 dichloromethane-methanol-conc. ammonia); Rt=4.89.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:36])[N:29]([CH2:31][CH2:32][N:33]=[N+]=[N-])[CH3:30])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:37]([C:40]1[CH:50]=[CH:49][C:43]([CH2:44][O:45][C:46](Cl)=[O:47])=[CH:42][CH:41]=1)([O-:39])=[O:38].C(N(CC)CC)C>CO.[OH-].[OH-].[Pd+2]>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:36])[N:29]([CH3:30])[CH2:31][CH2:32][NH:33][C:46]([O:45][CH2:44][C:43]3[CH:42]=[CH:41][C:40]([N+:37]([O-:39])=[O:38])=[CH:50][CH:49]=3)=[O:47])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCN=[N+]=[N-])C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.4 %

Procedure:
A solution of 3-t-butyldiphenylsilyloxy-1-{4-[N-(2-azidoethyl)-N-methyl-carbamoyl]-1,3-thiazol-2-yl}azetidine (1.05 g, 2.02 mmol) (obtained as described in Reference Example 58(2)) in methanol (60 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide on charcoal (1.05 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst, and the filtrate concentrated under reduced pressure. To a solution of the obtained crude product in methylene chloride (52.3 ml) were added chloroformic acid p-nitrobenzyl ester (650.7 mg, 3.02 mmol) and triethylamine (0.42 ml, 3.01 mmol) in an ice bath. The mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (2:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-{N-methyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]carbamoyl}-1,3-thiazol-2-yl)azetidine (699.5 mg, yield 52%) as a pale yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>O1CCOCC1>[NH2:16][C:8]1[N:9]=[C:10]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:11]([I:12])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:7]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1COCCO1
Product: Nc1nc(NCCc2ccc(O)cc2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-y-lamine and tyramine in dioxane. ES-MS m/e (%): 423 (M+H+, 100).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34]N.CCN(CC)CC>C(O)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccccc1NN
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccccc1-n1nccc1-c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 18.9 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 2-methoxyphenylhydrazine hydrochloride (262 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(2-methoxyphenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale yellow solid (78 mg, 19%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:43]=[CH:44][CH:45]=1)[CH2:12][C@H:13]1[C:17](=[CH2:18])[CH2:16][C@@H:15]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C@@H:14]1[CH2:27][CH2:28][C@@H:29]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.[OH:55]O.[OH-].[K+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:43]=[CH:44][CH:45]=1)[CH2:12][C@@H:13]1[C@@H:14]([CH2:27][CH2:28][C@@H:29]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C@H:15]([O:19][Si:20]([C:23]([CH3:25])([CH3:26])[CH3:24])([CH3:21])[CH3:22])[CH2:16][C@@H:17]1[CH2:18][OH:55])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CC[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)[C@H]1Cc1cccc(OCc2ccccc2)c1
Reactant: OO
Agent: B1C2CCCC1CCC2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCC[C@@H](CC[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](CO)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A degassed solution of ((1R,2R,3R)-3-(3-(benzyloxy)benzyl)-2-((S)-3-(tert-butyldimethylsilyloxy)octyl)-4-methylenecyclopentyloxy)(tert-butyl)dimethylsilane (0.75 g, 1.15 mmol) in 8 ml dry THF was cooled to 0° C. under nitrogen, and 9-borabicyclo[3,3,1]nonane (6.9 ml, 0.5M in THF) was dropwise added to the mixture. The colorless solution was stirred for overnight at 0° C. and treated with 30% hydrogen peroxide (3 ml) followed by 3N potassium hydroxide (3 ml). The resulting suspension was stirred for one hour at room temperature. The mixture was extracted with EtOAc, and the organic layer was washed with 20 ml brine, dried over MgSO4, and evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give the titled compound: 0.6 g (yield 78%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH3:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([F:8])[CH:5]=[CH:6][C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(F)cccc1Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(F)ccc([N+](=O)[O-])c1Cl
Reaction time: 0.08 h

Procedure:
1-Chloro-3-fluoro-2-methylbenzene (1.00 mL, 8.24 mmol) was dissolved in sulfuric acid (18 M, 10 mL) and cooled in an ice bath. Potassium nitrate (0.87 g, 8.65 mmol) dissolved in sulfuric acid (18 M, 10 mL) was added dropwise to the cold solution. The reaction mixture was stirred for 5 min, then the ice bath was removed and stirring was continued for another 2 h. The reaction mixture was poured onto ice (25 g) stirred for 5 min and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a clear yellow oil (1.34 g, purity 85%). The product was used without further purification in the next reaction step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1.[Br:15]C1C=CC=CC=1C=O>>[Br:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1Br
Reactant: Cc1cccc(-c2ccccc2Cl)n1
Product: Cc1cccc(-c2ccccc2Br)n1

Procedure:
6-(2-bromophenyl)-2-methylpyridine was prepared substantially according to the procedure of Example 1 for preparing 6-(2-chlorophenyl)-2-methylpyridine except 2-bromobenzaldehyde was used to afford 6-(2-bromophenyl)-2-methylpyridine.