Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[H-].[Na+].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O.C(OCC)C>[Cl:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][N:6]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2ccccc2)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 12.9 g (0.1 mol) of 5-hydroxy-2-chloropyridine in 50 ml of dimethylformamide is added to a suspension of 4.8 g (0.1 mol) of sodium hydride (a 50% dispersion in mineral oil; washed with toluene) in 100 ml of dimethylformamide. The mixture is stirred until the evolution of hydrogen has ceased and then, after cooling with the aid of an ice-bath, 12.6 g (0.1 mol, 11.5 cc) of benzyl chloride are introduced dropwise. The mixture is heated at 60° C. for one hour, left to stand overnight and then poured into iced water, and extraction is carried out with diethyl ether. The ether phase is washed with water, dried and filtered and the filtrate is evaporated. The product, i.e. 2-chloro-5-benzyloxypyridine, is distilled. Its boiling point (0.1 mm Hg) is 135° C.
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][NH:3]1.[OH-].[Na+].[C:11](O)(=O)C>O.IC>[CH3:11][S:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]=1
Reactant: O=c1cc[nH]c(=S)[nH]1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSc1nccc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-thioxo-2,3-dihydropyrimidin-4(1H)-one (21 g) was added dropwise a solution of sodium hydroxide (13 g) in water (120 mL), iodomethane (11.5 mL) was added thereto, and the mixture was stirred overnight at room temperature. To the reaction mixture was added acetic acid (9.5 mL), and the resulting solid was collected by filtration. The obtained solid was washed with cold water to give the title compound (24 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:20][C:21]1[C:25]([C:26]#[N:27])=[C:24]([CH3:28])[NH:23][N:22]=1>>[CH3:28][C:24]1[C:25]([C:26]#[N:27])=[C:21]2[N:20]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]2[N:23]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Reactant: Cc1[nH]nc(N)c1C#N
Product: Cc1nn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc2c1C#N
Yield: 63.2 %

Procedure:
Reaction of 1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg, 1.0 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and commercially available 3-amino-4-cyano-5-methyl-pyrazole (122 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (234 mg, 63%). MS (ISP) 371.1 [(M+H)+]; mp 184° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:19](C1C=C(NC2C=CC=CC=2)C=CC=1)[CH3:20].N1C=CC=CC=1C=O>>[CH2:19]([C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1)[CH3:20]
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Reactant: CCc1cccc(Nc2ccccc2)c1
Agent: O=Cc1ccccn1
Product: CCc1cccc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-ethylphenylaniline (36.4 mg, 0.3 mmol) and 2-pyridinecarboxaldehyde (32.1 mg, 0.3 mmol) were employed to obtain 2-[2-(3-ethylphenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][O:12][CH2:13][C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=O)[C:2]1=2.Cl.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])[C:2]1=2
Reactant: CCN(CC)C(=O)COCCc1cccc2ccsc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CC)CCOCCc1cccc2ccsc12
Temperature: 5 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
In 14 mL of tetrahydrofuran is dissolved 1.36 g of 2-(2-benzo[b]thiophen-7-ylethoxy)-N,N-diethylacetamide. The solution is cooled to 5° C., and 14 mL of 1 mol/L solution of borane-tetrahydrofuran complex in tetrahydrofuran is dropwise added thereto. The resulting mixture is stirred at ambient temperature overnight, and then 5.00 mL of 6 mol/L hydrochloric acid is dropwise added, and the resulting mixture is heated under reflux for 30 minutes. After cooling, water and ethyl acetate are added to the reaction mixture, pH is adjusted to 9 with 5 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=10:1) to obtain 1.10 g of N-[2-(2-benzo[b]thiophen-7-ylethoxy)ethyl]-N,N-diethylamine as an oily product.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]([N:16]=[O:17])[CH2:13][CH2:12][CH2:11]2)(=[O:5])[CH3:4].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(Cl)Cl>O.C(O)C>[C:19]1([CH:18]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]([N:16]=[O:17])[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1cccc2c1N(N=O)CCC2
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: O=NN1CCCc2cccc(C(=O)C=Cc3ccccc3)c21
Temperature: 10 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
20 g (0.5 mol) of sodium hydroxide were dissolved in 120 ml of water. A cold solution of 109 g (0.5 mol) of 8-acetyl-1-nitroso-1,2,3,4-tetrahydroquinoline and 53 g (0.5 mol) of benzaldehyde in 300 ml of ethanol was added at 0°-5° C. The mixture was stirred at 10° C. for 1 hour, 600 ml of methylene chloride were then added and the mixture was stirred for 1 hour at 10°-20° C. 500 ml of water were then added, the organic layer was separated, dried, and the solvent was distilled off. 153.5 g of crude 8-(3-phenyl-2-propen-1-on-1-yl)-1-nitroso-1,2,3,4-tetrahydroquinoline were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
To a solution of (2R)-(4-amino-phenyl)-tert-butoxycarbonylamino-acetic acid (100 mg, 0.376 mmol) in dichloromethane (2 mL) was added pyridine (36 μL, 0.45 mmol) and acetic anhydride (42 μL, 0.44 mmol) and the mixture stirred at ambient temperature for 2 hours. The reaction mixture was diluted with dichloromethane, washed with 1M aqueous citric acid solution, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted from 0 to 10% v/v methanol in dichloromethane to afford (2R)-(4-acetylamino-phenyl)-tert-butoxycarbonylamino-acetic acid as a yellow solid (59 mg, 51%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:5]([CH3:14])[C:4]=1[F:15])#[N:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20].[Cl-].[Li+]>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:18][N:19]([CH3:21])[CH3:20])[C:10]([O:12][CH3:13])=[O:11])=[C:5]([CH3:14])[C:4]=1[F:15])#[N:2]
Reactant: COC(=O)Cc1ccc(C#N)c(F)c1C
Reactant: COC(OC)N(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: COC(=O)C(=CN(C)C)c1ccc(C#N)c(F)c1C
Temperature: 10 °C
Yield: 62.8 %

Procedure:
Combined methyl 2-(4-cyano-3-fluoro-2-methylphenyl)acetate (10.0 g, 48.3 mmol), 1,1-dimethoxy-N,N-dimethylmethanamine (17.25 g, 145 mmol), and solid lithium chloride (0.205 g, 4.83 mmol) and heated to 105° C. for 1.5 h. The mixture was cooled to 10° C. and water (210 mL) was added slowly. The solid was collected by vacuum filtration, dissolved in DCM and was purified by column chromatography to afford the title compound (7.95 g, 63%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.07 (d, J=2.53 Hz, 3 H) 2.54-2.86 (m, 6 H) 3.50 (s, 3 H) 7.10 (d, J=7.83 Hz, 1 H) 7.62 (s, 1 H) 7.63-7.66 (m, 1 H). ESI-MS m/z [M+H]+ 263.2.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][O:7][C@:8]23[C@@H:21]4[N:22]([CH2:25][CH:26]5[CH2:28][CH2:27]5)[CH2:23][CH2:24][C@:13]52[C:14]2[C:15]([O:30][C@H:12]5[C:11](=[O:31])[CH2:10][CH2:9]3)=[C:16]([OH:29])[CH:17]=[CH:18][C:19]=2[CH2:20]4)=[CH:4][CH:3]=1.[CH3:34][I:35]>O>[I-:35].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C@:8]23[C@@H:21]4[N@+:22]([CH2:25][CH:26]5[CH2:28][CH2:27]5)([CH3:34])[CH2:23][CH2:24][C@:13]52[C:14]2[C:15]([O:30][C@H:12]5[C:11](=[O:31])[CH2:10][CH2:9]3)=[C:16]([OH:29])[CH:17]=[CH:18][C:19]=2[CH2:20]4)=[CH:32][CH:33]=1
Reactant: CI
Reactant: O=C1CC[C@@]2(OCc3ccc(Cl)cc3)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Solvent: O
Product: C[N@+]1(CC2CC2)CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(OCc2ccc(Cl)cc2)[C@H]1C5
Product: [I-]

Procedure:
A solution of 14β-[(4-chlorobenzyl)oxy]-17-cyclopropylmethyl-4,5α-epoxy-3-hydroxymorphinan-6-one (0.50 g, 1.07 mmol) and methyl iodide (0.76 g, 5.37 mmol) in 8 ml of water-free acetonitrile was stirred under N2 at 40° C. (bath temperature) for 6 days and then evaporated down. The residue (0.56 g of brown oil) was purified using column chromatography (silica gel; CH2Cl2/MeOH 250:4). Yield: 0.07 g (11%) of beige crystals of the compound 51. Fp. 214-219° C.; MS (CI): 480 (M+); IR (KBr): 1733 (C═O) cm−1; 1H-NMR (DMSO-d6 δ in ppm): 9.57 (s, OH), 7.57 (d, 2 arom. H, C14-OCH2Ph—Cl, J=8.6 Hz), 7.48 (d, 2 arom. H, C14-OCH2Ph—Cl, J=8.6 Hz), 6.71 (s, 2 arom. H), 5.10 (s, CH-5), 4.86 (d, 1H, C14-OCH2, J=11.4 Hz), 4.75-4.66 (m, 3H, C14-OCH2 and CH-9), 3.44 (s, CH3N+, axial).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:23]=[C:22](B(O)O)[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:22]2[C:16]3[CH2:17][C:18]([CH3:20])([CH3:21])[O:19][C:15]=3[CH:14]=[C:13]([Cl:12])[CH:23]=2)=[CH:4][N:3]=1
Reactant: CC1(C)Cc2c(cc(Cl)cc2B(O)O)O1
Reactant: Cc1c(Br)cnc(N)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(Cl)cc3c2CC(C)(C)O3)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 2.7 grams (0.012 mole) of 6-chloro-2,3-dihydro-2,2-dimethylbenzofuran-4-ylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 mL (catalyst) of tetrakis(triphenylphosphine)palladium(O)in 150 mL of toluene, yielding 2-amino-3-cyano-4-methyl-5-(6-chloro-2,3-dihydro-2,2-dimethylbenzofuran-4-yl)pyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N-].C(=O)([O-])[O-].[K+].[K+]>CCOCC>[CH2:24]([O:23][C:21]([CH:20]1[C:14](=[O:17])[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15]1)=[O:22])[CH3:25]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CCC1=O
Temperature: 25 °C

Procedure:
To 1.0 g (4.28 mmol) 4-oxo-piperidine-1-carboxylic acid benzyl ester in 5 mL anhydrous ether maintained between −25° C. and −30° C. were added, over 20 minutes, solutions of 0.7 mL (5.56 mmol) BF3Et2O in 1.5 mL anhydrous ether, followed by 0.67 mL (6.42 mmol) ethyl diazoacetate in 1.5 mL anhydrous ether, and the reaction was maintained between −25° C. and −30° C. for 1 hour. The mixture was allowed to warm up to room temperature, 10 mL 30% potassium carbonate solution was added and the mixture extracted with EtOAc (3×15 mL), the organic layers were combined and dried with MgSO4. After filtration and evaporation of the solvent the product was purified by flash column chromatography (silica, hexane/EtOAc 9:1 to 8:2).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Mg].Br[C:10]1[CH:15]=CC=[CH:12][C:11]=1F.[Cl-].[NH4+].[CH2:19]1COC[CH2:20]1>O>[CH3:15][C:10]1[CH:3]=[C:2]([OH:1])[C:6]2[C:7]([C:11]=1[CH3:12])=[CH:20][CH:19]=[CH:4][CH:5]=2
Reactant: Fc1ccccc1Br
Reactant: C1CCOC1
Reactant: Cc1ccoc1C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Product: Cc1cc(O)c2ccccc2c1C
Temperature: 35 °C

Procedure:
To a solution of 2,3-dimethylfuran (1.06 mL, 10 mmol) in anhydrous THF (10 mL) was added magnesium powder (0.292 g, 12 mmol). The reaction mixture was heated to reflux for 5 minutes. The reaction flask was placed in a room temperature oil bath and a solution of 1-bromo-2-fluorobenzene (1.08 mL, 10 mmol) in anhydrous THF (10 mL) was added. The reaction mixture was heated to 35° C. for 1 hour, heated to reflux over 1 hour, and stirred at reflux for 1 hour. The reaction mixture was cooled and poured into saturated ammonium chloride solution and diluted with water. The product was extracted with ethyl acetate (2×) and the combined organic layer dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give the desired product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[Si:19]([CH3:22])([CH3:21])[CH3:20].[B:23](OC)([O:26]C)[O:24]C>C1COCC1>[Cl:13][C:14]1[CH:18]=[C:17]([B:23]([OH:26])[OH:24])[S:16][C:15]=1[Si:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: C[Si](C)(C)c1sccc1Cl
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)c1sc(B(O)O)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of diisopropyl amine (1.8 ml, 13 mmol) at 0° C. in 50 mL anhdrous THF under nitrogen was added butyllithium, 2.5 M in hexanes (4.6 ml, 12 mmol). The solution was allowed to stir 5 min and then was cooled to −78° C. (3-Chlorothiophen-2-yl)trimethylsilane (2.0 g, 10 mmol) in 5 mL THF at RT was added slowly via cannula, dropwise, over about 10 min. The resulting solution was allowed to stir for 30 min, at which point trimethyl borate (2.4 ml, 2 μmol) was added dropwise. The solution was allowed to stir for 1 h, and was then warmed to 0° C. and quenched by the addition of 25 mL of 2NHCl, and warmed to ambient temperature with stirring. The mixture was extracted three times with DCM, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a semisolid. Purification by silica gel chromatography, (0-40% EtOAc/hexanes) provided 4-chloro-5-(trimethylsilyl)thiophen-2-ylboronic acid as an off-white solid.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH:13]1[CH:14]=[CH:15][C:16]2N(O)N=[N:19][C:17]=2C=1.C(N)CCCC.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:19][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: On1nnc2ccccc21
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCCCCN
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCCCNC(=O)c1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 127.1 %

Procedure:
4-Azidobenzoic acid (846 mg, 5.08 mmol), HOBt (694 mg, 5.08 mmol, 1.0 eq.) and n-pentylamine (0.783 ml, 6.61 mmol, 1.3 eq.) were dissolved in acetonitrile (6 ml) and DMF (6 ml), WSC (1.19 g, 6.10 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated at 30° C. or below to give the title compound as a pale-yellow solid (1.5 g, including residual solvent).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][C:7]=2[CH:14]=1.[Br:17][CH2:18][CH2:19][NH:20][CH2:21][CH:22]=[O:23]>C1C=CC=CC=1>[Br:17][CH2:18][CH2:19][N:20]([CH2:21][CH:22]=[O:23])[C:12]([NH:11][C:9]1[S:10][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:14][C:7]=2[N:8]=1)=[O:13]
Reactant: O=CCNCCBr
Reactant: O=C=Nc1nc2cc(C(F)(F)F)ccc2s1
Solvent: c1ccccc1
Product: O=CCN(CCBr)C(=O)Nc1nc2cc(C(F)(F)F)ccc2s1
Reaction time: 1 h

Procedure:
5-Trifluoromethylbenzothiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-β-bromoethylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about 1 hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-β-bromoethyl-3-(5-trifluoromethylbenzothiazol-2-yl)ureido]acetaldehyde as the residue.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38](Cl)[C:37]=3[CH3:43])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].C1(P(C2CCCCC2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:57]2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O1CCCC1.CN1CCCC1=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([CH2:57][CH:52]4[CH2:53][CH2:54][CH2:55][CH2:56][CH2:51]4)[C:37]=3[CH3:43])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: Cc1c(Cl)cccc1-c1ccc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)nc1C(=O)OC(C)(C)C
Reactant: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1c(CC2CCCCC2)cccc1-c1ccc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)nc1C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
A mixture of EXAMPLE 107A (60 mg), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos, 4.58 mg) and tris(dibenzylideneacetone)dipalladium(0) (2.25 mg) in tetrahydrofuran (0.5 mL) and 1-methyl-2-pyrrolidinone (0.5 mL) was stirred at room temperature for 5 minutes while bubbling N2 through the reaction mixture. To this solution was added 0.5 M (cyclohexylmethyl)zinc(II) bromide (0.393 mL) at room temperature. The reaction mixture in a sealed tube was heated in a preheated oil bath at 100° C. overnight and cooled. The reaction mixture was quenched with water and diluted with dichloromethane. The dichloromethane layer was washed with water and concentrated. The residue was purified by flash chromatography, and eluted with 5% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:14]([NH:18][S:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1)(=[O:12])=[O:11])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CCCc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-n-propylbenzenesulfonyl chloride (Lancaster) in anhydrous CH2Cl2 (0.5M solution) cooled to 0° C. under N2 was added t-butylamine (2.2 equivalents) slowly through a dropping funnel. After complete addition, the reaction was stirred at room temperature for 12 hours. The CH2Cl2 was removed under reduced pressure, and the residue was extracted into ether and washed with 2N NaOH, H2O and brine. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to afford the title compound; TLC in 3:1 hexane-EtOAc (Rf =0.46) (3:1 hexane-EtOAc). 200 MHz 1H NMR (CDCl3) δ0.93 (t, 3H), 1.22 (s, 9H), 1.62 (m, 2H), 2.65 (t, 2H), 4.67 (br s, 1H), 7.27 (d, 2H), 7.79 (d, 2H).
Reaction SMILES: [N:1]1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.Cl[CH2:26][C:27]1[N:31]2C=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][C:28]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1.[NH:43]1[CH:47]=[N:46][CH:45]=[N:44]1>>[N:43]1([CH2:26][C:27]2[N:31]3[N:1]=[CH:33][CH:34]=[CH:35][C:30]3=[N:29][C:28]=2[C:36]2[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=2)[CH:47]=[N:46][CH:45]=[N:44]1
Reactant: c1nc[nH]n1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: Clc1ccc(-c2nc3cccnn3c2Cn2cncn2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 1H-1,2,4-triazole. 1H-NMR (CDCl3, 400 MHz, δ) 8.74 (s, 1H) 8.07 (d, J=8.5 Hz, 2H), 8.07 (d, J=8.5 Hz, 2H), 8.01 (dd, J=1.3, 9.2 Hz, 1H), 7.95 (s, 1H), 7.51 (m, 2H), 7.17 (dd, J=4.5, 9.2 Hz, 1H), 5.85 (s, 2H) ppm; [M+H]+ 311
Reaction SMILES: ClC1C=C[C:5]([O:6]CC(OC(C)(C)C)=O)=C(CN(C)C2CCN(S(C3C=CC=CC=3)(=O)=O)C2)C=1.[Cl:34][C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][C:41]([OH:43])=[O:42])=[C:37]([CH2:46][N:47]2[CH2:52][CH2:51][N:50]([C:53](=[O:62])[CH2:54][C:55]3[CH:60]=[CH:59][C:58](F)=[CH:57][CH:56]=3)[C@@H:49]([CH3:63])[CH2:48]2)[CH:36]=1.ClC1C=CC(OCC(OC(C)(C)C)=O)=C(COS(C)(=O)=O)C=1.COC1C=CC(CC(Cl)=O)=CC=1>>[Cl:34][C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][C:41]([OH:43])=[O:42])=[C:37]([CH2:46][N:47]2[CH2:52][CH2:51][N:50]([C:53](=[O:62])[CH2:54][C:55]3[CH:60]=[CH:59][C:58]([O:6][CH3:5])=[CH:57][CH:56]=3)[C@@H:49]([CH3:63])[CH2:48]2)[CH:36]=1
Reactant: CN(Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2ccccc2)C1
Reactant: C[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1C(=O)Cc1ccc(F)cc1
Agent: CC(C)(C)OC(=O)COc1ccc(Cl)cc1COS(C)(=O)=O
Agent: COc1ccc(CC(=O)Cl)cc1
Product: COc1ccc(CC(=O)N2CCN(Cc3cc(Cl)ccc3OCC(=O)O)C[C@@H]2C)cc1

Procedure:
The title compound was prepared by the methods of example 89 part (f) and example 89 part (g) using the product of example 89 part (e) and 4-methoxy-benzeneacetyl chloride.