Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:11][CH:12]([CH2:18][Br:19])[C:13]([N:15]=[C:16]=[O:17])=[O:14]>C(#N)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:16]([NH:15][C:13](=[O:14])[CH:12]([Br:11])[CH2:18][Br:19])=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C=NC(=O)C(Br)CBr
Solvent: CC#N
Product: O=C(NC(=O)C(Br)CBr)Nc1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
14.0 g of 4-nitroaniline are dissolved in 200 ml of anhydrous acetonitrile, and 26.0 g of 2,3-dibromopropionyl isocyanate are added dropwise with cooling at 5° to 10° C. After stirring for 3 hours at 20° C., the solid precipitated is filtered off and dried. Yield: 35.0 g m.p.: 205° - 206° C. (decomp.).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][NH:15][N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1N2CCN(CC2)C1.I/[CH:29]=[CH:30]\[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32]>CN(C=O)C>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:29]=[CH:30]\[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: CC(C)OC(=O)/C=C\I
Reactant: FC(F)(F)c1cc(-c2nc[nH]n2)cc(C(F)(F)F)c1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CC(C)OC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
A 2-L, 3-necked, round-bottomed flask was charged with a solution of 3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazole (160 g) in DMF (960 mL). The solution was treated with DABCO (127.74 g, 2 eq.) and stirred for 30 min before adding (Z)-isopropyl 3-iodoacrylate (150.32 g, 1.1 eq.) dropwise. After ca. 1 hour, the reaction mixture was poured into an ice-water slurry (5 L) and extracted with EtOAc (3×1 L). The combined organic layers were washed with aqueous saturated brine (3×100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure (35° C., 20 mmHg) to afford 250 g of crude compound that was purified by column chromatography (60/120 silica gel) using a ethyl acetate/n-hexane gradient (the column was packed in hexane and the desired compound started eluting from 2% EtOAC/n-hexane). Fractions containing the desired compounds were combined to afford 138 g the pure desired compound (yield: 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc(Cl)cc3)n[nH]2)CC1
Agent: Cl
Solvent: ClCCl
Product: Clc1ccc(-c2cc(C3CCNCC3)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
INTERMEDIATE 7 was obtained by removal of the Boc group of INTERMEDIATE 1 with an acid. To a solution of INTERMEDIATE 1 (2.5 g, 6.92 mmol) in dichloromethane (10 mL) was added 4 M HCl (10 mL, 40 mmol in dioxane). The mixture was stirred at room temperature overnight. Solvent was evaporated under reduced pressure, and the residue was dried under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2(C#N)[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1.[CH3:24][NH:25][CH3:26]>C1COCC1.O>[CH3:24][N:25]([CH3:26])[C:9](=[O:10])[C:11]1[C:6]([C:7]([C:12]2[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[N:17]=2)=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[Cl:1]
Reactant: CNC
Reactant: COc1cc(OC)nc(C2(C#N)OC(=O)c3c(Cl)cccc32)n1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)nc(C(=O)c2cccc(Cl)c2C(=O)N(C)C)n1
Reaction time: 0.25 h

Procedure:
1.0 g of 7-chloro-3-cyano-3-(4,6-dimethoxy-2-pyrimidinyl) phthalide is dissolved in 15 ml of THF. 0.7 ml of a 40% aqueous dimethylamine solution is then added via syringe whereupon the solution darkens. Stirring is continued at R.T. for 15 minutes and the mixture diluted with water and partitioned between ethyl acetate and water. The organic phase is separated, washed with 2N H2SO4, then brine, dried and concentrated. The residue is purified on silica gel, eluant 200 ml of 50% ethyl acetate/hexane then 100% ethyl acetate. Fractions 12 to 15 yielded the title compound, m.p. 141-°42° C.
Reaction SMILES: C[Si](I)(C)C.[CH3:6][O:7][C:8](=[O:33])[C@H:9]([NH:22]C(OCC1C=CC=CC=1)=O)[CH2:10][C:11]1[C:20]([Br:21])=[CH:19][C:14]2[NH:15][C:16](=[O:18])[O:17][C:13]=2[CH:12]=1.C(N(CC)CC)C>C(#N)C>[CH3:6][O:7][C:8](=[O:33])[C@H:9]([NH2:22])[CH2:10][C:11]1[C:20]([Br:21])=[CH:19][C:14]2[NH:15][C:16](=[O:18])[O:17][C:13]=2[CH:12]=1
Reactant: COC(=O)[C@@H](Cc1cc2oc(=O)[nH]c2cc1Br)NC(=O)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](N)Cc1cc2oc(=O)[nH]c2cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trimethylsilyliodide (73 mL, 0.73 mmol) was added to a solution of azotropically dried (R)-2-benzyloxycarbonylamino-3-(5-bromo-2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester (146 mg, 0.33 mmol) in acetonitrile (10 mL) at room temperature, and the resulting mixture was stirred at room temperature for 2 h. Triethylamine (0.12 mL) was added and the mixture was stirred at room temperature for 15 min. The solvents were removed in vacuo, and the residue was extracted with ethyl acetate. The combined organics were washed with sodium bicarbonate and brine, dried over sodium sulfate and filtered. Solvents were removed and the residue was used directly in the next step. Mass spec. 315.10 (MH)+.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([SH:18])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]1([C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:10]([S:18][CH2:20][CH2:21][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Sc1[nH]nc(-c2ccccc2)c1-c1ccccc1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(-c2n[nH]c(SCCOC3CCCCO3)c2-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of 3,4-diphenyl-1H-pyrazole-5-thiol (1.2 g, 4.76 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.994 g, 4.76 mmol) in DMF (5 mL) was added K2CO3 (1.0 g, 7.23 mmol). The reaction was stirred at 60° C. for 2 h, cooled to room temperature, and quenched with H2O (5 mL). The mixture was extracted with EtOAc, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless oil (1.7 g). LCMS m/z=381.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.50 (m, 4H), 1.50-1.73 (m, 2H), 2.99-3.13 (m, 1H), 3.21-3.44 (m, 2H), 3.46-3.59 (m, 1H), 3.61-3.82 (m, 2H), 4.44-4.59 (m, 1H), 7.16-7.40 (m, 10H), 13.32 (bs, 1H).
Reaction SMILES: [NH:1]1[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O.[C:10]1([CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[OH-].[Na+].C1C=CC=CC=1>[C:10]1([CH2:16][CH2:17][CH2:18][C:19]([N:1]2[CH2:8][S:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)[C@@H]1CSCN1
Reactant: O=C(Cl)CCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)[C@@H]1CSCN1C(=O)CCCc1ccccc1
Yield: 81.9 %

Procedure:
Dissolved in 100 ml of 1N sodium hydroxide were 6.65 g of L-thioproline, and 50 ml of water were further added to the solution. A solution of 9.10 g of 4-phenylbutanoyl chloride in 50 ml of benzene was added dropwise to the solution under stirring. Thereafter, 50 ml of 1N sodium hydroxide were further added, and the mixture was stirred for 24 hours. A benzene layer was removed, and a water layer was washed twice with 70 ml of ether. After 7% hydrochloric acid was further added to the water layer to acidify it, the water layer was extracted three times with 70 ml of ethyl acetate. The resulting extract was dried over anhydrous sodium sulfate. Ethyl acetate was distilled off, and the resultant oily residue was subjected to column chromatography on silica gel, thereby obtaining 11.4 g of N-(4-phenylbutanoyl)-L-thioproline as colorless crystals from a chloroform-methanol fraction.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:32][O:31][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:37]1[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCN1CCN(C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (50 mg), 4-methylpiperazine (33 mg), and potassium carbonate (76 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (29 mg, yield 52%).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl.[Cl:13][CH2:14][CH2:15][N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:17][CH2:18]Cl.[Br-].C([P+](CC)(CC)CC)CCCCCCCCCCCCCCC.Cl.[OH-].[K+]>CO.O>[ClH:13].[CH2:20]([N:16]1[CH2:17][CH2:18][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:8]#[N:9])[CH2:14][CH2:15]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: N#CCc1ccccc1
Agent: CCCCCCCCCCCCCCCC[P+](CC)(CC)CC
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: CO
Product: N#CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Combine phenylacetonitrile (40 mmol), and aqueous sodium hydroxide solution (60 mL, 50% by weight). Add N,N-bis(2-chloroethyl)benzylamine hydrochloric acid salt (11.28 g, 42 mmol) and hexadecyltriethyl phosphonium bromide (1.02 g, 2 mmol). Heat to 100° C and stir vigorously. After 1 hour, cool the reaction mixture to ambient temperature. Add water and acidify the diluted reaction mixture with an aqueous 6M hydrochloric acid solution. Extract the acidified reaction mixture with diethyl ether. Adjust the pH of the aqueous layer to about 12 using solid potassium hydroxide and extract with ethyl acetate. Separate the ethyl acetate layer, dry over MgSO4, filter, and evaporate invacuo to give a residue. Combine the residue and a solution of hydrochloric acid in methanol. Evaporate in vacuo to give 1-benzyl-4-phenyl-4-cyanopiperidine hydrochloric acid salt.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CON(C)C(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CON(C)C(=O)c1ccc(OCc2ccccc2)cn1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
A mixture of 5-hydroxy-N-methoxy-N-methylpicolinamide (7.51 g), K2CO3 (6.27 g) and benzyl bromide (2.83 mL) in acetone (70 mL) was stirred at 50° C. for 14 h, evaporated, treated with water and extracted with AcOEt. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to the title compound (4.87 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17][CH2:16][C:4]21[CH2:8][N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:5]2.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:9]([N:7]1[CH2:6][CH2:5][C:4]2([CH2:16][CH2:17][CH2:18][NH:19][CH:3]2[CH2:2][NH2:1])[CH2:8]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCN(Cc3ccccc3)C2)C1CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1NCCCC12CCN(Cc1ccccc1)C2
Temperature: 25 °C

Procedure:
1 mmol of tert-butyl 6-aminomethyl-2-benzyl-2,7-diazaspiro[4.5]decane-7-carboxylate is dissolved in 2 ml of dichloromethane and the solution is admixed with 2 ml of trifluoroacetic acid. The reaction solution is stirred at room temperature until conversion is complete and then is poured into saturated aqueous sodium hydrogen carbonate solution. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine, dried over sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: [F:1][C:2]1[C:21]([NH:22][C:23]([NH:25]C2C=CN=C(C)C=2)=[O:24])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])C)=[O:12])[CH2:7][CH2:6]1.Cl.CCN(CC)CC.[CH:41]1[C:46]([N+:47]([O-])=O)=[CH:45][CH:44]=[C:43]([Cl-]C([O-])=O)[CH:42]=1.OC1C[CH2:59][O:58][CH2:57]C1.[H-].[Na+].C(=O)([O-])N>CO.O1CCOCC1.C(Cl)Cl>[O:58]1[CH2:59][CH2:16][CH:14]([O:13][C:11]([N:8]2[CH2:7][CH2:6][N:5]([CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[C:21]([NH:22][C:23]([NH:25][C:43]4[CH:42]=[N:47][C:46]([CH3:41])=[CH:45][CH:44]=4)=[O:24])[C:2]=3[F:1])[CH2:10][CH2:9]2)=[O:12])[CH2:17][CH2:57]1
Reactant: OC1CCOCC1
Reactant: Cc1cc(NC(=O)Nc2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2F)ccn1
Agent: Cl
Agent: NC(=O)[O-]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)Nc2cccc(CN3CCN(C(=O)OC4CCOCC4)CC3)c2F)cn1
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
To a solution of tert-butyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)piperazine-1-carboxylate (1.0 g, 2.26 mmol, 1.0 equiv) in MeOH (10 mL) was added HCl (71 (4N in dioxane, 10 mL, 40 mmol, 17.7 equiv). The mixture was stirred for 30 min, and the solvent was then removed in vacuo. The residue was suspended in dry DCM (20 mL) and Et3N (1.64 mL, 11.79 mmol, 5.2 equiv). To the resulting mixture was added 4-nitrophenylchloroformate (500 mg, 2.49 mmol, 1.1 equiv). The resulting solution was stirred for 30 min, diluted with DCM, washed with aq NH4Cl and brine and concentrated in vacuo. The resulting residue was divided into three equal portions for subsequent derivitization. To a solution of 4-hydroxytetrahydropyran (190 μL, 2 mmol, 2.65 equiv) was added NaH (120 mg of 60% dispersion in mineral oil, 3.0 mmol, 4 equiv) after stirring for 10 minutes, the activated carbamate was added to the reaction mixture, and the reaction was stirred at room temperature overnight. The excess NaH was quenched by the careful addition of water, and the reaction mixture was diluted with ethyl acetate. The organic layer was washed repeatedly with water and once with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by preparative reverse phase HPLC provided tetrahydro-2H-pyran-4-yl4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate (140 mg, 39%). LCMS m/z (APCI)=472.2 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.[CH3:22][N:23]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[C:24]1[N:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=[O:27]>C1COCC1>[CH3:22][N:23]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[C:24]1[C:25]([CH:26]([OH:27])[CH:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:28][CH:29]=[CH:30][N:31]=1
Reactant: c1cncc(Cc2cccnc2)c1
Reactant: CN(c1cccnc1)c1ncccc1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(c1cccnc1)c1ncccc1C(O)C(c1cccnc1)c1cccnc1
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
A solution of bis-(3-pyridyl)methane (61 mg) in 3 mL THF was cooled to 0 C, and LDA (1.5 M in cyclohexane, 0.240 mL) was added dropwise via syringe. After the mixture had been stirred for 30 min, a solution of 2-[methyl(pyridin-3-yl)amino]nicotinaldehyde (73 mg) in 3 mL THF was added dropwise over 30 min. After 3 h stirring at 0 C, the reaction was quenched with water, then partitioned between saturated aqueous sodium bicarbonate and CH2Cl2. The aqueous solution was extracted with CH2Cl2 (2×), and the combined organic solutions were dried (Na2SO4) and purified by reverse phase HPLC to give 40 mg of 1-{2-[methyl(pyridin-3-yl)amino]pyridin-3-yl}-2,2-dipyridin-3-ylethanol.
Reaction SMILES: [Br:1][C:2]1[C:6]([CH2:7]Cl)=[CH:5][N:4]([C:9]([CH2:12][CH3:13])([CH3:11])[CH3:10])[N:3]=1.[I-:14].[Na+]>CC(C)=O>[Br:1][C:2]1[C:6]([CH2:7][I:14])=[CH:5][N:4]([C:9]([CH2:12][CH3:13])([CH3:11])[CH3:10])[N:3]=1
Reactant: CCC(C)(C)n1cc(CCl)c(Br)n1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(C)(C)n1cc(CI)c(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a solution of 3-bromo-4-(chloromethyl)-1-tert-pentyl-1H-pyrazole (725 mg, 2.73 mmol) in acetone (25 mL) was added sodium iodide (4.09 g, 27.3 mmol). The reaction was heated at reflux for 2 hours, then cooled to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium thiosulfate and brine. The organics were dried over sodium sulfate, filtered, and concentrated to yield the title compound (824 mg, 85%) as a brown oil. 1H NMR (400 MHz, CDCl3, δ): 7.47 (s, 1H), 4.26 (s, 2H), 1.83 (q, J=7.41 Hz, 2H), 1.50 (s, 6H), 0.67 (t, J=7.51 Hz, 3H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[CH2:14][C:15]#[N:16].CCN(CC)CC>CN(C=O)C.CCOC(C)=O.[Cl-].[Na+].O>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:12])[N:2]1[O:1][CH2:14][C:15]#[N:16]
Reactant: N#CCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.7 %

Procedure:
To a solution of N-hydroxyphthalimide (5.20 g, 31.88 mmol) in DMF (20 ml) was added bromoacetonitrile (3.0 ml, 45.02 mmol) and Et3N (10.0 ml, 71.8 mmol) and the reaction stirred at room temperature for 2 d. The mixture was diluted with EtOAc (50 ml) and brine (40 ml) and the organic layer was washed with brine (4×20 ml) and 1 N NaOH (30 ml), dried (Na2SO4) and concentrated to afford (1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-acetonitrile (2.3 g, 36%) as a beige solid. 1H NMR (CDCl3) δ 4.96 (s, 2H), 7.80-7.84 (m, 2H), 7.89-7.92 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])O.[Na+].[C:15]([C:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([CH3:19])[CH3:18])#[N:16]>O1CCCC1>[C:15]([C:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1)=[O:24])([CH3:19])[CH3:18])#[N:16]
Reactant: Cc1ccc(N)cc1O
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (5.00 g, 26.4 mmol) in tetrahydrofuran (50 mL) were added N,N-dimethylformamide (40 μL) and oxalyl chloride (3.20 mL, 36.5 mmol), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure to give 3-(1-cyano-1-methylethyl)benzoyl chloride. To a solution of 5-amino-2-methylphenol (3.00 g, 24.3 mmol) in tetrahydrofuran (20 mL) was added an aqueous suspension (30 mL) of sodium hydrogen carbonate (3.00 g, 36.5 mmol), and the mixture was vigorously stirred at room temperature. To this mixture was added dropwise under ice-cooling a solution of the above-mentioned 3-(1-cyano-1-methylethyl)benzoyl chloride in tetrahydrofuran (30 mL), and the mixture was stirred at room temperature for 5 hr. The aqueous layer of the reaction mixture was separated, and the organic layer was diluted with ethyl acetate (200 mL) and washed with saturated brine (200 mL). The extract was dried over anhydrous magnesium sulfate and decolored with activated carbon. The insoluble material was filtered off through a pad packed with silica gel and celite in two layers. The solvent was evaporated under reduced pressure, and the obtained solid was washed with a mixed solvent of ethyl acetate and hexane to give the title compound (6.75 g, 94%) as a white powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].Cl.[NH2:13][C:14]1[O:15][C:16]2[CH:22]=[C:21]([CH2:23]Cl)[CH:20]=[CH:19][C:17]=2[N:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([NH:4][C:5]1[C:10]([O:11][CH2:23][C:21]2[CH:20]=[CH:19][C:17]3[N:18]=[C:14]([NH2:13])[O:15][C:16]=3[CH:22]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: Nc1nc2ccc(CCl)cc2o1
Reactant: CC(=O)Nc1ncccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ncccc1OCc1ccc2nc(N)oc2c1
Temperature: 40 °C
Reaction time: 4.3 h
Yield: 40.6 %

Procedure:
A mixture of 2-acetamido-3-hydroxypyridine (1.3 g), 2-amino-6-chloromethylbenzoxazolehydrochloride (1.5 g) and potassium carbonate (2.8 g) in N,N-dimethylformamide (20 ml) was stirred for 4.3 hours at 40° C. The reaction mixture was added to water and the mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was crystallized from ethyl acetate to give 6-(2-acetamido-pyridin-3-yloxymethyl}-2-aminobenzoxazole (0.83 g).