Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].CN(C=O)C.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>O>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:30][C:29]1[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=1)[CH:20]=[CH:19]2)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2ccc3cc(OCc4ccccc4)ccc32)cc1
Temperature: 10 °C
Reaction time: 0.08 h

Procedure:
The KOH pellets are added to the mixture of DMF and water, and the mixture is vigorously stirred for 5 minutes. After addition of the 5-benzyloxyindole, the mixture is stirred at room temperature for a further 45 minutes. Then, at an internal temperature of 10–20° C., 4-fluorobenzyl chloride is added dropwise while stirring. The mixture is then stirred at room temperature for a further 90 minutes. The mixture is cooled to 10° C., and 300 ml of water are added. It is cooled during this so that the internal temperature does not exceed 20° C. The mixture is stirred for 2 hours, and then the precipitate is filtered off with suction, washed with water and dried at 30° C. initially in circulating air and then in vacuo. The resulting product is very pure so that no additional purification operation is necessary.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].C(#N)C.[Cl:22]N1C(=O)CCC1=O.O>ClCCl>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:10][C:8]=2[C:9]=1[Cl:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
5.34 g (0.02 mol) of N-(2-butyl-1-benzofuran-5-yl)methanesulfonamide (II) is dissolved in 60 mL of dichloromethane and 60 mL of acetonitrile is added to the solution. 5.34 g (0.04 mol, 2 eq) of N-chlorosuccinimide in solid form is added dropwise at −8±2° C. in 20 min. The reaction mixture is stirred for 2 hours at this temperature and then heated up to 20° C. The reaction mixture is poured into 200 mL of water. The product is extracted with 2×80 mL of dichloromethane. The organic layer is evaporated and the residue is purified by column chromatography (spheric silica; eluent: toluene:methanol=7:3) to give 4.59 g (76%) of the title compound (IIIa) as a yellowish-brown solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1)[CH2:2][CH3:3].[Br:11]Br.C(=O)([O-])O.[Na+]>C(O)C>[Br:11][C:9]1[C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][C:6]([NH2:10])=[N:7][CH:8]=1
Reactant: BrBr
Reactant: CCCc1ccnc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCc1cc(N)ncc1Br
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of 4-propylpyridin-2-amine (5.70 g, 41.8 mmol) in ethanol (210 mL), a solution of bromine in ethanol (bromine 2.38 mL/ethanol 50 mL) was added under ice-cold conditions, and the mixture was stirred under ice-cold conditions for 0.5 hours. Under ice-cold conditions, the reaction solution was added an aqueous solution of sodium hydrogen carbonate, concentrated in vacuo, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (4.34 g (yield 48%)) was obtained as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([S:11](Cl)(=[O:13])=[O:12])=[C:8]([CH3:15])[C:7]=2[CH:16]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([S:11]([NH:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=[O:22])(=[O:13])=[O:12])=[C:8]([CH3:15])[C:7]=2[CH:16]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: COc1ccc2sc(S(=O)(=O)Cl)c(C)c2c1
Product: COc1ccc2sc(S(=O)(=O)Nc3cccc(C(=O)O)c3)c(C)c2c1
Yield: 33 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 5-methoxy-3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 8) (85 mg, 0.31 mmol) and 3-aminobenzoic acid (42 mg, 0.31 mmol). The title compound was obtained in 33% yield (38.2 mg). MS (ESI+) calcd mass for C17H15NO5S2 377.039164, found 377.039474.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH3:36][Zn]C.C1(C)C=CC=CC=1.C(Cl)Cl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:36])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (21.54 g, 40 mmol) in 1,4-dioxane (300 mL) was bubble with argon for 10 min. The reaction mixture was treated with 2N dimethylzinc in toluene (40 mL, 80 mmol) under argon. The reaction mixture was treated with PdCl2(dppf).CH2Cl2 adduct (0.326 g, 0.400 mmol) and heated to 80° C. After 2 h, the reaction was check by HPLC. The reaction was cooled to room temperature and slowly added MeOH until reaction was quenched. After quenched, the reaction mixture was diluted with NaHCO3 (sat'd) (200 mL) and extracted with EtOAc (3×, 200 mL). The EtOAc layers were stirred with activated carbon (darco G-60, 100 mesh, powder) for 1 h. The reaction mixture was filtered through pad of SiO2 (3″×3″) and washed with EtOAc. The reaction mixture was concentrated. IPA (350 mL) was to the reaction mixture and heated to reflux. After 2 h, the reaction mixture was cooled to room temperature and filtered and washed with IPA and water (200 mL). The product was dried under vacuum at 60° C. for 2 days. Title compound was obtained as an off-white solid (17.5 g, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.47 (d, J=5.3 Hz, 1H), 7.52-7.58 (m, 1H), 7.40-7.50 (m, 4H), 7.29 (t, J=7.8 Hz, 1H), 6.64 (d, J=5.3 Hz, 1H), 2.58 (s, 3H), 1.42 (s, 9H). MS (ESI): 519 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([C:24]([NH2:26])=[O:25])[C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH3:11])=[C:4]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:3]=1.[H-].[Na+].[CH3:35]I>CN(C)C=O>[CH3:35][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([C:24]([NH2:26])=[O:25])[C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][CH:23]=2)[CH2:9][CH2:10][CH3:11])=[C:4]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH:3]=1
Reactant: CCCC(c1ccc(O)cc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)OCC)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(c1ccc(OC)cc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)OCC)cc1
Reaction time: 0.25 h

Procedure:
A solution of 5.0 gm (11.4 m mol) of ethyl 4-[(1-(4-hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate in 45 ml of absolute dimethylformamide was added dropwise, under stirring, at ambient temperature, to 548 mg (11.4 m mol) of sodium hydride (50% in oil) in 10 ml of absolute dimethylformamide. The mixture was stirred for a further 15 minutes, and then a solution of 0.71 ml (11.4 m mol) of methyliodide in 8 ml of absolute dimethylformamide was slowly added thereto dropwise. The mixture was stirred for a further two and one-half hours at ambient temperature, evaporated in vacuo, and distributed between water and ether. The ether phase was dried, filtered, and concentrated by evaporation in vacuo. The evaporation residue was purified by column chromatography on silica gel [toluene/acetone (20:1)].
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8])(=[O:4])=[O:3].[C:11](Cl)(=[O:13])[CH3:12]>>[CH3:1][S:2]([O:5][CH:6]([CH3:10])[C:7]([O:9][C:11](=[O:13])[CH3:12])=[O:8])(=[O:4])=[O:3]
Reactant: CC(OS(C)(=O)=O)C(=O)O
Reactant: CC(=O)Cl
Product: CC(=O)OC(=O)C(C)OS(C)(=O)=O

Procedure:
The acyl halides can be converted to the symmetrical or mixed acid anhydrides corresponding to the compounds of formula II when Y is acyloxy, by contacting the acyl halide with an appropriate acid. For example, 2-methanesulfonyloxypropionyl chloride is allowed to react with acetic acid to afford the mixed anhydride, acetic 2-methanesulfonyloxypropionic anhydride. Additionally, for example, 2-methanesulfonyloxypropionyl chloride is allowed to react with 2-methanesulfonylotypropionic acid to afford bis(2-methanesulfonyloxypropionic)anhydride, a symmetrical anhydride. Alternatively, the acid precursors of the acyl halides of formula II can be contacted with an appropriate acyl halide to afford the symmetrical or mixed acid anhydrides. For example, 2-methanesulfonyloxypropionic acid is allowed to react with acetyl chloride to afford the mixed anhydride, acetic 2-methanesulfonyloxypropionic anhydride.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[C:28]([F:50])=[CH:29][C:30]([Cl:49])=[C:31]([CH:48]=1)[O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]3[CH2:47][CH2:46]3)=[O:44])[N:41]=2)[N:38]=1>CN(C)C=O.CN1CCCC1=O>[Cl:49][C:30]1[C:31]([O:32][C:33]2[CH:34]=[CH:35][C:36]3[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]4[CH2:46][CH2:47]4)=[O:44])[N:41]=3)[N:38]=2)=[CH:48][C:27]([NH:26][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=2)=[C:28]([F:50])[CH:29]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c(Cl)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c(Cl)cc2F)c1
Yield: 69.3 %

Procedure:
Using 3-(1-cyano-1-methylethyl)benzoic acid (100 mg, 0.55 mmol), oxalyl chloride (59 μL, 0.69 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (2.0 mL), N-[6-(5-amino-2-chloro-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (170 mg, 0.46 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (170 mg, 70%) was obtained as a white powder.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]=O)=[C:7]([NH2:14])[CH:6]=1)(=[O:3])[CH3:2]>C(O)(=O)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]2[NH:11][CH:12]=[N:14][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(NC=O)c(N)c1
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc2[nH]cnc2c1
Yield: 73.7 %

Procedure:
3-Amino-4-(formylamino)phenyl acetate (10.3 g, 53.1 mmol) was dissolved in ˜100 mL of glacial acetic acid and heated at 65 degrees centigrade for approximately 18 hours. The reaction was concentrated and dried under vacuum. The residue was dissolved in ethyl acetate and washed three times with saturated NaHCO3. The organic layer was dried over MgSO4 and concentrated to give 6.89 g of 1H-benzimidazol-5-yl acetate. (M+1) 177.1, 1.02 min (LC/MS method B)
Reaction SMILES: Cl[C:2]1[C:3]([CH3:19])=[C:4]([CH3:18])[C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[CH2:20]([N:27]1[CH2:34][CH:33]2[CH:29]([CH2:30][NH:31][CH2:32]2)[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>C(O)CCCC>[CH2:20]([N:27]1[CH2:34][CH:33]2[CH2:32][N:31]([C:2]3[C:3]([CH3:19])=[C:4]([CH3:18])[C:5]4[N:6]([CH:8]=[C:9]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)[N:10]=4)[N:7]=3)[CH2:30][CH:29]2[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(CN2CC3CNCC3C2)cc1
Reactant: Cc1c(Cl)nn2cc(-c3ccc(F)cc3)nc2c1C
Agent: Cl
Solvent: CCCCCO
Product: Cc1c(N2CC3CN(Cc4ccccc4)CC3C2)nn2cc(-c3ccc(F)cc3)nc2c1C
Temperature: 150 °C

Procedure:
A mixture of 3.00 g (10.9 mmol) of 6-chloro-2-(4-fluorophenyl)-7,8-dimethylimidazo[1,2-b]pyridazine and 6.6 g (33 mmol) of 2-benzyloctahydropyrrolo[3,4-c]pyrrole in 20 mL of pentanol is heated at 150° C. for 2 days in a reactor. The medium is then poured into aqueous 1N hydrochloric acid solution. The aqueous phase is washed with ethyl acetate and then basified with sodium hydroxide.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=O)=O)=[CH:22][CH:21]=3)=[CH:18][C:17]([CH:30]([F:32])[F:31])=[N:16]2)=[CH:11][CH:10]=1)(=O)[NH2:7]>CN(C)C=O>[C:6]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([S:26][CH3:29])=[CH:22][CH:21]=3)=[CH:18][C:17]([CH:30]([F:32])[F:31])=[N:16]2)=[CH:13][CH:14]=1)#[N:7]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)F)nn2-c2ccc(C(N)=O)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CSc1ccc(-c2cc(C(F)F)nn2-c2ccc(C#N)cc2)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 114.7 %

Procedure:
A solution of phosphorus oxychloride (1.7 g) in N,N-dimethylformamide (20 ml) was stirred at 5° C. for 30 minutes. To the solution was added 1-(4-carbamoylphenyl) -3-(difluoromethyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (2 g). The resulting mixture was stirred at 5° C. for 2 hours, poured into ice-water, and extracted with a mixture of tetrahydrofuran and ethyl acetate. The extract was washed with water, dried, and evaporated to give an oil of 1-(4-cyanophenyl)-3-(difluoromethyl)-5-[4-(methylthio)phenyl]pyrazole (2.0 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].Br[CH2:17][CH2:18][OH:19]>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][CH2:17][CH2:18][OH:19])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OCCBr
Product: OCCNc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 56.5 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)aniline (4.6 g) in 2-bromoethanol (25.0 g) was stirred at 70° C. for 14 hr, and concentrated under reduced pressure. The residue was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate/hexane) to give 2-{[3,5-bis(trifluoromethyl)phenyl]amino}ethanol (3.1 g, 58%) as a brown powder.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])C)=[O:2].C([Li])(C)(C)C.CCCCC.[C:25]([N:32]1[CH2:37]CC(=O)C[CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>O1CCCC1.C(OCC)C.CC(C)([O-])C.[K+]>[O:2]=[C:1]1[NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:4]2([CH2:6][CH2:37][N:32]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:33][CH2:7]2)[O:3]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)OC(=O)Nc1ccccc12
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
N-Boc-aniline (16.12 g, 83.4 mmol) was dissolved in anhydrous tetrahydrofuran (120 mL) and cooled to −70° C. To this solution was added dropwise, under nitrogen, a 1.7 M solution of tert-butyllithium in pentane (110 mL, 187 mmol) at −70° C. After 30 min at −70° C., the solution was warmed to −20° C. and maintained at that temperature for 2 h. The solution was again cooled to −70° C. and treated dropwise with a solution of N-Boc-4-piperidone (15.98 g, 80.2 mmol) in anhydrous tetrahydrofuran (50 mL). The solution was slowly warmed to room temperature, treated with potassium tert-butoxide (25 mg) and stirred at room temperature overnight under nitrogen. The solution was diluted with diethyl ether (300 mL), cooled in an ice-H2O bath and adjusted to pH 7 with 1.0 NHCl (aq). The layers were separated and the aqueous layer extracted once with diethyl ether (100 mL). The pooled organic layers were washed with H2O and saturated brine, then dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford 39.09 g crude product as a viscous pale yellow oil. The crude product was purified via silica gel flash chromatography (25-50% ethyl acetate in hexanes) to afford tert-butyl 2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate as a pale yellow solid (8.687 g, 34% yield). LC/MS m/z 319.0 [M+H]+, retention time 2.72 min (RP-C18, 10-99% CH3CN/0.05% TFA); 1H-NMR (400 MHz, CDCl3) δ 9.06 (br s, 1H), 7.28 (m, 1H), 7.12 (m, 2H), 6.91 (d, J=8.5 Hz, 1H), 4.12 (br d, J=9.9 Hz, 2H), 3.36 (br t, J=12.4 Hz, 2H), 2.13 (br d, J=13.1 Hz, 2H), 1.98 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH:12]([OH:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[C:20]1([CH3:47])[CH:25]=[CH:24][C:23]([C:26]([C@@:28]([C:44]([OH:46])=[O:45])([OH:43])[C@@:29]([C:34]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)=[O:35])([OH:33])[C:30]([OH:32])=[O:31])=[O:27])=[CH:22][CH:21]=1>>[C:20]1([CH3:47])[CH:25]=[CH:24][C:23]([C:26]([C@@:28]([C:44]([OH:46])=[O:45])([OH:43])[C@@:29]([C:34]([C:36]2[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=2)=[O:35])([OH:33])[C:30]([OH:32])=[O:31])=[O:27])=[CH:22][CH:21]=1.[NH2:3][C@H:4]([C@@H:12]([OH:19])[C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6]
Reactant: NC(C(=O)N1CCCC1)C(O)c1ccncc1
Agent: Cc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Agent: Cl
Product: N[C@@H](C(=O)N1CCCC1)[C@@H](O)c1ccncc1

Procedure:
Resolving the (+/−)-DL-threo-2-amino-3-hydroxy-3-pyridin-4-yl-1-pyrrolidin-1-yl-propan-1-one dihydrochloride in the presence of Di-p-toluoyl-L-tartaric acid to produce (−)-(2R,3S)-2-Amino-3-hydroxy-3-pyridin-4-yl-1-pyrrolidin-1-yl-propan-1-one di-p-toluoyl-L-tartrate;
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[Se:4][C:3]=1[C:11]#[N:12].[OH-:13].[Na+]>C(O)C>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:9])([CH3:8])[CH3:10])[Se:4][C:3]=1[C:11]([NH2:12])=[O:13]
Reactant: CC(C)(C)c1cc(N)c(C#N)[se]1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cc(N)c(C(N)=O)[se]1

Procedure:
As shown in scheme L, 3-amino-5-(tert-butyl)selenophene-2-carbonitrile is treated with 10% aqueous NaOH solution/ethanol to give 3-amino-5-(tert-butyl)selenophene-2-carboxamide. Which is cyclised using formic acid/sulfuric acid to give 6-(tert-butyl)-3-hydroselenopheno[3,2-d]pyrimidin-4-one and further treatment with thionyl chloride gave 6-(tert-butyl)-4-chloroselenopheno[3,2-d]pyrimidine (Hesse, S. et. al., Synthesis, 2009, 1204-1208) in good yield. Treatment of this 4-chlorocompound with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH gave 5-(tert-butyl)-3-{[6-(tert-butyl)selenopheno[2,3-e]pyrimidin-4-yl]amino}selenophene-2-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH:11][NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(OCC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:11][NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NO)OCc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(NOC(=O)c1ccc(Cl)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chlorobenzoyl chloride (13.1 mL, 102 mmol) is added slowly to a solution of benzyl hydroxycarbamate (19.0 g, 114 mmol) and triethylamine (14.4 mL, 104 mmol) in diethyl ether (500 mL) at 0° C. then stirred at room temperature for 1 h. The reaction is
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:14][CH2:15][C:16]3([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH2:12][F:13])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[OH-].[Na+].C(O)C.C1C(=O)N([Cl:48])C(=O)C1>>[Cl:48][C:5]1[C:4]2[C:8](=[C:9]([C@H:11]([O:14][CH2:15][C:16]3([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH2:12][F:13])[CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][N:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(COC(CF)c2cc(Cl)cc3cn[nH]c23)(c2ccc(F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CO[C@H](CF)c2cc(Cl)cc3c(Cl)n[nH]c23)(c2ccc(F)cc2)CC1
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-1H-indazol-7-yl)-2-fluoroethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (90 mg, 0.178 mmol) and sodium hydroxide (4N in water) (0.056 mL, 0.222 mmol) in ethanol (1.7 mL, 29.1 mmol) at 0 C was added NCS (47.5 mg, 0.356 mmol), it was stirred at 0 C for 2 h when most S.M. converted to product. The reaction was treated with 0.03 ml of 4 N NaOH, 1 eq. of NCS and was stirred at 0 C for another 2 h., there is still some unreacted SM by TLC. The reaction was quenched by addition of aqueous ammonia and diluted with Et2O. The organic layer was washed with water (2×) then brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (25% EtOAc/Hex) to give title compound (72 mg, 74.9% yield) as clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.57 (d, J=1.83, 1H), 7.28-7.25 (m, 2H), 7.09-7.06 (m, 3H), 4.6-4.4 (m, 3H), 3.77-3.6 (m, 2H), 3.51 (d, J=9.16 Hz, 1H), 3.39 (d, J=9.16 Hz, 1H), 3.08-2.95 (m, 2H), 2.27 (m, 1H), 2.05 (m, 1H), 1.86 (m, 1H), 1.74 (m, 1H), 1.43 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 161.8 (d, J=247.6 Hz), 154.9, 137.8, 137.6, 134.4, 128.73, 127.67, 126.7, 122.2, 121.8, 119.0, 115.9, 115.8, 85.7, 84.3, 81.1, 80.9, 79.7, 42.5, 41.4, 32.4, 32.1, 31.7, 28.5, 22.7, 14.2. LC/MS (HPLC method 3): tR=4.12 min, 540.1(MH)+.
Reaction SMILES: [N:1]1([CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:21][O:22][C:23](OC)(OC)OC.C(O)(=O)C>ClCCl>[N:1]1([CH:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:7]2[CH:12]=[CH:11][C:10]3[NH:13][C:21]([O:22][CH3:23])=[N:14][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1N
Reactant: COC(OC)(OC)OC
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1nc2cc(C(c3ccccc3)n3ccnc3)ccc2[nH]1
Temperature: 25 °C
Yield: 32.8 %

Procedure:
A mixture of 2.6 parts of 4-[(1H-imidazol-1-yl)phenylmethyl]-1,2-benzenediamine, 10 parts of tetramethoxymethane, 0.6 parts of acetic acid and 6.5 parts of dichloromethane was stirred over weekend at room temperature. After evaporation, the residue was treated with ammonium hydroxide. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (90:5:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was dried in vacuo, yielding 1 part (32.8%) of 5-[(1H-imidazol-1-yl)phenylmethyl]-2-methoxy-1H-benzimidazole; mp. 109.5° C. (compound 115).