Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[H-].[Na+].Br[CH:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:13]([O:15][CH3:16])=[O:14].Cl>CN(C=O)C.O>[Br:8][C:5]1[CH:4]=[N:3][C:2]([NH:1][CH:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:6]=1
Reactant: Nc1ncc(Br)cn1
Reactant: COC(=O)C(Br)CC(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CC(C)C)Nc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-amino-5-bromopyrimidine (3.12 g, 17.93 mmol) in dry DMF (60 mL) at 0° C. under dry nitrogen was added NaH (860 mg, 21.52 mmol) portionwise and the reaction was warmed to rt and stirred for 1 hour. The reaction was cooled again to 0° C. and methyl 2-bromo-4-methylpentanoate (4.7 g, 22.42 mmol, Bull. Chem. Soc. Jpn. 1989, 62, 2562) was added dropwise and the reaction was warmed to rt and stirred another 4 hours. Water was added, the aqueous phase neutralized with aq. 10 % HCl, and the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (EtOAc/Hex, 2/8 then 3/7 then 4/6) to afford methyl 2-[(5-bromo-2-pyrimidinyl)amino]-4-methylpentanoate.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[NH:4][CH2:5][CH:6]([OH:9])[CH2:7][N:8]=1.[N+](C1C=CC=CC=1)([O-])=O.C[O-].[Na+]>CO>[F:11][C:2]([F:1])([F:10])[C:3]1[N:4]=[CH:5][C:6]([OH:9])=[CH:7][N:8]=1
Reactant: OC1CN=C(C(F)(F)F)NC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=[N+]([O-])c1ccccc1
Product: Oc1cnc(C(F)(F)F)nc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 8.4 %

Procedure:
A mixture of 2-(trifluoromethyl)-1,4,5,6-tetrahydro-5-pyrimidinol (6.50 g, 38.7 mmol) and nitrobenzene (30 mL) was heated to 90° C. to form a homogeneous solution. At this temperature, a solution of sodium methoxide (8.5 g, 157 mmol) in methanol (30 mL) was added portionwise, allowing the methanol to distill off before next addition (the whole process took about 3 h). Then the reaction mixture was heated to 120° C. for 1 h. The reaction mixture was cooled to room temperature, and then partitioned between ethyl acetate and water. The organic phase was separated off. The aqueous phase adjusted to pH 4.0 with 6M aqueous HCl and then extracted with EA. The organic phase was dried over sodium sulfate, and filtered. Concentrated in vacuo then afforded the title compound (533 mg, 3.25 mmol, 8.4% yield). LCMS: rt=1.78 min, [M+H+]=165
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([NH:8][CH2:9][CH2:10][NH2:11])=[C:6]([Cl:14])[CH:5]=1)([O-:3])=[O:2].[N-:15]=[C:16]=[O:17].[K+]>O.C(O)(=O)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([NH:8][CH2:9][CH2:10][NH:11][C:16]([NH2:15])=[O:17])=[C:6]([Cl:14])[CH:5]=1)([O-:3])=[O:2]
Reactant: [N-]=C=O
Reactant: NCCNc1ccc([N+](=O)[O-])cc1Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)NCCNc1ccc([N+](=O)[O-])cc1Cl
Reaction time: 2 h
Yield: 92.4 %

Procedure:
100 g (0.46 mole) of 4-nitro-2-chloro-N-(β-aminoethyl) aniline is dissolved in a liter of water to which 29 cm3 of acetic acid has been added. 41.3 g (0.51 mole) of potassium isocyanate is added to this reaction mixture, which is then left at the ambient temperature for 2 hours. Drying yields 110 g of 4-nitro-2-chloro-N-(β-ureidoethyl) aniline which, after washing with dilute acetic acid and with water, followed by recrystallization in nitromethane, melts at 188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O.C(OCC)(=O)C>[Si:18]([O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][C:10]([NH2:12])=[O:11])=[CH:3][C:2]=1[Cl:1])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NC(=O)Cc1ccc(O)c(Cl)c1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(N)=O)cc1Cl
Yield: 77.4 %

Procedure:
A solution of 2-(3-chloro-4-hydroxy-phenyl)-acetamide (100 mg), imidazole (184 mg), and tert-butyldimethylsilyl chloride (163 mg) was stirred for 2 h in 5 mL of dimethylformamide. The solution was diluted with 50 mL of ethyl acetate and washed with 50 mL of sodium carbonate. The ethyl acetate was evaporated to afford 125 mg of 2-[4-(tert-butyldimethylsilanyloxy)-3-chlorophenyl]acetamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH3:16])=[O:14].[CH3:17][N:18]1CCCC1=O>>[C:17]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH3:16])=[O:14])#[N:18]
Reactant: CN1CCCC1=O
Reactant: COC(=O)C1CCOc2cc(F)c(Br)cc21
Product: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Temperature: 160 °C
Yield: 77 %

Procedure:
Methyl 6-bromo-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (415 mg, 1.44 mmol) was diluted with N-methylpyrrolidone (5 mL) followed by the addition of Cu(I) CN (643 mg, 7.18 mmol). The reaction was bubbled with argon for 20 minutes, then heated at 160° C. under a slight argon bubble for 6 hours. The reaction was cooled to ambient temperature and loaded directly onto a Biotage 25 column eluting with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield the title compound (260 mg, 77.0% yield).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.O.O1[C:17]2([CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:19][CH2:18]2)[O:16]CC1.CC(C)=O.C(=O)(O)[O-].[Na+]>O>[O:16]=[C:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[CH2:19][CH2:18]1
Reactant: O=C(CC1CCC2(CC1)OCCO2)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(CC(=O)OCc2ccccc2)CC1
Temperature: 55 °C
Reaction time: 15 h
Yield: 85.9 %

Procedure:
p-Toluene sulfonic acidmonohydrate (207 mg, 1.21 mmol) was added to a mixture composed of benzyl 2-(1,4-dioxaspiro[4,5]decan-8-yl)acetate (7.0 g, 24.11 mmol), acetone (220 ml), and water (10 ml) at room temperature, and the mixture was stirred at 55° C. for 15 hr. The mixture was cooled with ice and was adjusted to pH 5 by the addition of solid sodium bicarbonate. The mixture was concentrated under reduced pressure, and the residue was chromatographed on silica gel column (hexane:ethyl acetate=85:15) to give the title compound as a colorless solid (5.1 g, yield 86%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20]([O:22]CC)=O)[CH:12]=[N:11][C:10]1=2.C(#N)C>CO>[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20]([NH:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[O:22])[CH:12]=[N:11][C:10]1=2
Reactant: CC(=O)NCCN
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CO
Solvent: CC#N
Product: CC(=O)NCCNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 120 °C
Yield: 76.5 %

Procedure:
0.516 g (5.05 mmol) of N-acetylethylenediamine was placed into a 10 ml round bottom flask. The flask was heated to 120° C. and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added to the stirring solution. The solution was heated at 120° C. for one hour. 8 ml of acetonitrile was added to the viscous oil and stirred. Approximately 1 ml of methanol was added and the solution was stirred vigorously for 30 minutes. The resulting white precipitate was collected by vacuum filtration and was washed with acetonitrile and ether to yield 237 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[2-[(1-oxoethyl)amino]ethyl]propanamide (AIT-0051) as a white solid upon drying. Yield: 76%
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1.CN(C)C=O.S(Cl)([Cl:27])=O>C(Cl)(Cl)Cl>[Cl:27][CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1
Reactant: O=C(OCc1ccccc1)N1CCOC(CCO)C1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCOC(CCCl)C1

Procedure:
To a mixture of 2-(2-hydroxyethyl)-4-benzyloxycarbonylmorpholine (15 g), dimethylformamide (1 ml), and chloroform (50 ml) is dropwise added thionyl chloride (16.3 ml). The mixture is refluxed for 2 hours, allowed to cool, and evaporated under reduced pressure to give the title compound (16 g) as an oil.
Reaction SMILES: [CH3:1]I.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH:4]=1.[BH4-].[Na+]>ClCCl>[OH:14][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([C:5]2[CH2:4][N:3]([CH3:1])[CH2:8][CH2:7][CH:6]=2)=[CH:10][CH:11]=1
Reactant: O=Cc1ccc(-c2cccnc2)cc1
Reactant: CI
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCC=C(c2ccc(CO)cc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.1 %

Procedure:
Methyl iodide (0.8 ml, 12.9 mmol) was added to a solution of 4-(3-pyridyl)benzaldehyde (0.78 g, 4.3 mmol) in dichloromethane and stirred 2 days. Additional methyl iodide (0.8 ml, 12.9 mmol) was added and stirred for 3 hr. After removal of the solvent, methanol was added to the residue and ice-cooled. Sodium tetrahydroborate (6.4 g, 17.0 mmol) was added to the solution and stirred for 1.5 hr with warming to room temperature. Organic solvents were removed under reduced pressure after addition of water and extracted with ethyl acetate, washed with water and brine and dried over sodium sulfate. After removal of the solvent under reduced pressure, residue was purified by silica gel chromatography (eluent ethyl acetate to methanol) to give 3-(4-hydroxymethylphenyl)-1-methyl-1,2,5,6-tetrahydropyridine (0.63 g, 72%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[F:12][C:13]1[C:18]2[C:19](=[O:22])[O:20][CH2:21][C:17]=2[CH:16]=[C:15]([CH:23]=[CH2:24])[CH:14]=1>C(Cl)Cl>[F:12][C:13]1[C:18]2[C:19](=[O:22])[O:20][CH2:21][C:17]=2[CH:16]=[C:15]([CH:23]2[CH2:24][O:9]2)[CH:14]=1
Reactant: C=Cc1cc(F)c2c(c1)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1OCc2cc(C3CO3)cc(F)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
mCPBA (85%, 9.9 g, 48.9 mmol) was added to a solution of 7-fluoro-5-vinyl-2-benzofuran-1(3H)-one (2.9 g, 16.3 mmol) in 300 mL of DCM at 0° C. The mixture was stirred at room temperature for 16 hours before being cooled to 0° C. The mixture was washed sequentially with saturated NaHCO3 (50 mL), aqueous Na2SO3 (50 mL×2), 5% NaOH (50 mL) and brine, then concentrated. The residue was purified by column chromatography eluted with DCM to afford 7-fluoro-5-oxiran-2-yl-2-benzofuran-1(3H)-one as white solid.
Reaction SMILES: Cl[C:2]1[N:17]=[N:16][C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH:18]([C:2]1[N:17]=[N:16][C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1)=[CH2:19]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1Nc2ccccc2Nc2nnc(Cl)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc2c(nn1)Nc1ccccc1NC2=O
Temperature: 100 °C
Yield: 32.3 %

Procedure:
To a solution of 2-chloro-5,10-dihydro-3,4,5,10-tetraaza-dibenzo[a,d]cyclohepten-11-one from Example 2 (150 mg, 0.61 mmol) in toluene (3 ml) was added tri-n-butyl(vinyl)tin (231 mg, 0.73 mmol) followed by triphenylphosphine (4.8 mg, 0.02 mmol) and tetrakistriphenylphosphine palladium (7 mg, 0.01 mmol) and the resulting mixture was heated at 100° C. for 15 hours. The mixture was cooled to room temperature, concentrated in vacuo and purified directly by flash column chromatography (silica gel, 10% MeOH 90% dichloromethane) to afford the title compound as a yellow solid (47 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[NH:10]1[CH2:15][CH2:14][CH:13]([C:16](O)=O)[CH2:12][CH2:11]1.[OH-].[K+]>O>[NH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[O:9][C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[N:1]=2)[CH2:12][CH2:11]1
Reactant: Cc1ccc(O)c(N)c1
Reactant: O=C(O)C1CCNCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2oc(C3CCNCC3)nc2c1
Temperature: 180 °C
Yield: 83.4 %

Procedure:
2-Amino-4-methylphenol (400 mg) and 4-piperidinecarboxylic acid (420 mg) were mixed with polyphosphoric acid (2 g) and stirred with heating at 180° C. for 2 hours. After cooling to room temperature, the reaction was stopped by adding water. The filtrate was adjusted to pH 12 with 50% potassium hydroxide aqueous solution and then extracted with methylene chloride. The organic layer was washed with saturated brine and dried with magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain the title compound 2-(4-piperidyl)-5-methylbenzoxazole (586 mg).
Reaction SMILES: [CH:1]12[CH2:7][CH2:6][CH:5]1[C:4](=[O:8])[O:3][C:2]2=[O:9].C([Mg]Br)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1>C1COCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:4]([CH:5]2[CH2:6][CH2:7][CH:1]2[C:2]([OH:3])=[O:9])=[O:8])=[CH:12][CH:13]=1
Reactant: COc1ccc(C[Mg]Br)cc1
Reactant: O=C1OC(=O)C2CCC12
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCC2C(=O)O)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To 3-oxabicyclo[3.2.0]heptane-2,4-dione (8.00 g, 63.4 mmol) in THF (90.00 mL) at −78° C. was added 0.500 M of p-anisyl magnesium bromide (133 mL, 66.6 mmol) in THF (90 mL) dropwise. After stirring at −78° C. for 2 h, the reaction was quenched with ice cold water and concentrated. The aqueous layer was acidified and the white solid was filtered off and dried to obtain 9.72 g product (65%); MS m/z 233 (M−H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(S)CCC.[CH2:10]([C:12]1[S:21][C:20]2[N:19]3[C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[N:23][N:24]=[C:18]3[CH2:17][N:16]=[C:15]([C:36]3[CH:41]=[CH:40][C:39]([O:42]C)=[CH:38][CH:37]=3)[C:14]=2[CH:13]=1)[CH3:11]>ClCCl>[CH2:10]([C:12]1[S:21][C:20]2[N:19]3[C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[N:23][N:24]=[C:18]3[CH2:17][N:16]=[C:15]([C:36]3[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=3)[C:14]=2[CH:13]=1)[CH3:11]
Reactant: CCCCCCCCCCCc1nnc2n1-c1sc(CC)cc1C(c1ccc(OC)cc1)=NC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCS
Solvent: ClCCl
Product: CCCCCCCCCCCc1nnc2n1-c1sc(CC)cc1C(c1ccc(O)cc1)=NC2
Yield: 51.5 %

Procedure:
Anhydrous aluminum chloride (78.1 g) was suspended in dichloromethane (700 ml) and thereto was dropwise added n-butylmercaptan (106 ml) with stirring under ice-cooling. Thereto was added 2-ethyl-4-(4-methoxylphenyl)-9-undecyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (40 g) obtained in Example 1 under ice-cooling. After stirring at room temperature for 20 hours, the reaction mixture was washed with 5% aqueous sodium hydrogencarbonate and water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give 20 g of 2-ethyl-4-(4-hydroxyphenyl)-9-undecyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine as crystals, melting point 164.5°-166.5° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:24])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=1)[C:9]([OH:11])=O.[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH2:36])=[N:33][CH:32]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH:36][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([O:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=[C:6]([O:5][C@@H:4]([CH3:24])[CH2:3][O:2][CH3:1])[CH:7]=2)=[N:33][CH:32]=1)[CH3:26]
Reactant: COC[C@H](C)Oc1cc(OCCc2ccccc2)cc(C(=O)O)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(OCCc3ccccc3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-((S)-2-methoxy-1-methyl-ethoxy)-5-phenethyloxy benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:24]1(=[O:29])(=[O:28])[CH2:27][CH2:26][NH:25]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:25]4[CH2:26][CH2:27][S:24]4(=[O:29])=[O:28])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=S1(=O)CCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 2 %

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 165 and [1,2]thiazetidine 1,1-dioxide (54 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (4 mg) was obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Mg].Br[C:9]1[CH:10]=[C:11]([CH3:16])[C:12]([CH3:15])=[CH:13][CH:14]=1.Cl[P:18](=[O:31])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(OCC)C.O1CCCC1>[C:19]1([P:18]([C:9]2[CH:10]=[C:11]([CH3:16])[C:12]([CH3:15])=[CH:13][CH:14]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:31])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(Br)cc1C
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(P(=O)(c2ccccc2)c2ccccc2)cc1C
Yield: 77 %

Procedure:
A reaction vessel was charged with 100 ml of tetrahydrofuran (THF) which had been dried with lithium aluminum hydride, to which 2.83 g (0.1209 mol) of turning magnesium was added. With refluxing, a dried THF solution of 19.6 g (0.106 mol) of 4-bromo-o-xylene was added dropwise over one hour. After the completion of the addition, it was refluxed for about one hour and then cooled to 5° to 10° C. at which a dried THF solution of 25 g (0.106 mol) of chlorodiphenylphosphine oxide was added dropwise over about 3 hours. After the completion of the addition, it was mixed at 50° to 60° C. for 2 hours and allowed to stand for cooling. Then, 100 ml of dilute hydrochloric acid and 100 ml of diethyl ether were added to the resultant solution and mixed for 30 minutes. It was then extracted three time with 200 ml of diethyl ether. The extracted solution was rinsed three times with a 5% sodium hydrogencarbonate solution and dried with anhydrous sodium sulfate. The ether solution was condensed and subjected to column chromatography to obtain 25 g of white solid which had a chart (FIG. 1) of NMR spectrum in CDCl3 to find the following chemical structure; ##STR13##
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[CH:47]1([C:52]([OH:54])=O)[CH2:51][CH2:50][CH2:49][CH2:48]1.C(N(C(C)C)C(C)C)C.[CH3:64][O:65][C:66]1[C:71]2[CH2:72][C@@H:73]3[C:78]([CH3:80])([CH3:79])[C@:77]([CH3:81])([C:70]=2[CH:69]=[CH:68][CH:67]=1)[CH2:76][CH2:75][NH:74]3>CN(C)C=O.C(OCC)(=O)C>[CH:47]1([C:52]([N:74]2[CH2:75][CH2:76][C@:77]3([CH3:81])[C:78]([CH3:80])([CH3:79])[C@H:73]2[CH2:72][C:71]2[C:66]([O:65][CH3:64])=[CH:67][CH:68]=[CH:69][C:70]=23)=[O:54])[CH2:48][CH2:49][CH2:50][CH2:51]1
Reactant: O=C(O)C1CCCC1
Reactant: COc1cccc2c1C[C@H]1NCC[C@]2(C)C1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cccc2c1C[C@H]1N(C(=O)C3CCCC3)CC[C@]2(C)C1(C)C

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.27 g; alternatively N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate may be used) is added to a solution of cyclopentanecarboxylic acid (100 mg) and ethyldiisopropylamine (0.2 mL) in N,N-dimethylformamide (10 mL). The resulting solution is stirred at ambient temperature for 15 min before (2R,6S)-10-methoxy-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine (0.20 g) is added. After stirring the solution overnight, ethyl acetate is added and the resulting mixture is washed with aqueous Na2CO3 solution and dried (Na2SO4). After evaporation of the solvent under reduced pressure, the product is obtained as a yellow oil.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][N:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([C:25]([NH:16][CH:13]2[CH2:12][CH2:11][N:10]([C:4]3[N:3]=[CH:2][NH:1][C:6]4=[N:7][CH:8]=[CH:9][C:5]=34)[CH2:15][CH2:14]2)=[O:26])[CH:22]=[CH:21][N:20]=1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Reactant: COc1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(c3nc[nH]c4nccc3-4)CC2)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (65.2 mg), 2-(methyloxy)-4-pyridinecarboxylic acid (45.9 mg, 0.300 mmol), HATU (137 mg, 0.360 mmol) and HOAt (24.50 mg, 0180 mmol) in DMF (1.5 mL) was added DIPEA (252 μL, 1.440 mmol). The reaction mixture was stirred at room temperature for 3 hours then the solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E15 (40 mg); 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 8.50 (1H, d), 8.30 (1H, d), 8.17 (1H, s), 7.35 (1H, d), 7.20 (2H, d), 6.60 (1H, d), 4.67 (2H, dt), 4.15 (1H, m), 3.88 (3H, s), 3.20 (2H, dt), 1.90 (2H, m), 1.55 (2H, m), MS(ES+) 353 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2F)/[N:7]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:30][NH:31][C:32](=[O:34])[CH3:33].CC(C)([O-])C.[Na+]>C1COCC1.CCOCC>[C:32]([NH:31][O:30][C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]=1[C:11](/[N:10]=[C:8]1\[S:9][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][N:7]\1[CH2:24][C@H:25]1[CH2:29][CH2:28][CH2:27][O:26]1)=[O:23])(=[O:34])[CH3:33]
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Reactant: CC(=O)NO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)NOc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of Example 1A (150 mg, 0.35 mmol) and N-hydroxyacetamide (52.3 mg, 0.70 mmol) in THF (10 mL) was added sodium tert-butoxide (67.0 mg, 0.70 mmol). The mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with ether and washed with brine. The aqueous phase was extracted with ether (2×20 mL), dried over MgSO4, and filtered. The mixture was concentrated under reduced pressure and the residue was purified by FC on SiO2 using an Analogix® Intelliflash280™ (eluted with Hexanes-EtOAc: 0-30%) to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.19 (s, 9 H), 1.21 (m, 1 H), 1.37 (s, 1 H), 1.94 (s, 2 H), 1.97-2.11 (m, 1 H), 3.65-3.92 (m, 2 H), 3.99-4.33 (m, 2 H), 4.34-4.55 (m, 1 H), 6.82 (s, 1 H), 7.66 (dd, J=9.2, 2.4 Hz, 1 H), 8.34 (d, J=8.8 Hz, 1 H), 8.61 (d, J=2.4 Hz, 1 H); MS (ESI) m/z 486 (M+H)+.