Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC=O
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.1 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (14 g, 42.68 mmol) and acetaldehyde (3.75 g, 85.36 mmol) in dichloroethane (150 mL), acetic acid (15.36 g, 256.08 mmol) was added and the reaction stirred at room temperature for 20 minutes. Sodium triacetoxyborohydride (27.01 g, 128.04 mmol) was then added at 0° C. and the reaction mixture stirred at room temperature for 2 h. The solvent was then removed under reduced pressure and water added to the residue. The mixture was extracted with DCM. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to give the crude product was purified by column chromatography to afford methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (14 g, 93.33%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:39]=[CH:40][C:41]=1[CH3:42])[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:10]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][C:41]1[CH:40]=[CH:39][C:6]([CH2:7][CH2:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:10]=2)=[CH:5][C:4]=1[C:1]([NH2:2])=[O:3]
Reactant: Cc1ccc(CCc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)cc1C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(CCc2nc(Nc3ccc(N4CCNCC4)cc3)ncc2C(F)(F)F)cc1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.5 %

Procedure:
To tert-butyl 4-(4-((4-(3-carbamoyl-4-methylphenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I73) (0.029 g, 0.054 mmol) in DCM (2 mL) was added TFA (0.100 mL, 1.36 mmol) and the mixture stirred overnight (16 hours) at room temperature. The resulting mixture was then concentrated under reduced pressure and the residue taken up in EtOAc (10 mL). The resulting organic suspension was washed with 10% aqueous NaOH (10 mL) and the aqueous layer extracted with EtOAc (2×10 mL). The combined organics were washed with water (15 mL) then concentrated under reduced pressure. The residue was taken up in DCM (4 mL) and TFA (0.200 mL) and stirred overnight (16 hours). The resulting mixture was concentrated under reduced pressure then diluted with EtOAc (15 mL). The resulting solution was washed with 10% aqueous NaOH (15 mL) then the aqueous layer was extracted with EtOAc (15 mL). The combined organic extracts were washed with water (20 mL) then dried using a phase separation cartridge before concentrating under reduced pressure to give the title compound (19) (5.1 mg, 21%); 1H NMR (400 MHz, d5-DMSO) δ 9.96 (s, 1H), 8.60 (s, 1H), 7.67 (s, 1H), 7.53 (d, J=9.0 Hz, 2H), 7.33 (s, 1H), 7.25 (s, 1H), 7.16 (m, 2H), 6.90 (d, J=9.1 Hz, 2H), 3.01 (m, 8H), 2.83 (m, 4H), 2.32 (s, 3H). LCMS Method C: rt 4.76 min; m/z 485.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:11](Cl)(=O)[C:12](Cl)=O>CN(C)C=O.ClCCl>[CH2:11]([O:9][C:8]([C:3]1[C:2]([CH3:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10])[CH3:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nccnc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1nccnc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methyl-pyrazine-2-carboxylic acid (10 g) (commercially available) and N,N-dimethylformamide (“DMF”) (1 drop) in dichloromethane (20 ml) at ambient temperature was added drop wise oxalyl chloride (2.57 ml). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated and the residue dissolved in dichloromethane (20 ml). Triethylamine (4.04 ml) was added to this solution followed by drop wise addition of ethanol (10 ml). The reaction mixture was stirred at ambient temperature for one hour and then concentrated. The residue was purified by chromatography on silica gel (eluent: 0-10% v/v ethyl acetate in iso-hexane) to give 3-methyl-pyrazine-2-carboxylic acid ethyl ester (9.85 g). MH+=167, RT=0.73 min (Method A). 1H-NMR (400 MHz, CDCl3): 8.61 (d, 1H), 8.54 (d, 1H), 4.49 (q, 2H), 2.85 (s, 3H), 1.46 (t, 3H) ppm.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Cl:12][C:13]1[CH:14]=[C:15]([Cl:19])[CH:16]=[CH:17][C:18]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: Clc1cccc(Cl)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1Cl
Yield: 54.2 %

Procedure:
To a solution prepared by adding 30 g (0.2 mol.) of phthalic anhydride to 146 g (1.0 mol.) of dried 1,3-dichlorobenzene, was added 64 g (0.48 mol.) of well-ground anhydrous aluminium chloride with stirring. The mixture was heated and stirred for 3 hours on the oil bath kept at 120° C. Thereafter, the reaction mixture was sufficiently cooled on an ice bath and thereto, 100 ml of water was added dropwise. The thus produced white precipitate was thoroughly washed with successive, water and cooled ethanol to obtain 32 g of crude crystals. These crude crystals were recrystallized from benzene to obtain the marked compound. Yield 24 g, Melting Point 178° to 181° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[OH-].[Na+].[N:9]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.Cl>O1CCCC1.O>[O:12]1[CH2:13][CH2:14][N:9]([C:15]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:16])[CH2:10][CH2:11]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: C[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)N1CCOCC1)C(=O)O
Temperature: 0 °C
Yield: 39.6 %

Procedure:
4 g(50 mmol) of L-alanine and 2 g(50 mmol) of NaOH were added to 30 ml of distilled water. The mixture was cooled to 0° C. and then stirred vigorously. To the mixture was added slowly a solution of 7.1 g(50 mmol) of morpholinecarbonyl-chloride in 30 ml of tetrahydrofuran, while adjusting the whole mixture to pH 8.5-pH 9.5 with the addition of 0.05N NaOH. After the reaction was completed, the reaction mixture was acidifiedto pH 2 with 6N HCl. The reaction mixture was extracted with a mixed solvent of ethyl acetate and THF(1:1) (30 ml×3) and the organic layer was concentrated under a reduced pressure to give 4 g of the title compound(yield: 40%).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([N:9]=[C:10]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:11]=2)[CH:8]=1.[CH3:32][N:33]1[C:37]([CH:38]=O)=[N:36][C:35]([N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[N:34]1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([N:9]=[C:10]([CH:12]=[CH:38][C:37]3[N:33]([CH3:32])[N:34]=[C:35]([N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[N:36]=3)[N:11]=2)[CH:8]=1
Reactant: Cn1nc(N2CCCC2)nc1C=O
Reactant: Clc1ccc2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nn2c1
Agent: [Cl-]
Product: Cn1nc(N2CCCC2)nc1C=Cc1nc2ccc(Cl)cn2n1
Yield: 91.1 %

Procedure:
The desired product was prepared in analogy to Example 1 g) from ((6-chloro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methyl)triphenylphosphonium chloride (170 mg, 366 μmol, Eq: 1.00) and 1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazole-5-carbaldehyde (66.0 mg, 366 μmol, Eq: 1.00). 110 mg (91%) of the desired product were obtained as a light yellow solid. MS: m/z=330.4 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:1][C:2]1[CH:7]=[C:6]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[CH:5]=[CH:4][C:3]=1[CH2:17][N:18]1[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)CC1
Reactant: Cc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)n1
Temperature: 75 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A 25 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen and charged with tert-butyl 4-[[2-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine-1-carboxylate (1.50 g, 3.57 mmol, 1.00 equiv), 2-bromo-6-methylpyridine (0.916 g, 5.32 mmol, 1.49 equiv), Tetrakis(triphenylphosphine)palladium (0.413 g, 0.360 mmol, 0.10 equiv), potassium carbonate (1.50 g, 10.8 mmol, 3.04 equiv), dioxane (15 mL) and water (3 mL). The resulting solution was stirred overnight at 75° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (3×20 mL) and the organic layers were combined, washed with brine (2×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3) to yield 1.10 g (80% yield) of tert-butyl 4-[[2-fluoro-4-(6-methylpyridin-2-yl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 386 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)=[CH:23][CH:22]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[N:15]=1)([CH3:10])[CH3:9].C(#N)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>N1C=CC=CC=1>[C:40]([N:17]1[CH2:18][CH2:19][CH2:20][CH:16]1[C:14]1[N:15]=[C:11]([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])([CH3:10])[CH3:9])[N:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)=[CH:23][CH:22]=2)[CH:13]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(c1ccccc1Cl)c1nc(C2CCCN2)cn1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)N1CCCC1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(C(C)(C)c2ccccc2Cl)n1

Procedure:
To a solution of 2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-4-pyrrolidin-2-yl-1H-imidazole, acetonitrile and pyridine was added acetic anhydride. The solution was heated to reflux for 1 h. After a routine aqueous work up, the crude product was purified by prep HPLC to give 4-(1-acetylpyrrolidin-2-yl)-2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-1H-imidazole: 1H NMR (CDCl3): δ 1.6 (m, 3H,), 1.8 (m, 1H), 1.9 (br, 2H), 2.1 (m, 4H), 2.3 (m, 2H), 3.1 (s, 3H), 3.5 (m, 1H) 3.7 (m, 1H), 4.5 (m, 1H), 5.0 (m, 1H), 6.8 (m, 2H), 7.1 (m, 5H), 7.6 (m, 2H), 7.7 (m, 1H), 7.8 (m, 1H), 7.9 (m, 1H), 8.2 (m, 1H); LC/MS M+H 562 (observed).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>[OH-].[Na+].O1CCOCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH:2]2[C:10]([OH:12])=[O:11])=[O:22])=[CH:16][CH:15]=1
Reactant: O=C(O)C1Cc2ccccc2N1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C1Cc2ccccc2N1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a solution of (D,L) indoline-2-carboxylic acid (548 mg, 3.36 mmol) in 1N aq. NaOH (8 mL), a solution of 4-chlorophenylisocyanate (728 mg, 4.74 mmol) in dioxane (8 mL) was added. The mixture was stirred at room temperature overnight. It was then washed with Et2O (2×). The aqueous layer was separated, acidified with 4N HCl to pH 1 to 2. The product was extracted with EtOAc. The EtOAc solution was dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC to give the desired product as a powder (325 mg).
Reaction SMILES: [CH:1]1[C:2]([CH2:19][C:20]([OH:22])=[O:21])=[CH:3][C:4]([I:18])=[C:5]([O:8][C:9]2[CH:10]=[C:11]([I:17])[C:12]([OH:16])=[C:13]([I:15])[CH:14]=2)[C:6]=1[I:7].[CH2:23](OC(Cl)=O)C1C=CC=CC=1>CO>[CH3:23][O:21][C:20](=[O:22])[CH2:19][C:2]1[CH:1]=[C:6]([I:7])[C:5]([O:8][C:9]2[CH:10]=[C:11]([I:17])[C:12]([OH:16])=[C:13]([I:15])[CH:14]=2)=[C:4]([I:18])[CH:3]=1
Reactant: O=C(O)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CO
Product: COC(=O)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
In anhydrous conditions, Tetrac (1.0 g, 1.3 mmol, 1.0 eq.) was suspended in MeOH (20 mL). TEA (181.4 μL, 1.3 mmol, 1.0 eq.) was then added dropwise followed by benzylchloroformate 184.8 μL, 1.3 mmol, 1.0 eq.). After stirring for 30 minutes, the solution was filtered, the solvent was removed from the residue and the product was separated by silica gel chromatography (eluent=DCM). The collected fractions were then evaporated to give a white powder which was recrystallized to give orange crystals (990 mg, 1.3 mmol) of methyl-2-(4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl)acetate in a quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:27]3[C:13](=[CH:14][C:15]4[O:16][CH2:17][CH2:18][CH2:19]S[CH2:21][CH2:22][CH2:23][O:24][C:25]=4[CH:26]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.O[O:29][S:30]([O-:32])=O.[K+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:27]3[C:13](=[CH:14][C:15]4[O:16][CH2:17][CH2:18][CH2:19][S:30](=[O:32])(=[O:29])[CH2:21][CH2:22][CH2:23][O:24][C:25]=4[CH:26]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: Clc1cccc(Nc2ncnc3cc4c(cc23)OCCCSCCCO4)c1
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=S1(=O)CCCOc2cc3ncnc(Nc4cccc(Cl)c4)c3cc2OCCC1
Reaction time: 4 h

Procedure:
(3-Chloro-phenyl)-(2,10-dioxa-6-thia-14,16-diaza-tricyclo[9.8.0.013,18]nonadeca-1(11),12,14,16,18-pentaen-17-yl)-amine (19, 100 mg, 0.23 mmol) was suspended in MeOH, to which was added a cloudy aqueous solution of oxone (monopersulfate compound) (551 mg, 0.897 mmol) at room temperature. The suspension was stirred and monitored by TLC which indicated that the reaction was completed in 4 h. The reaction mixture was poured into H2O (40 mL), and extracted with EtOAc (3×50 mL). The organic layers were collected, dried and concentrated to give a pale yellow residue which was recrystalized from EtOAc to give the product as an off-white solid: 31.5 mg (30%). 1H NMR (CDCl3) δ 8.75 (s, 1H), 7.95 (s, 1H), 7.65 (d, 1H), 7.50 (s, 1H), 7.35 (t, 1H), 7.28 (s, 1H), 7.20 (s, 1H), 7.15 (d, 1H), 4.25 (m, 4H), 3.05 (t, 2H), 2.80 (t, 2H), 2.30 (m, 2H), 2.00 (m, 2H).
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.C([Li])(C)(C)C.[F:10][C:11]1[CH:12]=[CH:13][C:14]([O:29][CH3:30])=[C:15]([C:17]([CH3:28])([CH3:27])[CH2:18][C:19](N2CCOCC2)=[O:20])[CH:16]=1>C1COCC1>[CH:1]1([C:19](=[O:20])[CH2:18][C:17]([C:15]2[CH:16]=[C:11]([F:10])[CH:12]=[CH:13][C:14]=2[O:29][CH3:30])([CH3:28])[CH3:27])[CH2:3][CH2:2]1
Reactant: BrC1CC1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)N1CCOCC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(=O)C1CC1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a solution of cyclopropyl bromide (0.120 g) in THF (0.8 mL) cooled to −70° C., a solution of tert-butyl lithium (1.7 M in pentane, 0.8 mL) was added dropwise over 5 minutes. The mixture was stirred at −70° C. for 30 minutes. A solution of 3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one (0.29 g) in THF (1 mL) was then added all at once and the mixture was stirred for 30 minutes. The mixture was quenched with EtOH (0.3 mL) and warmed to room temperature. The mixture was diluted with EtOAc, washed with water, dried over sodium sulfate, filtered, and evaporated to give the title compound as an oil (0.23 g).
Reaction SMILES: [CH2:1]([O:3][P:4](=[S:9])([SH:8])[O:5][CH2:6][CH3:7])[CH3:2].Br[CH2:11][CH:12]=[CH:13][CH2:14]Br>C(O)C.O>[CH2:1]([O:3][P:4](=[S:8])([O:5][CH2:6][CH3:7])[S:9][CH2:11][CH:12]=[CH:13][CH2:14][S:9][P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[S:8])[CH3:2]
Reactant: CCOP(=S)(S)OCC
Reactant: BrCC=CCBr
Solvent: O
Solvent: CCO
Product: CCOP(=S)(OCC)SCC=CCSP(=S)(OCC)OCC
Yield: 100.9 %

Procedure:
To a stirred solution of the ammonium salt of dithiophosphoric acid O,O-diethyl ester (15.8 g, 78 mmol) in ethanol (130 mL) at 80° C. is added 1,4-dibromo-2-butene (7.55 g, 35 mmol) in portions. The resulting mixture is cooled, diluted with water (150 mL) and extracted with methylene chloride (3×100 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield 15 g (99%) of S-[4-(diethoxy-thiophosphorylsulfanyl)-but-2-enyl]dithiophosphoric acid O,O′-diethyl ester, having the structure:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15][CH2:16][CH:17]=O)=[CH:13][C:12]([CH2:19][CH2:20][CH3:21])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:17][CH2:16][CH2:15][C:14]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[N:11]=[C:12]([CH2:19][CH2:20][CH3:21])[CH:13]=2)[CH2:31][CH2:30]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCc1cc(CCC=O)n(-c2ccc([N+](=O)[O-])cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
70 mg (82.5%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-nitrophenyl)-3-propyl-1H-pyrazol-5-yl)propanal 54 mg, 0.188 mmol), 1-(2-fluorophenyl)piperazine (39 mL, 0.244 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:28])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:20]3[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=3)[C:26]#[N:27])[CH2:17][C:16](=[O:28])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(I)cc3NC(=O)C2)c1
Yield: 98.8 %

Procedure:
Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-iodo-phenyl}-carbamic acid tert.-butyl ester (Example K1) (1.15 g, 2.3 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (880 mg).
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1.Cl>CN(C)C=O>[C:1]1([C:7]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=2)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)(c1ccccc1)c1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 146.4 %

Procedure:
14.9 g of diethyl phenylmalonate was dissolved in 50 ml of N,N-dimethylformamide and 2.52 g of sodium hydride (60% oily) was added thereto at room temperature. Next, 5.0 g of 2-chloro-5-nitropyridine was added thereto and the resulting mixture was stirred at 80° C. for 2 hours. After the completion of the reaction, the reaction mixture was poured into ice-water/ethyl acetate and neutralized with dilute hydrochloric acid. After extracting with ethyl acetate, the extract was dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 16.55 g of the title compound as a reddish brown oily substance.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[CH:13][C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[OH:34].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[Cl:23][C:12]1[CH:13]=[C:14]2[C:15](=[CH:20][C:11]=1[CH2:10][C:9]1[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[CH:25][CH:24]=1)[C:16](=[O:17])[N:27]([C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[OH:34])[CH2:21]2
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(Cl)cc1C=O
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2cc(Cc3ccc(-n4cccn4)cc3)c(Cl)cc2CN1[C@@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 0 %

Procedure:
A solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-formylbenzoate (0.12 g), trans-2-aminocyclohexanol hydrochloride (0.05 g), triethylamine (0.05 mL) and anhydrous magnesium sulfate (0.08 g) in THF (2.50 mL) was stirred at room temperature for 1 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (2.50 mL) and THF (2.50 mL), sodium triacetoxyborohydride (0.15 g) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.05 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][C:7]1[N:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[C:19](OCC)(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].N1CCCCC1>C(O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[C:7]2[C:8](=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:9]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]1=[O:26]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccccc1CNc1ncccc1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2cccnc2n(Cc2ccccc2OC)c1=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 74.7 %

Procedure:
7.40 g (30.5 mmol) of 2-(2-methoxybenzylamino)nicotinaldehyde was dissolved in ethanol (100 mL), and 7.34 g (45.8 mmol) of diethyl malonate and 0.95 g (10.0 mmol) of piperidine were added thereto. The resulting mixture was stirred for 48 hours at 100° C. The mixture was cooled, and a solid precipitated thereby was separated by filtration. The solid was washed with hexane, and thus 7.71 g (yield: 75%) of the title compound was obtained as a pale yellow solid.