Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][N:12]1[C:16]2[CH:17]=[C:18]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:19]=[C:20]([C:21]#[N:22])[C:15]=2[N:14]=[C:13]1[CH3:29].OO>O.C1COCC1>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][N:12]1[C:16]2[CH:17]=[C:18]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:19]=[C:20]([C:21]([NH2:22])=[O:1])[C:15]=2[N:14]=[C:13]1[CH3:29]
Reactant: [OH-]
Reactant: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Agent: OO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c(C(N)=O)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 50 °C
Yield: 51.1 %

Procedure:
A solution of KOH (78 mg, 1.4 mmol) in water (10 mL) was added dropwise to solution of 1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carbonitrile (280 mg, 0.7 mmol) and 30% H2O2 (3 mL) in THF (10 mL) at rt. The mixture was heated at 50° C. for 2 h. When TLC showed no starting material left, the pH of the mixture was acidified to pH ca. 5 and extracted with EtOAc (50 mL×3). The organic layer was washed with brine, dried over MgSO4, concentrated. The resulting residue was purified by silica gel chromatography eluted with EtOAc to give the product (150 mg, 51%), as a white solid. 1H NMR (300 Mhz, DMSO-d6) δ ppm 2.44 (s, 3H), 3.11 (t, 4H, J=4.8 Hz), 3.71 (t, 4H, J=4.8 Hz), 5.60 (s, 2H), 6.31 (d, 1H, J=8.1 Hz), 7.16 (br s, 2H), 7.25 (t, 1H, J=8.1 Hz), 7.35 (d, 1H, J=1.8 Hz), 7.41 (d, 1H, J=1.8 Hz), 7.60 (d, 1H, J=8.1 Hz); LC-MS: m/e=419 [M+1]+
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].[CH2:15](Br)[CH3:16]>>[CH2:15]([N:6]1[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]12)[CH3:16]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Product: CCn1c(=O)oc(=O)c2ccccc21
Yield: 61 %

Procedure:
From Hardtmann et al., Journal of Heterocyclic Chemistry, Vol. 12, p. 565 (1975), it is known that isatoic anhydride can be alkylated with a sodium hydride/ethyl bromide system to provide a 61% yield of N-ethyl isatoic anhydride after recrystallization.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[F:19][C:20]([F:35])([F:34])[CH2:21][O:22][C:23]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26].O>C(OCC)C.O1CCCC1>[N+:31]([C:29]1[CH:28]=[CH:27][C:24]([CH:25]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:26])=[C:23]([O:22][CH2:21][C:20]([F:19])([F:34])[F:35])[CH:30]=1)([O-:33])=[O:32]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1OCC(F)(F)F
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])c1ccc(C(O)c2ccccn2)c(OCC(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-bromopyridine (2.8 ml) was dissolved in diethylether (80 ml), and the mixture was cooled to −78° C. under argon atmosphere. 1.6M n-butyllithium hexane solution (18 ml) was added dropwise to the solution, and the mixture was stirred for 30 minutes. The reaction solution was added dropwise to a solution of 2-(2,2,2-trifluoroethoxy)-4-nitrobenzaldehyde (6 g) in tetrahydrofuran (100 ml) under argon atmosphere at −78° C. The mixture was allowed to be at room temperature and stirred overnight, and water was added to the mixture. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give [4-nitro-2-(2,2,2-trifluoroethoxy)phenyl](pyridin-2-yl)methanol (4.5 g) as pale brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OCC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.2 %

Procedure:
To a solution of 4-tert-butoxycarbonylmethoxy-benzoic acid methyl ester (5 g, 18.8 mmol) in dry DCM (40 ml) is added trifluoro-acetic acid (40 ml) at 0° C. The solution is stirred for 5 h at rt and evaporated in vacuo to give 4-carboxymethoxy-benzoic acid methyl ester 4 g as a white solid. LC-MS2: tR=3.24 min, [M+1]+=211.04, [M−1]−=208.96.
Reaction SMILES: [CH3:1][CH:2]1[C:6]([N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:8]2=[O:24])=[CH:5][C:4](=[O:25])[O:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][CH:2]1[C:6]([N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:8]2=[O:24])=[CH:5][C:4](=[O:25])[O:3]1
Reactant: CC1OC(=O)C=C1N1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1OC(=O)C=C1N1CCC2(CCNCC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(2-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (127 mg, 0.362 mmol) in methylene chloride (1 mL) was added trifluoroacetic acid (1.396 mL, 18.12 mmol), the resulting solution was stirred at rt for 1 h. After concentration, the residue was treated with methylene chloride (1 mL) and hydrogen chloride (1 mL, 4 N in dioxane). The resulting mixture was concentrated to give the title compound as hydrogen chloride salt. LC/MS: (M+1)+: 251.19.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH2:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C>CN(C=O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:13][CH2:14][CH2:15][OH:16])=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCNCCO)cc1

Procedure:
A mixture of 1-(2-Bromoethyl)-4-nitrobenzene (5.0 g, 22 mmol), 2-aminoethanol (1.7 g, 28 mmol), and triethylamine (6.6 mL, 48 mmol) was heated to 60° C. for 16 hours in DMF. LC showed formation of the desired product. DMF was removed under reduced pressure, and the residue was dissolved in EtOAc. The desired product was precipitated out with hexanes. LC-MS (IE, m/z): 211 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([Cl:20])=[CH:14][C:15]=3[Cl:19])[NH:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[CH:23](=O)[CH3:24].[Na]>>[Cl:19][C:15]1[CH:14]=[C:13]([Cl:20])[CH:12]=[C:11]2[C:16]=1[C:17](=[O:18])[C:8]([CH3:22])([C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:23][CH3:24])=[CH:7][CH:6]=1)[C:9](=[O:21])[NH:10]2
Reactant: CC=O
Reactant: CC1(c2ccc(N)cc2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Agent: [Na]
Product: CCNc1ccc(C2(C)C(=O)Nc3cc(Cl)cc(Cl)c3C2=O)cc1
Yield: 3.9 %

Procedure:
The objective compound was prepared by the same procedure for the example 39 and 40, using a 3-(4-amino-phenyl)-5,7-dichloro-3-methyl-1H-quinoline-2,4-dione (235 mg, 0.70 mmol), acetaldehyde (148 mL, 2.10 mmol), and sodium borocyanohydride (44 mg, 0.70 mmol). After normal workup, The residue was purified by a flash column chromatography (n-hexane:EtOAc=8:1) to give two separable objective chemical compounds of 5,7-dichloro-3-methyl-3-(4-ethylamino-phenyl)-1H-quinoline-2,4-dione (10 mg, 4%, yellow solid) and 5,7-dichloro-3-(4-diethylamino-phenyl)-3-methyl-1H-quinoline-2,4-dione (220 mg, 87%, pale yellow solid:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[C:4]([CH3:16])[N:3]=1.[N+:17]([O-])([O-:19])=[O:18].[K+].[OH-].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=[CH:11][C:10]=2[Cl:15])=[C:4]([CH3:16])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1ccccc1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,4-diamino-5-(2-chlorophenyl)-6-methyl pyrimidine (11.84 g) (Example 22) in concentrated H2SO4 (100 ml), was added potassium nitrate (5.1 g). After stirring at room temperature for 90 minutes, the solution was poured onto ice and basified with 10N NaOH. The product was extracted with ethyl acetate, bulked, dried (MgSO4) and evaporated, 13.9 g, 236°-240° C.
Reaction SMILES: Br.Br.[OH:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[CH3:17].Cl[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:3][C:4]1[C:5]([CH3:17])=[CH:6][C:7]([N:11]2[CH2:12][CH2:13][N:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=3)[CH2:15][CH2:16]2)=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(N2CCNCC2)cc(C)c1O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)cc(C)c1O
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 58.8 %

Procedure:
2.21 g (6 mmol) of 1-(4-hydroxy-3,5-dimethylphenyl)piperazine dihydrobromide, 1.14 g (6.25 mmol) of 2-chloro-5-trifluoromethylpyridine and 1.245 g (9 mmol) of K2CO3 in 27 ml of absolute DMF were reacted by the same procedure as described in Example 20. The mixture was subsequently stirred for 3.5 hours at 90° C. After evaporation of the DMF, the residue was mixed with water, and the oily crystalline material produced during this was filtered off under suction, dissolved in methanol and clarified using activated charcoal. After filtration, a little water was added to the filtrate, a crystalline precipitate being produced. This was filtered off under suction (yield 1.63 g) and chromatographed as described in Example 15 on a silica gel/CH2Cl2 column (diameter 2.0 cm, height 22 cm). In this fashion, 1.24 g (=59% yield) of 1-(4-hydroxy-3,5-dimethylphenyl)-4-(5-trifluoromethylpyrid-2-yl)piperazine, melting point 143°-44° C., were obtained;
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Cl:5][C:6]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:14](=[O:15])[O:13][C:12]2([CH2:20][CH3:21])O.Cl>O1CCCC1>[Cl:5][C:6]1[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:14](=[O:15])[O:13][C:12]2([CH2:20][CH3:21])[CH:1]=[CH2:2]
Reactant: C=C[Mg]Br
Reactant: CCC1(O)OC(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3Cl)cc21
Agent: Cl
Solvent: C1CCOC1
Product: C=CC1(CC)OC(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3Cl)cc21
Reaction time: 1 h

Procedure:
To a 1M solution of vinyl magnesium bromide in tetrahydrofuran (46 ml) was added dropwise at 25° C. a solution of 5-(2'-chloro-4'trifluoromethylphenoxy)-3-ethyl-3-hydroxy- phthalide (2.3 g) in dry tetrahydrofuran (25 ml). After the addition was complete, the solution was stirred for 1 hour and poured into a mixture of ice and concentrated hydrochloric acid. The mixture was stirred for one hour, extracted with methylene chloride, washed with water and dried with sodium sulphate. Chromatography on silica with methylene chloride as eluant yielded a pale orange oil later obtained as colorless crystals (mp. 77°-79° C.).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]N1C(=O)CCC1=O.O.C(OCC)(=O)C>C(O)(=O)C>[Br:16][C:13]1[CH:14]=[C:9]([O:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:10]([NH2:15])=[N:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1OCC1CCCCC1
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)cc1OCC1CCCCC1
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of 2 g of 3-(cyclohexylmethoxy)pyridin-2-amine in 10 ml of acetic acid was added 1.90 g of N-bromosuccinimide over 30 minutes under ice-cooling, followed by stirring for 30 minutes under ice-cooling. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.25 g of 5-bromo-3-(cyclohexylmethoxy)pyridin-2-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([CH3:13])[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:10]2[CH2:11][CH:12]([CH3:13])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9]2)=[O:23])=[CH:17][CH:16]=1
Reactant: CC1CNN=C1c1ccc(Cl)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: CC1CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
In a 500 ml round bottomed flask was placed 82 g (0.42 mole) of 3-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole dissolved in 300 ml of methylene chloride and the solution was brought to boiling. A solution of 64.5 g of 4-chlorophenyl isocyanate (0.42 mole) in 100 ml of methylene chloride was added at a rate to maintain reflux. After stirring for an additional 30 minutes the solvent was removed in vacuo and the resulting oil was crystallized from ethyl ether yielded 140 g of N,3-bis-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide. mp 139°-140° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][N:4]=1.CN[C@@H]1CCCC[C@H]1NC.[F:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:5]2[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([C:2]([F:1])([F:13])[F:14])=[N:4]2)=[CH:28][CH:27]=1
Reactant: Fc1ccc(I)cc1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)nc1C(F)(F)F
Yield: 96.5 %

Procedure:
To a solution of ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (100 mg, 0.480 mmol) in toluene (0.5 mL) was added (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (13.67 mg, 0.096 mmol), 1-fluoro-4-iodobenzene (0.166 mL, 1.441 mmol), potassium carbonate (139 mg, 1.009 mmol), and copper(I) iodide (9.00 mg, 0.047 mmol). This reaction was heated to reflux overnight. The next day, the reaction was complete by HPLC so it was filtered through a frit with EtOAc and purified on a SiO2 column using 25-100% EtOAc hexanes gradient to give white crystalline ethyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (140 mg, 0.463 mmol, 96% yield). The structure was assigned by small molecule X-ray crystallography. 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (1H, s), 7.62 (2H, m), 7.14 (2H, m), 4.25 (2H, q), 1.37 (3H, t).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[S:3][CH:2]=1.S1C2=NC=CC=C2C(CN)=C1>>[N:1]1[C:9]2[C:4](=[N:5][C:6]([CH2:10][NH2:11])=[CH:7][CH:8]=2)[S:3][CH:2]=1
Reactant: N#Cc1ccc2ncsc2n1
Agent: NCc1csc2ncccc12
Product: NCc1ccc2ncsc2n1

Procedure:
Intermediate Q was prepared from thiazolo[5,4-b]pyridine-5-carbonitrile (Q-5) following similar procedures for synthesizing intermediate J from J-4, as described above. MS (m/z): 166 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[F:14])[N:5]([CH2:9][CH3:10])[C:6](=[O:8])[CH3:7].[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:13]([F:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[C:4]([CH:3]=1)[N:5]([CH2:9][CH3:10])[C:6](=[O:8])[CH3:7]
Reactant: O=[N+]([O-])[O-]
Reactant: CCN(C(C)=O)c1ccc(F)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCN(C(C)=O)c1cc(Cl)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 61319.6 %

Procedure:
3'-Chloro-N-ethyl-4'-fluoroacetanilide (101 g, 0.468 mmol) is dissolved in conc. sulfuric acid (300 ml). A solution of potassium nitrate (57 g, 0.564 mol) in conc. sulfuric acid (220 ml) is added dropwise thereto at 5°. The solution obtained is stirred overnight, then poured on to ice/water and extracted with ethyl acetate (2×200 ml). The organic phase is washed in succession with water (200 ml), saturated sodium bicarbonate solution (100 ml) and saturated sodium chloride solution (100 ml). The organic phase is treated with active charcoal, filtered and dried over magnesium sulfate. The solvent is distilled off and the residue is recrystallized from ether/n-hexane. There are obtained 74.8 g (61%) of 5'-chloro-N-ethyl-4'-fluoro-2'-nitroacetanilide with a m.p. of 68°.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3OCCl)[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4].[C:66]([O:70][C:71]([NH:73][CH2:74][CH2:75][CH2:76][C:77]([OH:79])=[O:78])=[O:72])([CH3:69])([CH3:68])[CH3:67].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:78][C:77](=[O:79])[CH2:76][CH2:75][CH2:74][NH:73][C:71]([O:70][C:66]([CH3:69])([CH3:67])[CH3:68])=[O:72])[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4]
Reactant: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OCCl)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OC(=O)CCCNC(=O)OC(C)(C)C)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C

Procedure:
The compound of Example 8B is dissolved in DMF; 4-tert-butoxycarbonylaminobutanoic acid (1.3 eq) is added, along with 1.2 equivalents of Cs2CO3. The resultant mixture is stirred overnight at ambient temperature. The reaction mixture is partitioned between aqueous phosphoric acid (1N) and ethyl acetate. The organic extract is dried (Na2SO4), filtered, and concentrated in vacuo. The crude material is purified on silica gel using a gradient of ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:33][CH2:32][N:24]2[C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=3[CH:31]=[C:23]2[C:22]1=[O:34])(=[O:3])[CH3:2].Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1.CC([O-])=O.[Na+]>CC#N.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]>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:33][CH2:32][N:24]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=[C:23]3[C:22]2=[O:34])=[CH:8][CH:9]=[CH:10][C:11]=1[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(F)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(F)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 72 %

Procedure:
A sealed tube was charged with the mixture of 2-(1-oxo-3,4,6,7,8,9-hexa-hydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (232 mg, 0.5 mmol), 148a (148 mg, 0.50 mmol), Pd(dppf)Cl2 (25 mg, 0.03 mmol), K3PO4.3H2O(266 mg, 1.0 mmol), and NaOAc (82 mg, 1.0 mmol) in CH3CN (18 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 110° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 30:1 DCM/MeOH to afford 148b as a yellow solid (200 mg, 72%). MS: [M+H]+ 556.
Reaction SMILES: [CH2:1]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([OH:25])[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:26]Br.C([O-])(=O)C.[K+]>C(O)(=O)C>[Br:26][C:21]1[C:22]2[C:17](=[CH:16][C:15]([C:7]3[O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:6]=3[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:24][CH:23]=2)[CH:18]=[CH:19][C:20]=1[OH:25]
Reactant: CCCCCc1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCCCCc1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Yield: 88 %

Procedure:
Following the procedure described in Step 4 of Example 1, 6-(3-pentyl-benzofuran-2-yl)-naphthalen-2-ol (3.3 g, 10.0 mmol) was brominated using bromine (0.6 mL, 11.8 mmol), and potassium acetate (1.0 g. 10.2 mmol) in glacial acetic acid (40 mL). Purification by chromatography on a Biotage apparatus using 5% % ethyl acetate in hexane as the mobile phase furnished the title compound as an off-white solid (3.6 g), mp 75-77° C. Mass spectrum (+APCl, [M+H]+) m/z 409. 1HNMR (300 MHz, DMSO-d6): δ10.76 (br s,1H), 8.25 (d, 1H, J=1.2 Hz), 8.14 (d, 1H, J=8.9 Hz), 7.98-7.92 (m, 2H), 7.68-7.58 (m, 2H), 7.35-7.27 (m, 3H), 2.98 (t, 2H, J=7.3 Hz), 1.71 (p, 2H, J=6.9 Hz), 1.42-1.27 (m, 4H), and 0.87-0.80 ppm (tm 3H). Elemental Analysis for C23H21BrO2.0.7H2O: Calculated: C, 65.47; H, 5.35; N, 0.00. Found: C, 65.17; H, 4.92; N, 0.08.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][C:33]1[O:37][C:36]([C:38]([F:41])([F:40])[F:39])=[C:35]([S:42](Cl)(=[O:44])=[O:43])[CH:34]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([C:35]1[CH:34]=[C:33]([CH3:32])[O:37][C:36]=1[C:38]([F:41])([F:39])[F:40])(=[O:44])=[O:43]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: Cc1cc(S(=O)(=O)Cl)c(C(F)(F)F)o1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)c(C(F)(F)F)o1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (50 mg, 0.120 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 5-methyl-2-(trifluoromethyl)furan-3-sulfonyl chloride (24 mg, 0.130 mmol) and pyridine (11 uL, 0.130 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 72 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-5-methyl-2-(trifluoromethyl)furan-3-sulfonamide (percentage yield: 94%), was obtained.