Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]#[N:17])[C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:4]1.[N+:24]([O-])([OH:26])=[O:25]>C(Cl)Cl>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]#[N:17])[C:9]=3[C:8]([N+:24]([O-:26])=[O:25])=[CH:7][C:6]=2[N:5]([C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])[CH2:4]1
Reactant: N#Cc1cccc2c3c(ccc12)N(C(=O)C(F)(F)F)CC3CCl
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: N#Cc1cccc2c3c(cc([N+](=O)[O-])c12)N(C(=O)C(F)(F)F)CC3CCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
A solution of 126 (60 mg, 0.18 mmol) in CH2Cl2 (10 mL) was treated with fuming HNO3 (1.5 mL) and stirred for 30 min at room temperature. The reaction was quenched with ice and extracted with CH2Cl2 (3×50 ml). The extracts were dried and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with EtOAc/petroleum ether (from 1:4 to 1:1), to give 1-(chloromethyl)-5-nitro-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-6-carbonitrile (127) (28 mg, 41%) as a brown solid: mp EtOAc/petroleum ether) 201-205° C. (dec.); 1H NMR [(CD3)2SO] δ 8.87 (s, 1H), 8.63 (dd, J=8.5, 1.1 Hz, 1H), 8.40 (dd, J=7.3, 1.0 Hz, 1H), 7.93 (dd, J=8.5, 7.3 Hz, 1H), 4.73-4.61 (m, 2H), 4.55-4.49 (m, 1H), 4.22-4.15 (m, 1H), 4.12-4.07 (m, 1H); 13C NMR δ 153.8 (q, JC-F 37.6 Hz), 146.8, 139.8, 137.7, 132.6, 130.3, 129.4, 128.3, 118.7, 115.4 (q, JC-F 288 Hz), 115.1, 114.8, 105.4, 52.7, 47.4, 41.1. Anal. (C16H9ClF3N3O3) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1>C(O)(C)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:5][CH:4]([OH:8])[CH2:3][CH3:2])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC(C)O
Product: CCC(O)CN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 48 h
Yield: 53.6 %

Procedure:
A stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5.5 g, 25 mmol) and 1,2-expoxybutane (1.89 g, 26.3 mmol) in isopropyl alcohol (1130 ml) was heated at 65 C. for 2 days. This mixture was cooled and the solvent was removed to leave a brown oil which was purified by flash chromatography over a silica gel column (SiO2, 70 g; eluted with DCM, 1 l and MeOH:DCM 2%: 98%) to give an off-white solid weighing 6.3 g. Recrystallization from hot ethanol yielded 1.96 g of fine crystals, m.p. 87°-88° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[C:13]([O-])(O)=O.[Na+]>CO>[CH3:13][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: O=C([O-])O
Reactant: Nc1cccc(CC(=O)O)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1cccc(N)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
To a solution of 3-aminophenylacetic acid (3 g, 19.85 mmol) in methanol (50 mL) at room temperature was added HCl conc. (37%, 7.5 mL). The mixture was stirred 6 h at room temperature then treated with a saturated aqueous solution of NaHCO3. The solvent was removed under reduced pressure then the aqueous phase was extracted several times with CH2Cl2. The combined organic extracts were dried over (MgSO4) and evaporated. The crude mixture was purified by flash chromatography using hexane/AcOEt (1:1) yielding 1 as a yellow oil (3.06 g, 79%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH:19]=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:15]=2)[CH2:10]1)=O)(C)(C)C.C(O)C.Cl>C(O)C>[NH2:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH:19]=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:15]=2)[CH2:10]1
Reactant: CCOC(=O)C=Cc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C=Cc1ccc2c(c1)C[C@@H](N)CC2
Yield: 99.9 %

Procedure:
Ethyl (S)-3-[2-(tert-butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yl]acrylate (516 mg) was dissolved in ethanol (10 ml), and 3 M hydrogen chloride ethanol solution (2 ml) was added to the solution at room temperature with stirring. After reaction for 13 hours, the reaction mixture was concentrated in vacuo. A saturated aqueous sodium bicarbonate solution (20 ml) and dichloromethane (5 ml) were added to the residue, and the resulting mixture was stirred for an hour at room temperature. Water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The extract was washed with water and dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave ethyl (S)-3-(2-amino-1,2,3,4-tetrahydronaphthalen-7-yl)acrylate (366 mg) as an oil.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][C:10]([C:12]([O:14]C)=[O:13])=[CH:11][C:6]2=[N:5][C:4]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:3]1=2.O[Li].O.Cl>CO>[O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11][C:6]2=[N:5][C:4]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:3]1=2
Reactant: COC(=O)c1ccn2c(=O)c3c(nc2c1)CCCCCC3
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)c1ccn2c(=O)c3c(nc2c1)CCCCCC3

Procedure:
A solution of methyl 12-oxo-7,8,9,10,11,12-hexahydro-6H-cycloocta[d]pyrido[1,2-a]-pyrimidine-3-carboxylate (80 mg, 0.28 mmol) and LiOH H2O in MeOH (5 mL) was stirred at room temperature for 0.5 h. The reaction mixture was adjusted to pH around 6 with 1 N HCl and extracted with ethyl acetate (2×25 mL). The combined ethyl acetate layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH:8]([CH3:10])[CH3:9])=[N:3]1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)(=O)C>[CH3:1][N:2]1[C:6]([NH2:7])=[C:5]([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)[C:4]([CH:8]([CH3:10])[CH3:9])=[N:3]1
Reactant: CC(C)c1cc(N)n(C)n1
Reactant: O=C1CCCCC1
Solvent: CC(=O)O
Product: CC(C)c1nn(C)c(N)c1C1=CCCCC1
Reaction time: 8 h
Yield: 54 %

Procedure:
Under nitrogen atmosphere, to a 100 mL of round bottom flask were added the compound of Example 2B (5.2 g, 38 mmol) and 40 mL of glacial acetic acid. After the compound was dissolved with stirring, cyclohexanone (8.22 g, 76 mmol) was added. The resultant mixture was warmed to 50° C. The reaction was kept overnight. The reaction was stopped. Glacial acetic acid was rotary-evaporated. The resultant product was dissolved with ethyl acetate and washed to alkalescence with aqueous solution of sodium bicarbonate. The ethyl acetate layer was separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined and dried over MgSO4. The solvent was rotary-evaporated. The product was purified with column chromatography (eluant: petroleum ether:ethyl acetate=1:1) to give 4.5 g of the title compound. MS (ESI): m/z 220 (M+H)+
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([C:20](O)=[O:21])[CH2:16][CH2:15]3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH:35][C:20]([C@H:17]2[CH2:16][CH2:15][C@H:14]([C:11]3[NH:12][CH:13]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:4]=4)[N:10]=3)[CH2:19][CH2:18]2)=[O:21])(=[O:34])=[O:33])=[CH:30][CH:31]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)[C@H]1CC[C@H](c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)[C@H]2CC[C@H](c3nc(-c4cccc(C(F)(F)F)c4)c[nH]3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-water cooled mixture of trans-4-{4-[3-(trifluoromethyl)phenyl]imidazol-2-yl}cyclohexanecarboxylic acid (1.48 mmol), 4-methylbenzenesulfonamide (1.48 mmol), and DMAP (1.48 mmol) in dichloromethane (10 mL) under nitrogen, EDC (1.48 mmol) was added. The mixture was stirred at room temperature overnight, concentrated and chromatographed on silica gel (19:1 EtOAc-MeOH eluent) to give trans-N-[(4-methylphenyl)sulfonyl](4-{4-[3-(trifluoromethyl)phenyl]-imidazol-2-yl}cyclohexyl)carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][CH:3]=1.[CH2:11]([N:17](CCCCCC)CCCCCC)[CH2:12]CCCC.C(#N)C=C>O1CCOCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[CH:12][C:11]#[N:17])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCCCCCN(CCCCCC)CCCCCC
Solvent: C1COCCO1
Solvent: C=CC#N
Product: N#CC=Cc1ccc(F)cc1
Yield: 17.9 %

Procedure:
The procedure described in Example 1 is repeated, except that 15.86 g (0.1 mol) of 4-fluorobenzoyl chloride, 26.95 g (0.1 mol) of tri-n-hexylamine, 6.53 g (0.125 mol) of acrylonitrile and 0.575 g (0.001 mol) of bis-(dibenzylidene-acetone)-palladium(O) in 50 ml of dioxane are used. After a reaction time of 33 hours at 100° C., 2.63 g (0.0179 mol) of 4-fluorocinnamonitrile are obtained, corresponding to a yield of 17.9% of theory; analysis for C9H6FN (molecular weight 147): calculated C 73.46%, H 4.11%, N 9.52%; found C 73.16%, H 4.19%, N 9.61%.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4]Cl.[OH-].[Na+].[C:8]1([CH:14]([C:30]([F:33])([F:32])[F:31])[CH:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[C:8]1([CH:14]([C:30]([F:33])([F:31])[F:32])[CH:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:2][O:3][CH3:4])=[CH:20][CH:21]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCOCCl
Reactant: Oc1ccc(C(c2ccc(F)cc2)C(c2ccccc2)C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COCOc1ccc(C(c2ccc(F)cc2)C(c2ccccc2)C(F)(F)F)cc1
Reaction time: 1 h
Yield: 67.2 %

Procedure:
9.6 g (120 mmoles) of chloromethyl ether and 8.4 g (210 mmoles) of powdered sodium hydroxide are added to a solution of 27.7 g (76 mmoles) of 2-phenyl-3,3,3-trifluoro-1-(4-fluorophenyl)-1-(4-hydroxyphenyl)-propane in 100 ml of benzene, prepared as described in Example 22, and the mixture is boiled for one hour. The reaction mixture is diluted with 150 ml of benzene, washed with a 20% aqueous ammonium chloride solution until neutral, dried and evaporated. The residue is dissolved in benzene and passed through a chromatographic column filled with 650 g of silica gel. The first eluate fractions are combined and evaporated to obtain 20.66 g (66.6%) of 2-phenyl-3,3,3-trifluoro-1-(4-fluorophenyl)-1-(4-methoxymethoxy-phenyl)-propane, which is applied in the subsequent step without purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH:22]=[CH:21][N:20]=[N:19]1>CN1CCCC1=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:19]2[N:20]=[CH:21][CH:22]=[N:18]2)=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=1
Reactant: c1c[nH]nn1
Reactant: CC(=O)c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(=O)c1cc(F)ccc1-n1nccn1
Temperature: 140 °C
Yield: 35 %

Procedure:
To a solution of 2′,5′-difluoroacetophenone (10.0 g, 64 mmol) in 1-methyl-2-pyrrolidinone (10 mL) was added potassium carbonate (8.84 g, 64 mmol) and 1H-1,2,3-triazole (6.64 g, 96 mmol). This mixture was heated to 140° C. for 3 hr, under an atmosphere of nitrogen. After this time, the reaction was cooled and then partitioned between ethyl acetate (300 mL) and aqueous ammonium chloride solution (1M, 100 mL). The organic phase was washed with water (3×200 mL) and then dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with ethyl acetate in heptane (10:90 by volume) to produce the title compound as a brown oil (4.6 g, 35%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN(C=O)C>[CH3:17][CH:14]1[CH2:15][CH2:16][N:11]([C:4]2[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[CH:3]=2)[CH2:12][CH2:13]1
Reactant: CN1CCNCC1
Reactant: CC1CCN(c2cc(Cl)cnc2[N+](=O)[O-])CC1
Solvent: CN(C)C=O
Product: CC1CCN(c2cc(N3CCN(C)CC3)cnc2[N+](=O)[O-])CC1
Temperature: 125 °C
Yield: 64 %

Procedure:
To a solution of 5′-chloro-4-methyl-2′-nitro-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl (as prepared in the previous step) (255 mg, 1.00 mmol) in DMF (10 mL) was added 1-methyl piperazine (110 μL, 1.00 mmol). The resulting mixture was heated at 125° C. overnight. The reaction mixture was allowed to cool to room temperature and partitioned between water and EtOAc. The EtOAc layer was separated, dried (Na2SO4) and concentrated in vacuo. The residue obtained was purified on silica (10-50% EtOAc:hexane) to obtain the title compound (204 mg, 64%). 1H-NMR (CDCl3; 400 MHz): δ 7.67 (d, 1H, J=2.52 Hz), 6.69 (d, 1H, J=2.52 Hz), 3.39 (m, 4H), 3.29 (m, 2H), 2.75 (m, 2H), 2.56 (m, 4H), 2.35 (s, 3H), 1.71 (m, 2H), 1.6-1.5 (m, 3H), 0.99 (d, 3H, J=6.3 Hz).
Reaction SMILES: [Cl-].[CH3:2][C@:3]12[C@@:20]3([CH3:21])[C@@H:11]([C@:12]4([CH3:25])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:23])([CH3:22])[C:15](=[O:24])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:6]1([NH3+:32])[CH2:5][CH2:4]2.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:32][C@:6]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:7]1[C@@H:8]1[C@@:3]([CH3:2])([CH2:4][CH2:5]2)[C@@:20]2([CH3:21])[C@@H:11]([C@:12]3([CH3:25])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:22])([CH3:23])[C:15](=[O:24])[CH2:14][CH2:13]3)[CH2:10][CH2:9]1
Reactant: C=C(C)[C@@H]1CC[C@]2([NH3+])CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-3a-aminium chloride (462 mg, 1.000 mmol) in DCM (6 mL) was added saturated solution of sodium bicarbonate 10 mL. The 2-phase mixture was vigorously stirred, DCM layer separated, it was washed with another portion of 6 mL of saturated sodium bicarbonate solution. The mixture was extracted with 10 mL DCM three times. The combine DCM fractions was finally washed with 5 mL DI water. Upon evaporation and drying, a thick semi-solid was isolated. This crude material was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:14]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([N:40]2[CH2:45][CH2:44][CH:43]([O:46][C:47]([O:49]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:42][CH2:41]2)=[O:39])=[O:29])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[O:14]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([N:40]2[CH2:41][CH2:42][CH:43]([O:46][C:47]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:49])[CH2:44][CH2:45]2)=[O:39])=[O:29])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C1CCNCC1
Reactant: O=C(NCCCCCCOC(=O)N1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1)Oc1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCOC(=O)N1CCC(OC(=O)N2CCCCC2)CC1)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
A solution of piperidine (382 μl, 3.86 mmol) and triethylamine (2.24 mL, 16.1 mmol) in 30 mL of methylene chloride was added under nitrogen dropwise to a solution of the carbonate prepared in Example 5 (2.0 g, 3.22 mmol) in 30 mL of methylene chloride at ice bath temperature. After the addition the cooling bath was removed and the reaction stirred at room temperature overnight. The reaction was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 1.85 g of an oil. Purification of the oil on silica gel (230-400 mesh) using 5%-20% ethyl acetate-methylene chloride as the eluent gave 1.23 g (68%) of the title compound as a white crystalline solid, mp 56°-61° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27](O)=[O:28])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:74][CH2:75][CH2:76][CH2:77][N:78]1[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]1>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:74][CH2:75][CH2:76][CH2:77][N:78]4[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]4)=[O:28])[S:26][C:19]=23)=[CH:30][CH:31]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2)c1
Reactant: NCCCN1CCCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCN5CCCCC5)sc34)cc2)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred, cooled (0° C.) solution of 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.27 mmol) in anhydrous DMF (10 ml) were added PyBOP (156 mg, 0.30 mmol) and N,N-diisopropylethylamine (70 mg, 0.54 mmol). The mixture was stirred at 0° C. for 5 minutes, followed by addition of N-(3-aminopropyl)piperidine (58 mg, 0.41 mmol). Stirring was continued at 0° C. for another 30 minutes. The mixture was poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried to give 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-piperidin-1-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide as beige solid. Yield: 151 mg, 98%. 1H NMR (600 MHz, DMSO-d6) δ ppm 9.21 (s, 1H) 8.94 (t, J=5.58 Hz, 1H) 8.56 (d, J=5.28 Hz, 1H) 8.50 (d, J=2.64 Hz, 1H) 8.22 (s, 1H) 7.98 (dd, J=7.63, 2.05 Hz, 1H) 7.57-7.60 (m, 2H) 7.23-7.27 (m, 2H) 7.11 (dd, J=11.30, 8.36 Hz, 1H) 6.80-6.83 (m, 1H) 6.71 (d, J=5.28 Hz, 1H) 3.30-3.35 (m, 2H) 2.31 (br. s., 6H) 2.28 (s, 3H) 1.69-1.75 (m, 2H) 1.47-1.52 (m, 4H) 1.38 (br. s., 2H)
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>N1C=CC=CC=1>[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([CH3:8])[CH:7]=1)=[O:14]
Reactant: Cc1c[nH]c(=O)c(N)c1
Reactant: O=C(Cl)c1ccccc1F
Solvent: c1ccncc1
Product: Cc1c[nH]c(=O)c(NC(=O)c2ccccc2F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.1 g. of 3-amino-5-methyl-2-pyridone in 25 ml. of pyridine was cooled in ice and treated with 4.5 g. of 2-fluorobenzoyl chloride dropwise. After stirring about 3 hours at room temperature, the mixture was diluted with 200 ml. of ice-water. After 0.5 hour the precipitate was collected, washed with water, dried and recrystallized from ethanol to give 3-(2-fluorobenzoylamino)-5-methyl-2-pyridone, m.p. 230°-232° C.
Reaction SMILES: CCCCCC.C([Li])CCC.BrC1C=C(F)C=CC=1.[N:20]1[C:29]2[C:24](=[C:25]3C=CC=C[C:26]3=[C:27]3C=CC=C[C:28]3=2)[N:23]=[CH:22][CH:21]=1>O1CCCC1>[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1
Reactant: c1ccc2c(c1)c1ccccc1c1nccnc21
Agent: Fc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc2nccnc2c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
First, 27.5 mL of a hexane solution of n-butyllithium (1.58 mol/L) was dropped in a mixed solution of 6.87 g of 3-bromofluorobenzene and 40 mL of tetrahydrofuran at −78° C. under nitrogen atmosphere, and immediately after that, the obtained solution was stirred at −78° C. for 2 hours. To this solution was added 7.54 g of dibenzo[f,h]quinoxaline at −78° C. in five separate additions. The reaction temperature was increased to room temperature, and then the solution was stirred at room temperature for 12 hours. Water was added to this mixture, and an organic layer was extracted with dichloromethane used as an extraction solvent. The obtained organic layer was dried over anhydrous magnesium sulfate. The dried solution was filtered. After the solvent of this solution was distilled, the resultant substance was recrystallized with ethanol to obtain an objective quinoxaline derivative Hdbq-3FP (light orange power, yield 23%). Synthetic scheme of Step 1 is shown in the following (a-2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([NH2:20])[CH:11]=1.[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>CN(C)C=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([NH:20][CH2:34][C:33]2[CH:36]=[CH:37][C:30]([O:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:31][CH:32]=2)[CH:11]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1NCc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
A solution of 0.80 g of N-(2-pyridylmethyl)-4-acetylamino-3-aminobenzamide in 10 ml of N,N-dimethylformamide were added 1.31 g of 4-benzyloxybenzyl chloride and 1.18 g of sodium hydrogencarbonate, and the mixture was stirred at 90° C. for 2 hours. Chloroform and water were added to the reaction solution, and the chloroform extraction was conducted. The organic layer was washed with water, concentrated, and purified through silica-gel column chromatography to give 0.434 g of N-(2-pyridylmethyl)-4-acetylamino-3-(4-benzyloxybenzylamino)benzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[Cl:48][C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][NH:57][C:58](=[O:60])[CH3:59])=[C:51]([OH:61])[CH:50]=1>>[C:58]([NH:57][CH2:56][CH2:55][C:52]1[CH:53]=[CH:54][C:49]([Cl:48])=[CH:50][C:51]=1[O:61][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1)(=[O:60])[CH3:59]
Reactant: CC(=O)NCCc1ccc(Cl)cc1O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2cc(Cl)ccc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.458 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.30 g of N-[2-(4-chloro-2-hydroxyphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.70 (EtOAc); Rt=5.75.