Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20](F)=[C:21]([F:24])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1COCC1.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:21]([F:24])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)c(F)cc23)CC1
Reactant: C1COCCN1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(N4CCOCC4)c(F)cc23)CC1
Yield: 89.4 %

Procedure:
A solution of 4-(6,7-Difluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (37.8 mg, 108 μmol) (preparation in Example 205c) and morpholine (19.8 μL, 227 μmol) in THF (100 μL) and DMSO (50 μL) was heated at 100° C. for 1 hr. The crude reaction was loaded onto a flash silica cartridge (1:1 hexanes/EtOAc eluent) to provide the title compound (40.2 mg, 89%). NOe experiments support the assigned regioisomer. Select 1H-NMR resonances and nOes (300 MHz, CDCl3) δ 7.68 (d, J=13.7 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 3.45 (tt, 1H), 3.31 (m, 4H). Irradiation of the diagnostic methine proton at δ 3.45 generates an nOe to the quinazoline C5 proton at δ 7.68, but not to the quinazoline C8 proton at δ 7.37. The C5 proton has a larger coupling constant than the C8 proton, indicating fluorine substitution at C6 of the quinazoline. Furthermore, irradiation of the C8 proton at δ 7.37 generates an nOe only to the morpholine C3 protons at δ 3.31, while irradiation of the C5 proton generates an nOe only to the methine proton at δ 3.45. These data indicate morpholine substitution at the quinazoline C7 carbon. LC/MS (ESI): calcd mass 416.2, found 417.3 (MH)+.
Reaction SMILES: [OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:23]C4CCOCC4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1.[F:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42]N>>[F:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][NH:20][C:18]([C:16]1[N:17]2[CH2:12][CH2:13][O:14][C:8]3[CH:7]=[CH:6][C:5]([C:4]#[C:3][C@@:2]([OH:1])([C:32]4[CH:36]=[C:35]([CH3:37])[O:34][N:33]=4)[CH3:31])=[CH:30][C:9]=3[C:10]2=[N:11][C:15]=1[C:21]([NH2:23])=[O:22])=[O:19]
Reactant: NCc1cccc(F)c1
Reactant: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)no1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NCc4cccc(F)c4)n2CCO3)no1

Procedure:
Prepared as described for (R)-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-N3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide replacing oxan-4-amine hydrochloride with 3-fluorobenzylamine. off-white solid (45.4 mg, 5%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11](B3OC(C)(C)C(C)(C)O3)[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][C:6]=1[N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:4].Cl[C:36]1[CH:37]=[CH:38][C:39]2[O:52][CH2:51][N:42]3[C:43]4[CH:44]=[CH:45][CH:46]=[C:47]([F:50])[C:48]=4[CH:49]=[C:41]3[C:40]=2[N:53]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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]>[F:50][C:47]1[C:48]2[CH:49]=[C:41]3[C:40]4[N:53]=[C:36]([C:11]5[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][C:8]6[O:7][C:6]([N:29]7[CH2:34][CH2:33][O:32][CH2:31][CH2:30]7)=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[C:9]=6[CH:10]=5)[CH:37]=[CH:38][C:39]=4[O:52][CH2:51][N:42]3[C:43]=2[CH:44]=[CH:45][CH:46]=1
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(N2CCOCC2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(N2CCOCC2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 10.3 %

Procedure:
To a degassed solution of N-methyl-6-(N-methylmethylsulfonamido)-2-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (80 mg, 0.16 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (47 mg, 0.17 mmol), Na2CO3 (34 mg, 0.32 mmol) in dioxane (1.5 mL) and H2O (0.1 mL) was added Pd(dppf)Cl2 (3 mg) under N2. Then the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H2O and dried over Na2SO4. After concentration, the residue was purified by prep-HPLC to give the product of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)-2-morpholinobenzofuran-3-carboxamide (10 mg, yield: 10%). 1H-NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 7.45˜7.47 (m, 3H), 7.18˜7.21 (m, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.82˜6.87 (m, 1H), 6.64 (s, 1H), 5.99 (s, 2H), 3.89 (t, J=4.4 Hz, 4H), 3.51 (t, J=6.4 Hz, 4H), 3.36 (s, 3H), 3.01 (d, J=4.8 Hz, 3H), 2.68 (s, 3H). MS (M+H)+: 606.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]([CH:18]=1)=[N:16][C:15]1[C:10](=[CH:11][CH:12]=[C:13]([NH2:19])[CH:14]=1)[C:9]=2[NH2:20])(=[O:3])[CH3:2].[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(O)(=O)C>[C:21]([NH:19][C:13]1[CH:12]=[CH:11][C:10]2[C:15]([CH:14]=1)=[N:16][C:17]1[C:8](=[CH:7][CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:18]=1)[C:9]=2[NH2:20])(=[O:23])[CH3:22]
Reactant: CC(=O)Nc1ccc2c(N)c3ccc(N)cc3nc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(N)c3ccc(NC(C)=O)cc3nc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Acetamidyl-6,9-diaminoacridine (10 mg, 0.048 mmol) was dissolved in acetic acid (5 mL) and heated at reflux under a nitrogen atmosphere. Acetic anhydride (4.7 μL, 0.05 mmol) was added and reflux was continued for 10 min. On cooling to room temperature, the solution was concentrated to dryness and the residue was dissolved in water (10 mL) and washed with DCM (3×10 mL). The aqueous layer was lyophilised to give a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1ccccc1Cl
Reactant: Cc1cccc(N)c1C(=O)O
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Cc1cccc(N)c1C(=O)Nc1ccccc1Cl
Yield: 50.9 %

Procedure:
Prepared according to Procedure A using 2-amino-6-methylbenzoic acid (2.5 g, 16.5 mmol) and SOCl2 (3.0 mL, 41.3 mmol) in benzene (75 mL), followed by 2-chloroaniline (3.5 mL, 33.0 mmol) and CHCl3 (75 mL). The product was chromatographed in CH2Cl2 to provide 2.19 g of a brown oil (51%). 1H NMR (CDCl3) δ: 8.58 (d, J=8.1 Hz, 1H); 7.99 (br s, 1H); 7.40 (dd, J=1.4, 8.0 Hz, 1H); 7.34 (t, J=7.7 Hz, 1H); 7.11 (t, J=7.8 Hz, 1H); 7.09 (dt, J=1.5, 7.7 Hz, 1H); 6.64 (d, J=7.5 Hz, 1H); 6.59 (d, J=8.1 Hz, 1H); 4.29 (br s, 2H); 2.45 (s, 3H). MS (ES) m/z 283.0 (M+22).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].C[Al](C)C.C[O:21][C:22]([C@H:24]1[CH2:28][C@H:27]([OH:29])[C@@H:26]([NH:30][C:31]([C:33]2[S:34][C:35]([Cl:38])=[CH:36][CH:37]=2)=[O:32])[CH2:25]1)=O.[O-]S([O-])(=O)=O.[Mg+2]>O1CCOCC1.O>[F:15][C:3]1[CH:4]=[C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([C@@H:24]1[CH2:25][C@H:26]([NH:30][C:31]([C:33]2[S:34][C:35]([Cl:38])=[CH:36][CH:37]=2)=[O:32])[C@@H:27]([OH:29])[CH2:28]1)=[O:21]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a stirred suspension of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (296 mg; CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) at r.t. in dioxane (3 ml) under an argon atmosphere was added carefully trimethyl aluminium solution (0.72 ml; 2M in heptane). After stirring for 2 hrs at r.t., a solution of (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentane-carboxylic acid methyl ester (110 mg) in dioxane (3 ml) was added. The mixture was heated to 100° C. and stirring at that temperature was continued for 24 h. The mixture was cooled to r.t. and water (0.8 ml) was added. After 15 min stirring, MgSO4 was added and stirring was continued for another 15 min. The solids were filtered off and washed with dichloromethane. The filtrate was concentrated. The crude product was isolated by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-hydroxy-cyclopentyl}-amide (81 mg) as light yellow solid. MS: 476.0 ([M+H]+).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:23]([C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30])([CH3:26])([CH3:25])[CH3:24].C(OC(N1CCN(C2C=CC(C(=O)NC3C=CC=C(C(C)(C)C)C=3)=CC=2)CC1)=O)(C)(C)C>>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:28]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)c1cccc(N)c1
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1

Procedure:
4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was prepared from N-Boc-4-(4-carboxyphenyl)piperidine and 3-tert-butyl aniline in a manner similar to the one described in the synthesis of 4-[4-(3-tert-butyl-phenylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester, above. The product was isolated after silica gel column purification with 10-50% Et2O in hexanes. HRMS m/z calcd for C26H35N3O3I [M+H]+: 437.2799. Found: 437.2796.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][N:59]1[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][N:59]5[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NN2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-amino 4-methylpiperazine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.85 (m, 10 H) 2.18 (s, 3 H) 2.93 (br. s., 3 H) 3.22-3.47 (m, 7 H) 3.93 (s, 3 H) 4.06 (t, J=13.39 Hz, 2 H) 4.46 (m, 1 H) 7.44 (br. s., 1 H) 7.42 (d, J=8.84 Hz, 1 H) 7.90 (s, 1 H) 8.21 (s, 1 H) 8.27 (d, J=8.08 Hz, 1 H) 9.40 (s, 1 H). [M+H] calculated for C27H36F2N8O3, 559; found 559.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C@@:10]3([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)[CH2:9][N:8]([C:22](=[O:30])[NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1.[C:31]([O:34][CH2:35][C:36](Cl)=[O:37])(=[O:33])[CH3:32]>>[C:31]([O:34][CH2:35][C:36]([N:12]1[CH2:13][CH2:14][C@@:10]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:8]([C:22](=[O:30])[NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)[CH2:9]2)[CH2:11]1)=[O:37])(=[O:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CC[C@@]2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12
Reactant: CC(=O)OCC(=O)Cl
Product: CC(=O)OCC(=O)N1CC[C@@]2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Examples 2 and 3, with the exceptions that (S)-t-butyl 5-chloro-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was used instead of t-butyl 5-bromo-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate, and that acetoxyacetyl chloride was used instead of acetyl chloride.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:25][CH2:24]2)=[CH:19][C:18]=1[F:26])=[O:5])C.[OH-].[Na+]>C(O)(=O)C>[CH:23]1([C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:7]3[C:8]4[CH:9]=[N:10][CH:11]=[CH:12][C:13]=4[N:14]([CH3:15])[C:6]=3[C:4]([OH:5])=[O:3])=[C:18]([F:26])[CH:19]=2)[CH2:25][CH2:24]1
Reactant: CCOC(=O)c1c(Nc2ccc(C3CC3)cc2F)c2cnccc2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cn1c(C(=O)O)c(Nc2ccc(C3CC3)cc2F)c2cnccc21
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 3-(4-cyclopropyl-2-fluoro-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (197 mg, 0.50 mmol) and 1M NaOH (1.02 ml, 1.02 mmol) in IMS (3 ml) was heated at 60° C. for 2 hours. The reaction mixture was cooled to ambient temperature then acidified to pH 4 using acetic acid. The brown solid was filtered off, the residue dried to provide the title compound (161 mg, 97%). LCMS (method B): RT=2.18 min, M+H+=326.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=O)[CH:8]=2)[NH:3]1.[CH2:15]1[C@H:24]2[C@H:19]([CH2:20][CH2:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=32)[NH:18][CH2:17][CH2:16]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:15]1[C@H:24]2[C@H:19]([CH2:20][CH2:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=32)[N:18]([C:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH:11]=[N:10]3)=[O:14])[CH2:17][CH2:16]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]c(=O)cnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]c(=O)cnc2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 19 %

Procedure:
The title compound is prepared from 2-oxo-1,2-dihydro-quinoxaline-6-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 19% of theory; LC (method 4): tR=1.92 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:12]2[C:13]3[C:5]([CH2:6][C:7](=[O:14])[C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[F:1][C:2]1[C:12]2[C:13]3[C:5]([CH2:6][CH:7]([OH:14])[C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(F)c3cccc1c23
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OC1Cc2ccc(F)c3cccc1c23
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 93.7 %

Procedure:
5-Fluoroacenaphthen-1-one (1.9 g) was dissolved in methanol (40 ml), sodium borohydride (470 mg) was added, and the mixture was stirred at room temperature for 40 min. To the reaction mixture was gradually added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 5-fluoro-1-acenaphthenol (1.8 g). The obtained alcohol form (1.56 g) was dissolved in chloroform (12 ml). Thionyl chloride (2 ml) was added under ice-cooling, and the mixture was heated under reflux for 1 hr. The solvent was evaporated, and the obtained residue was dissolved in N,N-dimethylformamide (20 ml). 4-(2-Keto-1-benzimidazolinyl)piperidine (1.4 g), potassium carbonate (3.4 g) and sodium iodide (1.3 g) were added, and the mixture was stirred at 145° C. for 40 min. After allowing to cool, the reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, and recrystallized from ethyl acetate to give the title compound (690 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1.[NH2:48][C:49]1[CH:50]=[C:51]2[C:56](=[CH:57][C:58]=1[O:59][CH:60]1[CH2:64][CH2:63][O:62][CH2:61]1)[N:55]=[CH:54][C:53]([C:65]#[N:66])=[C:52]2[NH:67][C:68]1[CH:73]=[CH:72][C:71]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][N:77]=2)=[C:70]([Cl:82])[CH:69]=1>N1C=CC=CC=1.C1COCC1>[Cl:82][C:70]1[CH:69]=[C:68]([NH:67][C:52]2[C:51]3[C:56](=[CH:57][C:58]([O:59][CH:60]4[CH2:64][CH2:63][O:62][CH2:61]4)=[C:49]([NH:48][C:15](=[O:17])[CH:14]=[C:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]4)[CH:50]=3)[N:55]=[CH:54][C:53]=2[C:65]#[N:66])[CH:73]=[CH:72][C:71]=1[O:74][CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][N:77]=1
Reactant: N#Cc1cnc2cc(OC3CCOC3)c(N)cc2c1Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=CC(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(=CC(=O)Nc2cc3c(Nc4ccc(OCc5ccccn5)c(Cl)c4)c(C#N)cnc3cc2OC2CCOC2)CC1
Temperature: -5 °C

Procedure:
To a single-neck reaction flask (100 ml) were added 2-(1-(tert-butyloxycarbonyl)piperidin-4-ylidene)acetic acid (1 g) and anhydrous THF (20 ml). The mixture was stirred to dissolve and cooled to the temperature of −5° C. To the mixture were added isobutyl chloroformate (0.6 ml) and N-methylmorphine (0.5 ml). The resultant mixture was stirred for 20 min. 6-amino-4-(3-chloro-4-(pyridin-2-yl-methoxy) phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-3-carbonitrile (2 g, 4.1 mmol) was dissolved in anhydrous pyridine (20 ml). The resulting solution was added into the reaction flask in an ice-water bath. After the reaction finished, the solvent was rotary-evaporated to dryness. To the residue were added chloroform and water. The solution was stood for separation. The chloroform layer was wash once with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and rotary-evaporated to dryness to give a crude product. The product was recrystallized with ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH:13]2[CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:16][C:17]1[CH:18]=[C:19]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[CH3:39])=[O:30])[C:20]2[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[NH:22][C:21]=2[CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH:13]2[CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4]([NH:16][C:17]1[CH:18]=[C:19]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[CH3:39])=[O:30])[C:20]2[N:24]=[C:23]([N:25]([CH3:26])[CH3:27])[NH:22][C:21]=2[CH:28]=1)=[O:6]
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(N)cc2[nH]c(N(C)C)nc12
Reactant: O=C(O)c1cc(C#CC2CC2)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2cc(C#CC3CC3)ccc2Cl)cc2[nH]c(N(C)C)nc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.1 %

Procedure:
To a solution of 2-chloro-5-(cyclopropylethynyl)benzoic acid (33 mg, Reference Example 3), 6-amino-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (50 mg) and HATU (72 mg) in DMF (1 mL), was added N,N-diisopropylethylamine (66 μL), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate, and washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain 6-({[2-chloro-5-(cyclopropylethynyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (74 mg). This was suspended in MeOH (1 mL), 2N hydrogen chloride/EtOH solution (1 Eq) was added to obtain a homogeneous solution, and the solvent was removed under reduced pressure. The residue was triturated in ethyl acetate, and the precipitate was collected by filtration and dried under reduced pressure to obtain the titled compound (58 mg) as pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](N(OC)C)=[O:13])[CH:6]=[CH:5]2.[CH3:18][Mg]Br.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](=[O:13])[CH3:18])[CH:6]=[CH:5]2
Reactant: CON(C)C(=O)c1ccc2cc(Br)ccc2c1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 12.5 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
6-bromo-N-methoxy-N-methyl-2-naphthamide (82.9 g, 282 mmol, 1 equiv.) was dissolved in tetrahydrofurane (600 mL) in a 4-neck flask under nitrogen. The reaction mixture was cooled in an ice bath and methyl magnesium bromide (3.2 M in methyl-tetrahydrofurane, 197 mL, 2.2 equiv.) was added drop wise during 1 hour, while maintaining the temperature of the reaction mixture between 10-15° C. The reaction mixture was stirred 30 minutes further in an ice bath. Aqueous hydrochloric acid (2 M, 100 mL) was then carefully added drop wise while cooling on an ice bath. The organic solvent was evaporated and the precipitated product extracted with dichloromethane (500 mL). The solution was dried over sodium sulphate, filtered and concentrated. The solid residue was dried in vacuum at 40° C. yielding 1-(6-bromonaphthalen-2-yl)-ethanone (70.6 g, 99%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]([C:15]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:16]=1[C:17]([O:19]C(C)(C)C)=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[NH:8]([C:15]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:16]=1[C:17]([OH:19])=[O:18])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2ccccc2)cc1Nc1ccccc1

Procedure:
Trifluoroacetic acid 3.0 mL solution of the obtained tert-butyl 2-anilino-4-phenylbenzoate was stirred at room temperature for 3 hours. The solvent of reaction mixture was removed under reduced pressure, and the obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate:acetic acid=30:10:1] to give 2-anilino-4-phenylbenzoic acid 8 mg of pale yellow solid.