Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C@@H:10]([C@H:20]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[C:29]([CH2:36][CH3:37])=[N:30][N:31]([CH2:34][CH3:35])[C:32]=3[CH3:33])[CH2:24][CH2:23]2)[CH3:21])[CH2:9]1)=O)(C)(C)C.N1CCCCC1>>[CH2:34]([N:31]1[C:32]([CH3:33])=[C:28]([CH:25]2[CH2:24][CH2:23][N:22]([C@@H:20]([C@@H:10]3[C@@H:11]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=4)[CH2:12][NH:8][CH2:9]3)[CH3:21])[CH2:27][CH2:26]2)[C:29]([CH2:36][CH3:37])=[N:30]1)[CH3:35]
Reactant: CCc1nn(CC)c(C)c1C1CCN([C@H](C)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2c2cccc(F)c2)CC1
Solvent: C1CCNCC1
Product: CCc1nn(CC)c(C)c1C1CCN([C@H](C)[C@H]2CNC[C@@H]2c2cccc(F)c2)CC1

Procedure:
The title compound was prepared from 1-tert-butoxycarbonyl-3-(R)-(1-(R)-(4-(1,3-diethyl-5-methylpyrazol-4-yl)piperidin-1-yl)ethyl)-4-(S)-(3-fluorophenyl)pyrrolidine (from Step E) using a procedure analogous to that described for Piperidine 8, Step F. 1H NMR (500 MHz) δ 0.94 (d, J=6.4, 3H), 1.08 (m, 1H), 1.19 (t, J=7.5, 3H), 1.35 (t, J=7.2, 3H), 1.56 (m, 1H), 1.79 (m, 1H), 1.92 (m, 1H), 2.10–2.25 (m, 5H), 2.33 (m, 1H), 2.45–2.88 (m, 8H), 3.19–3.39 (m, 3H), 4.01 (q, J=7.2, 2H), 6.83 (m, 1H), 7.04 (m, 1H), 7.10 (m, 1H), 7.22 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:19][C:20]([C:23]2[CH:28]=[C:27]3[CH2:29][O:30][C:31]4[CH:58]=[C:57]5[C:34]([CH:35]=[CH:36][C:37]6[NH:41][C:40]([C@@H:42]7[CH2:46][C@H:45]([CH2:47][O:48][CH3:49])[CH2:44][N:43]7C(OC(C)(C)C)=O)=[N:39][C:38]=65)=[CH:33][C:32]=4[C:26]3=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].Cl.[CH3:60][O:61][C:62]([NH:64][CH:65]([CH:69]([CH3:71])[CH3:70])[C:66](O)=[O:67])=[O:63].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C.C(O)C>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@@H:6]([CH:7]([CH3:9])[CH3:8])[C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:19][C:20]([C:23]2[CH:28]=[C:27]3[CH2:29][O:30][C:31]4[CH:58]=[C:57]5[C:34]([CH:35]=[CH:36][C:37]6[N:41]=[C:40]([C@@H:42]7[CH2:46][C@H:45]([CH2:47][O:48][CH3:49])[CH2:44][N:43]7[C:66](=[O:67])[C@@H:65]([NH:64][C:62]([O:61][CH3:60])=[O:63])[CH:69]([CH3:71])[CH3:70])[NH:39][C:38]=65)=[CH:33][C:32]=4[C:26]3=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:11]
Reactant: COC[C@H]1C[C@@H](c2nc3c(ccc4cc5c(cc43)OCc3cc(-c4cnc([C@@H]6CC[C@H](C)N6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]4)ccc3-5)[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)NC(C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc([C@@H]4CC[C@H](C)N4C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]3)ccc2-5)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
A solution of tert-butyl(2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-3,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxy methyl)pyrrolidine-1-carboxylate (108 mg, 0.14 mmol), ethanol (2 mL) and concentrated HCl (0.7 mL) was heated to 60° C. for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (10 mL). This solution was concentrated and to this material was added a solution of 2-methoxycarbonylamino-3-methylbutyric acid (31 mg, 0.18 mmol) and HATU (60 mg, 0.16 mmol) in DMF (2 mL). To the resulting solution was added diisopropylethylamine (70 μL, 0.41 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with 5% NaHCO3 solution, water and brine, dried (Na2SO4). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with 5% NaHCO3 solution, water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 43% ACN/H2O+0.1% TFA). The product fractions were lyophilized to give methyl{(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methoxy methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (52 mg, 45%). MS (ESI) m/z 850 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=1.[NH:19]1[CH2:23][CH:22]=[CH:21][CH2:20]1>C(Cl)Cl>[N:19]1([C:2]2[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=2)[CH2:23][CH:22]=[CH:21][CH2:20]1
Reactant: COC(=O)Nc1cc(Cl)nc(NC(=O)OC)[n+]1[O-]
Reactant: C1=CCNC1
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CC=CC2)nc(NC(=O)OC)[n+]1[O-]

Procedure:
A suspension of 12.5 g. of dimethyl 6-chloro-2,4-pyrimidine-dicarbamate-3-oxide in 100 ml. of methylene chloride is treated with 15 g. of 3-pyrroline and the mixture is stirred at room temperature under an argon atmosphere for 26 hours. The white precipitate formed is filtered off and recrystallized from a mixture of methylene chloride and methanol, there being obtained pure dimethyl 6-(3-pyrrolin-1-yl)-2,4-pyrimidine-dicarbamate-3-oxide, having a melting point of 206° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[O:9])[N:3]=1.[C-:10]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11]1.[CH-:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.[Fe+2:23].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>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].CO.O.C1(C)C=CC=CC=1>[C-:10]1([C:2]2[N:3]=[C:4]([CH:8]=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11]1.[CH-:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.[Fe+2:23]
Reactant: OB(O)[c-]1cccc1
Reactant: O=Cc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1cccc(-[c-]2cccc2)n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
See Scheme 1. Toluene (500 mL) was added to a mixture of 2-bromo-6-pyridinecarboxaldehyde (16.25 g, 87.36 mmol, purchased from Sigma-Aldrich), ferrocenylboronic acid (24.10 g, 104.9 mmol, purchased from Sigma-Aldrich), and (dppf)PdCl2.CH2Cl2 (2.14 g, 2.62 mmol, purchased from Strem), under a nitrogen atmosphere. Then a nitrogen-sparged solution of Na2CO3 (210 mL, 210 mmol) in 4:1 water:methanol was added. The biphasic mixture was heated to 60° C. After 1 hour, the solution was heated to 80° C. for one week. The mixture was then filtered and the organics were separated and dried over MgSO4. Evaporation yielded the crude 6-ferrocenyl-2-pyridinecarboxaldehyde which was purified on SiO2 using 3:1 to 4:1 CH2Cl2:hexane as the elutant. Yield: 6.02 g, 23.7%. 1H NMR (C6D6): δ 10.18 (1H, s), 7.58 (1H, d), 8.03-6.85 (2H, m), 4.91 (2H, m), 4.20 (2H, m), 3.86 (5H, s).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:9]1(OB(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+].CN([CH:24]=[O:25])C>>[C:9]1([C:9]2[CH:14]=[C:13]3[C:12]([CH:14]=[CH:9][C:10]([O:25][CH3:24])=[CH:11]3)=[CH:11][CH:10]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)Oc1ccccc1
Reactant: CN(C)C=O
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Product: COc1ccc2ccc(-c3ccccc3)cc2c1
Temperature: 80 °C
Yield: 73 %

Procedure:
n-Hydrate of potassium phosphate (34 g, 0.16 mol) and phenylboric acid (3.7 g, 30 mmol) were added to a DMF (350 ml) solution of 7-methoxy-2-naphthyltrifluoromethane sulfonate (6.1 g, 20 mmol). The solution was bubbled with nitrogen for 30 minutes to perform replacement with nitrogen. PdCl2(PPh)2 (0.71 g, 1 mmol) was added, and the solution was heated for 4 hours at 80° C. A saturated ammonium chloride aqueous solution (500 ml) was added to the obtained mixture. Crystals deposited by this operation was filtered out, washed with water (100 ml×3), and dried with an electric dryer (60° C.). The crude product was refined by column chromatography (silica gel, developed with dichloromethane) to obtain 7-phenyl-2-methoxynaphthalene (compound (3)-22), 3.4 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N+:11]([O-])=O>CO.[Pd]>[NH2:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[CH3:1]
Reactant: Cc1nc(C(=O)O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1nc(C(=O)O)ccc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-methyl-5-nitropicolinic acid (31C, 500 mg, 2.75 mmol) in methanol (10 ml) was added Pd/C (50 mg). The solution was stirred at r.t. under H2 atmosphere for 1 h, when LC-MS showed that s.m. was consumed. Then the mixture was filtered and concentrated to give the crude product which was used to the next step without further purification. LC-MS: m/z 153 (M+H)+
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:23])[CH:4]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15]([O:17]C(C)(C)C)=[O:16])=[C:7]1[CH3:22])[CH3:5].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][CH:3]([CH3:23])[CH:4]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15]([OH:17])=[O:16])=[C:7]1[CH3:22])[CH3:5]
Reactant: COC(C)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(C)C(C)n1c(C)c(C(=O)O)c2cccnc21
Temperature: 27 °C
Reaction time: 1.5 h

Procedure:
To the pre-cooled solution of tert-butyl 1-(3-methoxybutan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (3.0 g, 9.42 mmol) in CH2Cl2 (20 mL) was added trifluoroacetic acid (20 mL) dropwise. The solution was stirred at 27° C. for 1.5 hours. The solvent was removed under vacuum at 27° C. The residue was used for next step without purified. LCMS (M+H+) m/z: calcd 263.30. found 262.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O.[CH2:22]([O:24][C:25](=[O:32])[C@H:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH2:27])[CH3:23].Cl.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([NH:27][C@@H:26]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:25]([O:24][CH2:22][CH3:23])=[O:32])=[O:12]
Reactant: COc1ccc(CC(Sc2ccccc2Br)C(=O)O)cc1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)C(Cc1ccc(OC)cc1)Sc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-bromophenyl)thio-3-(4-methoxyphenyl)propanoic acid (1.102 g) and L-leucine ethyl ester.HCl (704 mg) in DMF (10 mL), HOBt (551 mg) and EDC.HCl (690 mg) were added. The reaction mixture was stirred at r.t. overnight. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with 1N HCl, 5% Na2CO3 aq. and brine. The organic layer was dried over Na2SO4 and concentrated to give the pure product as a pale yellow oil (1.561 g, quant.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:16][C:15]3[CH:14]=[CH:13][N:12]([C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][N:21]=[CH:20]5)[C:11](=[O:26])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CN1C(=O)CCC1.O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:16][C:15]3[CH:14]=[CH:13][N:12]([C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[N:22]([CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[N:21]=[CH:20]5)[C:11](=[O:26])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCN1CCCC1
Reactant: O=c1c2cc(-c3cccc(Cl)c3)oc2ccn1-c1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=c1c2cc(-c3cccc(Cl)c3)oc2ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.9 %

Procedure:
To a solution of 2-(3-chlorophenyl)-5-(1H-indazol-5-yl)furo[3,2-c]pyridin-4(5H)-one (0.365 g, 0.732 mmol) in DMSO (1.5 mL) and NMP (0.94 mL) was added (2-chloroethyl)pyrrolidine hydrochloride (0.273 g, 1.61 mmol) and Cs2CO3 (1.43 g, 4.39 mmol). The reaction mixture was stirred at ambient temperature for 18 h; then the reaction mixture was diluted with H2O (10 mL) and EtOAc (20 mL). The desired solids were collected by filtration. Purification by flash chromatography (silica gel, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) yielded the title compound (83.8 mg, 25%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.79 (t, J=2.0 Hz, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.42 (dd, J=8.5, 2.0 Hz, 1H), 7.39-7.35 (m, 2H), 7.33-7.31 (m, 1H), 7.29 (s, 1H), 6.68 (d, J=7.5 Hz, 1H), 4.58 (t, J=7.5 Hz, 2H), 3.03 (t, J=7.0 Hz, 2H), 2.60 (m, 4H), 1.80 (m, 4H); ESI MS m/z 459 [M+H]+; HPLC (Method A) >99% (AUC), tR=16.7 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-])=O)=[CH:4][C:5]2[NH:9][CH:8]=[N:7][C:6]=2[CH:10]=1>C1COCC1.[Pd]>[NH2:11][C:3]1[C:2]([CH3:1])=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1
Reactant: Cc1cc2nc[nH]c2cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc2nc[nH]c2cc1N
Yield: 92.3 %

Procedure:
To a solution of 6-Methyl-5-nitrobenzimidazole (300 mg) in THF (35 mL) was added 10% Pd/C (100 mg). The flask was evacuated and charged with H2 several times. The mixture was stirred under a balloon of H2. After 24 h the flask was purged with N2. The catalyst was filtered off and washed with THF. The solvent was removed under reduced pressure giving 230 mg of the title compound.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][CH:4]=1.Br[C:14]1[CH:15]=[CH:16][C:17]2[N:23]([CH3:24])[CH2:22][CH2:21][C:20]([C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][N:35]([CH3:42])[CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:30][CH:29]=3)=[O:26])=[CH:19][C:18]=2[CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([CH3:24])[CH2:22][CH2:21][C:20]([C:25]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([CH2:34][N:35]([CH3:42])[CH:36]5[CH2:37][CH2:38][O:39][CH2:40][CH2:41]5)=[CH:32][CH:33]=4)=[O:26])=[CH:19][C:18]=3[CH:43]=2)=[CH:4][CH:5]=1)[CH3:10]
Reactant: CN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Reactant: CCc1ccc(OB([O-])[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C)cc1
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
In water:ethanol:toluene (1:1:10, 18.0 ml) were dissolved 4-ethylphenyl borate (227 mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]-methyl]phenyl]-2,3-dihydro-1-benzoazepine-4-carboxamide (611 mg), and to the mixture was added potassium carbonate (418 mg). The mixture was stirred under argon atmosphere for 30 minutes, and to the mixture was added tetrakistriphenylphosphine palladium (59 mg). Under argon atmosphere, the mixture was refluxed for 17 hours, and the mixture was diluted with ethyl acetate (200 ml) and washed with water (50 ml) and saturated brine (50 ml). The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (75 g, ethyl acetate:ethanol=9:1) and recrystallized from ethanol to give 7-(4-ethylphenyl)-1-methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepine-4-carboxamide (Compound 307) (252 mg, 39%).
Reaction SMILES: Br[C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:24][C:25]([CH2:31][CH3:32])([CH2:29][CH3:30])[C:26]([OH:28])=[O:27])=[C:4](F)[CH:3]=1.[F:36][C:37]([F:48])([F:47])[C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.FC(F)(F)C1C=CC(B(O)O)=CC=1>>[CH2:29]([C:25]([CH2:24][C:8]1[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:41]3[CH:42]=[CH:43][C:38]([C:37]([F:48])([F:47])[F:36])=[CH:39][CH:40]=3)=[CH:34][CH:33]=2)[C:11]2[CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)[CH:14]=[CH:15][C:10]=2[N:9]=1)([CH2:31][CH3:32])[C:26]([OH:28])=[O:27])[CH3:30]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(Br)cc1F)C(=O)O
Product: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared using analogous conditions described in Example 144 using (4-(trifluoromethyl)phenyl)boronic acid 2-((1-(4-bromo-2-fluorobenzyl)-6-((1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)methyl)-2-ethylbutanoic acid and (4-(trifluoromethyl)phenyl)boronic acid. MS (ESI): mass calcd. for C33H32F4N4O3, 608.24; m/z found, 609.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.81 (d, J=8.3, 2H), 7.73 (d, J=8.4, 2H), 7.57-7.54 (m, 1H), 7.54-7.52 (m, 1H), 7.49 (d, J=2.3, 1H), 7.41 (dd, J=8.0, 1.8, 1H), 7.03 (d, J=2.3, 1H), 6.93 (dd, J=8.8, 2.3, 1H), 6.88 (t, J=7.9, 1H), 6.28 (d, J=2.3, 1H), 5.61 (s, 2H), 5.01 (s, 2H), 3.81 (s, 3H), 3.12 (s, 2H), 1.90-1.73 (m, 4H), 0.88 (t, J=7.5, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([N:18]4[CH2:23][CH2:22][CH:21]([C:24]5[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=5)[CH2:20][CH2:19]4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[N:3]=1.[CH3:40][NH2:41]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([N:18]4[CH2:23][CH2:22][CH:21]([C:24]5[CH:25]=[CH:26][C:27]([C:28]([NH:41][CH3:40])=[O:30])=[CH:31][CH:32]=5)[CH2:20][CH2:19]4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[N:3]=1
Reactant: CN
Reactant: CN1CCN(c2cc(N3CCc4ccc(N5CCC(c6ccc(C(=O)O)cc6)CC5)cc4C3)nc(N)n2)CC1
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C2CCN(c3ccc4c(c3)CN(c3cc(N5CCN(C)CC5)nc(N)n3)CC4)CC2)cc1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 4-(1-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}piperidin-4-yl)benzoic acid and methylamine in THF (2.0 M). LCMS (M+H)+: m/z=541.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH2:22][CH:21]([OH:23])[C:20]4[S:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:19]=4[CH:18]3[C:31]([OH:33])=O)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.ClC(OCC)=O.C(N1CCOCC1)C.C[Si](C)(C)[O:50][NH2:51]>C1COCC1>[OH:50][NH:51][C:31]([CH:18]1[C:19]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][C:20]=2[CH:21]([OH:23])[CH2:22][N:17]1[S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15])=[O:33]
Reactant: O=C(O)C1c2c(sc3ccccc23)C(O)CN1S(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: C[Si](C)(C)ON
Agent: CCN1CCOCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: O=C(NO)C1c2c(sc3ccccc23)C(O)CN1S(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 1 h

Procedure:
The carboxylic acid from step 3 (239 mg, 0.49 mmol) was dissolved in 4 ml of THF. After that, ethyl chloroformate (64 mg, 0.59 mmol) and N-ethylmorpholine (79.7 mg, 0.69 mmol) were added at 0° C. and preactivation was carried out at this temperature for one hour. O-Trimethylsilylhydroxylamine (208 mg, 1.98 mmol) was then added and the mixture was stirred overnight at from 0° C. to RT. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate; this solution was extracted by shaking with dilute HCl, water and sodium carbonate solution. The residue was dissolved, for direct preparative RP-HPLC, in a small quantity of a mixture of acetonitrile, water and 0.01% trifluoroacetic acid. Resulting fractions were pooled, acetonitrile was removed under reduced pressure and the remaining aqueous phase was freeze-dried. Yield: 4.5 mg; unreacted carboxylic acid and other, not specifically characterized, byproducts are obtained in addition. Analytical data are given in Table 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[Cl:24].[CH3:25][O:26][C:27]([CH:29]1[CH2:33][C:32](=[O:34])[NH:31][CH2:30]1)=[O:28]>>[CH3:25][O:26][C:27]([CH:29]1[CH2:33][C:32](=[O:34])[N:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=4[CH3:23])[CH2:12][CH2:11]3)=[O:9])=[CH:4][C:3]=2[Cl:24])[CH2:30]1)=[O:28]
Reactant: COC(=O)C1CNC(=O)C1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)c(Cl)c3)CC2)c(C)c1
Product: COC(=O)C1CC(=O)N(c2ccc(C(=O)N3CCN(c4ccc(C)cc4C)CC3)cc2Cl)C1
Yield: 85.3 %

Procedure:
Using (4-bromo-3-chlorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (2.90 g) described in Preparation Example 171 and 5-oxopyrrolidine-3-carboxylic acid methyl ester (1.00 g) and by the reaction and treatment in the same manner as in Example 1, 1-{2-chloro-4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid methyl ester (2.80 g) was obtained. The so obtained 1-{2-chloro-4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid methyl ester (1.40 g) was dissolved in methanol (6 mL), 1N aqueous sodium hydroxide solution (6 mL) was added, and the mixture was stirred with heating under reflux for 3 hr. The reaction mixture was cooled, neutralized with 1N hydrochloric acid (6 mL), 1-methylpiperazine (0.33 mL) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (1.00 g) were added, and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture, water was added, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give 1-{2-chloro-4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-4-(4-methylpiperazine-1-carbonyl)pyrrolidin-2-one. The obtained 1-{2-chloro-4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-4-(4-methylpiperazine-1-carbonyl)pyrrolidin-2-one was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate (0.75 mL) was added, and the precipitate was collected by filtration to give the title compound (0.74 g).
Reaction SMILES: [CH:1]([P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])=[CH2:2].[NH3:11]>O>[NH:11]([CH2:2][CH2:1][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[CH2:2][CH2:1][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6]
Reactant: N
Reactant: C=CP(=O)(OCC)OCC
Solvent: O
Product: CCOP(=O)(CCNCCP(=O)(OCC)OCC)OCC
Yield: 73 %

Procedure:
A solution of diethyl vinylphosphonate (10.52 g; 0.062 moles) in concentrated ammonia (14.4 g) is stirred for 2 days at room temperature. The reaction mixture is diluted with water (100 ml), extracted with dichloromethane (4×30 ml) and dried over MgSO4. Stripping of the solvent in vacuo until constant weight affords a colorless liquid (8.36 g; yield 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1.O>C(Cl)(Cl)Cl.C(O)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:9]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[N:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: Fc1ccc(I)cn1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Fc1ccc(C2CC2)cn1
Temperature: 100 °C
Yield: 62.7 %

Procedure:
In a flask, combine 2-fluoro-5-iodo-pyridine (1.12 g, 5 mmol), cyclopropylboronic acid (645 mg, 7.5 mmol), palladium acetate (56 mg, 0.25 mmol), potassium phosphate (3.2 g, 15 mmol), and toluene-water (20:1, 21 mL). Heat the mixture at 100° C. for 4 hours. Dilute the mixture with chloroform-isopropanol (3:1, 100 mL). Wash the organic phase with saturated aqueous sodium chloride and water. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo to a brown oil. Purify by column chromatography (20% ethyl acetate in hexane) to afford the title compound (430 mg, 63%) as a pale yellow oil. 1H NMR (400 MHz-CDCl3) δ 7.99 (d, J=3 Hz, 1H), 7.39 (td, J=3, 5 Hz, 1H), 6.79 (dd, J=3, 8 Hz, 1H), 0.96-1.02 (m, 2H), 0.63-0.69 (m, 2H).