Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[Cl:33][CH2:34][C:35](Cl)=[O:36]>C(Cl)Cl.O>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:25])([F:26])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1)=[O:36]
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3N)C2=O)cnc1OCC(F)(F)F
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(C(C)N2Cc3c(ccnc3NC(=O)CCl)C2=O)cnc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (230 mg, 0.63 mmol, Example-17, single enantiomer) and pyridine (250 mg, 3.1 mmol) in DCM (5 mL) is added 2-chloroacetyl chloride (89 mg, 0.79 mmol) at rt. The mixture is stirred for 1 hour at rt, and the mixture is diluted with water. The mixture is extracted with DCM. The organic layer is washed with brine, dried over sodium sulfate, and filtered. The filtrate is concentrated. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (3:1 to 1:1) to give 270 mg (96% yield) of the title compound as pale brown solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].C(=O)([O-])[O-].[K+].[K+].O.Cl[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:47]>O1CCCC1>[CH3:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][O:48][C:46](/[N:3]=[C:1](\[NH2:2])/[C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:8][CH:9]=1)=[O:47]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.5 %

Procedure:
10.0 g (16 mmol) of crude ethyl 3-{[(2-{[(4-{carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (HPLC purity, method 3: 82.1%) as obtained in Example 2, step (g), was suspended in a mixture of 7.07 g (51 mmol) of potassium carbonate, 42.7 mL of water and 427 mL of tetrahydrofuran. The mixture was stirred at room temperature for 30 minutes. After cooling to 15° C., 2.81 g (17 mmol) of hexyl chloroformate were added while keeping the reaction temperature between 15 to 20° C. The resulting mixture was stirred at room temperature for 2 hours. The mixture was filtered and the solid was discarded. The organic phase was extracted from the mother liquors, and the solvent was removed by vacuum distillation. The residue was dissolved in 200 mL of dichloromethane, and residual aqueous phase was extracted. The organic phase was dried with anhydrous sodium sulfate. The solvent was removed under vacuum to yield 11.0 g of crude dabigatran etexilate as a red slurry. Purity (HPLC, method 1): 87.3%. Content of compound (A2) (HPLC, method 1): 9.8%.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:14]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:13]=[C:12]1[CH3:30])C.[OH-].[Na+]>CCO.CCOC(C)=O>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:14]2[N:13]=[C:12]([CH3:30])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:31])=[O:3])[C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)CCCCCCn1c(C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
(Scheme 1, (C)) To a solution of 7-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-heptanoic acid ethyl ester (1.9 g, 4.4 mmol) in EtOH (10 mL) was added NaOH (10 N, 2 mL, 20 mmol). The resulting mixture was stirred at rt for 1 hour, diluted with EtOAc (100 mL), washed by HCl (0.5 N), and then was dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: MeOH/CH2Cl2). This compound was obtained as a white solid in HCl salt form (1.9 g, 4.3 mmol, 98% yield): 1H NMR (DMSO): δ1.15 (m, 4H), 1.37 (t, 2H), 1.47 (t, 2H), 2.13 (t, 2H), 2.73 (s, 3H), 4.03 (t, 2H), 7.35 (t,2H), 7.45 (m, 4H), 7.57 (m, 2H), 12.1 (b, 1H).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[F:32][C:33]([F:43])([F:42])[O:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1>CN(C=O)C>[F:32][C:33]([F:42])([F:43])[O:34][C:35]1[CH:40]=[CH:39][C:38]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:16](=[O:25])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]2=[O:24])=[CH:37][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCN2C(=O)c3ccccc3C2=O)cc1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc(OC(F)(F)F)cc1
Temperature: 120 °C
Yield: 32.8 %

Procedure:
To a solution of 3-(1,3-dioxoisoindolin-2-yl)propyl 4-methylbenzenesulfonate (3 g, 8.35 mmol) in DMF (25 mL, 3 mL/mmol) was added potassium carbonate (1.8 g, 12.5 mmol) and 4-trifluoromethoxyphenol (1.5 g, 8.35 mmol) and the reaction was heated at 120° C. for 2 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×60 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 2-(3-(4-(trifluoromethoxy)phenoxy) propyl) isoindoline-1,3-dione (1 g, 33%) as a solid. Observed mass (M+1): 366.0.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:3]1.[NH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]1.C(OCC)C>O1CCOCC1>[C:37]([O:36][C:34]([N:31]1[CH2:32][CH2:33][CH:29]([NH:28][C:11]2[N:10]=[CH:9][C:8]3[CH2:7][CH2:6][C:5]4[C:4]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:3][N:2]([CH3:1])[C:14]=4[C:13]=3[N:12]=2)[CH2:30]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(OS(=O)(=O)C(F)(F)F)nc1-2
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(C(=O)OC(C)(C)C)C3)nc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of 1.5 g (3.7 mmol) of ethyl 1-methyl-8-{[(trifluoromethyl)sulfonyl]oxy}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate in 150 mL of anhydrous dioxane, 756 mg (4.1 mmol) of tert-butyl 3-aminopyrrolidine-1-carboxylate were added. The reaction mixture was stirred at room temperature overnight. The solvent was then removed under reduced pressure, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over sodium sulfate and evaporated. 1.2 g (88% yield) of the title compound was collected by filtration after trituration with diethylether.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[O:8]=[C:9]1[CH:18]=[C:17]([CH:19]=[O:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10]1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>C(OCC)(=O)C.O>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]([CH:19]=[O:20])=[CH:18][C:9]2=[O:8])=[CH:24][CH:23]=1
Reactant: O=Cc1cc(=O)[nH]c2ccccc12
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
Sodium hydride (60% in oil) (1.3 g) was added at 0° C. to a DMF solution (50 ml) of 2-oxo-1,2-dihydroquinoline-4-carboxaldehyde (5.13 g), followed by stirring for 30 minutes. 4-chlorobenzylbromide (7.0 g) was added, and the resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture, extraction with ethyl acetate was performed, and the extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:10→1:4). The purified product was recrystallized from a chloroform-diisopropyl ether-n-hexane mixed solvent to thereby obtain 4.13 g (yield: 47%) of 1-(4-chlorobenzyl)-2-oxo-1,2-dihydroquinoline-4-carboxaldehyde as a white powder.
Reaction SMILES: OC1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][C:4]2C=C[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:3]1=2.[H-].[Na+].[CH3:30]I.O.[CH2:33]1[CH2:37][O:36][CH2:35][CH2:34]1>CCOC(C)=O>[CH3:35][O:36][CH:37]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][C:4]2[CH:3]=[CH:22][C:21]([N:23]([CH3:30])[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:34][C:33]1=2
Reactant: C1CCOC1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(O)c1cc(-c3ccccc3)cnc1C=C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC1c2cc(N(C)S(C)(=O)=O)ccc2C=Cc2ncc(-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of N-(5-hydroxy-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide (30 mg, 0.079 mmol) in THF (3 mL) was added NaH (60%, 10 mg, 0.25 mmol) at 0° C. After 10 min, MeI (50 uL, 0.80 mmol) was added, and the resultant mixture was allowed to stir at room temperature for 4 h. The reaction mixture was treated with water, diluted with EtOAc, washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.71 (s, 1H); 8.07 (s, 1H); 7.19-7.60 (m, 10H); 4.71 (br s, 1H); 3.50 (br s, 3H); 3.28 (s, 3H); 2.79 (s, 3H). LRMS (APCI) calc'd for (C23H23N2O3S) [M+H]+, 407.1; found 407.2.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][NH:8][C:9]2[C:10]([CH3:21])=[N:11][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]=2[CH3:14])C(=O)C2=CC=CC=C12.BrCCN1C(=O)C2=CC=CC=C2C1=O.NC1C(C)=NN(C2C=CC=CC=2)C=1C>>[NH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:10]([CH3:21])=[N:11][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]=1[CH3:14]
Reactant: Cc1nn(-c2ccccc2)c(C)c1NCCN1C(=O)c2ccccc2C1=O
Agent: Cc1nn(-c2ccccc2)c(C)c1N
Agent: O=C1c2ccccc2C(=O)N1CCBr
Product: Cc1nn(-c2ccccc2)c(C)c1NCCN

Procedure:
The 4-(2-phthalimidoethylamino)-3,5-dimethyl-1-phenylpyrazole used as starting material is obtained in a manner analogous to that described in Example 1 by reacting N-(2-bromoethyl)-phthalimide with 4-amino-3,5-dimethyl-1-phenylpyrazole. After chromatographic purification on a silica gel column (methylene chloride-ethyl acetate 6:4 v/v), it is obtained in a yield of 56% of theory in the form of a light brownish colored oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([B:24]2[O:28][C:27]([CH3:30])(C)C(C)(C)[O:25]2)=[C:17]([C:20]([F:23])=[CH:21][CH:22]=1)C=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[N+:34]([O-:36])=[O:35].Cl>O>[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]2[B:24]([OH:25])[O:28][CH:27]([CH2:30][N+:34]([O-:36])=[O:35])[C:17]=2[C:20]([F:23])=[CH:21][CH:22]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC1(C)OB(c2c(OCCCOCc3ccccc3)ccc(F)c2C=O)OC1(C)C
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])CC1OB(O)c2c(OCCCOCc3ccccc3)ccc(F)c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26.7 %

Procedure:
NaOH (48 mg, 1.20 mmol) was added to 3-(3-benzyloxy-propoxy)-6-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (500 mg, 1.2 mmol) in H2O (3 mL) at rt, and the reaction mixture was stirred at rt for 5 min. MeNO2 (219 mg, 3.6 mmol) was added dropwise and the mixture was stirred at rt for 16 h. The reaction mixture was acidified with 2 N HCl and extracted with EtOAc. The organic fraction was washed with H2O then brine, dried (MgSO4), and concentrated in vacuo. Purification was accomplished by flash chromatography (10-40% EtOAc/hexane) to give 120 mg of the title compound by 1H NMR spectrum. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.40-7.22 (m, 5H), 7.11 (t, J=8.8 Hz, 1H), 6.81 (t, J=8.6 Hz, 1H), 5.93 (dd, J=9.0, 2.3 Hz, 1H), 4.99 (dd, J=13.1, 2.5 Hz, 1H), 4.62-4.53 (m, 2H), 4.43 (dd, J=12.9, 9.0 Hz, 1H), 4.19-4.01 (m, 2H), 3.66 (dt, J=15.9, 5.7 Hz, 2H), 2.18-1.94 (m, 2H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −72.81 (s, 1F); MS (ESI) m/z=374 (M−1, negative).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[OH:22][N:23]=[C:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.FC(F)(F)C([O-])=O.C(N(CC)CC)C.CS(C)=O>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][CH2:28][C:24](=[N:23][OH:22])[CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: ON=C1CCNC1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: O=C([O-])C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(F)c(N2CCC(=NO)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
298 mg of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3 -carboxylic acid 535 mg of 3-hydroxyiminopyrrolidine-trifluoroacetate and 404 mg of triethylamine were reacted at 80° C. for 15 hours using as a solvent a mixture of 5 ml of dimethyl sulfoxide and 15 ml of acetonitrile. After cooling, the precipitate thereby formed was collected by filtration and recrystallized from a mixture of 10 ml of dimethyl sulfoxide and 15 ml of isopropanol to give 210 mg of the desired product as yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][C:3]=1[F:14].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][C:3]=1[F:14]
Reactant: Fc1cc2c(Cl)nc(Cl)nc2cc1Br
Reactant: C1COCCN1
Solvent: ClCCl
Product: Fc1cc2c(N3CCOCC3)nc(Cl)nc2cc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.9 %

Procedure:
To an ice cold solution of 7-bromo-2,4-dichloro-6-fluoro-quinazoline (0.35 g, 0.001178 mol) in DCM (15 mL), morpholine (0.247 mL, 2.946 mol) was slowly added and the reaction was continued for 20 min. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over sodium sulfate and evaporated to get the crude. The crude was purified using column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to get the title compound (220 mg, 57%). 1H NMR (300 MHz, DMSO-d6): δ 8.16 (d, J=6.6 Hz, 1H), 8.01 (d, J=9.6 Hz, 1H), 3.83-3.86 (m, 4H), 3.76-3.73 (m, 4H); LC-MS (ESI): Calculated mass: 344.9; Observed mass: 347.8 [M+H]+ (RT: 1.70 min).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH:18]=O.[Na].[C:27]([O:37][CH2:38][CH3:39])(=[O:36])[CH2:28][C:29]([C:31](OCC)=[O:32])=[O:30]>CCO>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH:18]1[CH:28]([C:27]([O:37][CH2:38][CH3:39])=[O:36])[C:29](=[O:30])[C:31](=[O:32])[N:11]1[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(OC)c1C=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1C(=O)C(=O)N(Cc2ccc(OC(F)(F)F)cc2)C1c1c(OC)cccc1OC
Temperature: 25 °C

Procedure:
A solution of commercially available (4-(trifluoromethoxy)phenyl)methanamine (11.858 g; 60.17 mmol) and commercially available 2,6-dimethoxybenzaldehyde (10.000 g; 60.17 mmol) in anh. EtOH (160 ml) was treated with diethyl oxalacetate sodium salt (13.312 g; 60.17 mmol). The resulting mixture was then refluxed, under nitrogen, for 8 h. After cooling to rt, the reaction mixture was concentrated to dryness under reduced pressure. DCM was added and the resulting heterogeneous mixture was washed with 1 M aq. HCl (2×), and with brine. The separated organic layer was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM to DCM/MeOH=30/1) afforded ethyl 2-(2,6-dimethoxyphenyl)-4,5-dioxo-1-(4-(trifluoromethoxy)benzyl)pyrrolidine-3-carboxylate as an orange oil. LC-MS (conditions A): tR=0.89 min.; [M+H]+: 481.92 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[CH:29][NH:30][CH:31]=2)=[CH:23][CH:22]=1.C(OCC)(=O)C.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:30]2[CH:31]=[C:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=3)[N:28]=[CH:29]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: COc1ccc(-c2c[nH]cn2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(-n2cnc(-c3ccc(OC)cc3)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 79.9 %

Procedure:
A mixture of 1.200 g (4.49 mmol) of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester and 0.861 g (4.94 mmol) of 4-(4-methoxy-phenyl)-1H-imidazole in 15 ml of tetrahydrofuran are refluxed for 5 hours. After cooling, the reaction mixture is distributed between ethyl acetate and water, the organic phase separated and washed with brine, dried over Na2SO4 and concentrated to dryness. The residue is purified by flash chromatography on silica (20 μm particle size) with ethyl acetate/hexane 2:3, yielding 1.511 g of 5-[4-(4-methoxy-phenyl)-imidazol-1-yl]-2-nitro-4-trifluoromethyl-benzoic acid methyl ester as a yellow powder. 1H-NMR (DMSO-d6, 400 MHz): 3.80 s, 3H; 3.95 s, 3H; 7.00 d, J=10.4 Hz, 2H; 7.78 d, J=10.4 Hz, 2H; 7.95 s, 1H; 8.00 s, 1H; 8.28 s, 1H; 8.72 s, 1H.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[O:2].CC#N.O.F[C:18](F)(F)[C:19]([OH:21])=O.[O:24]1[CH2:28]C[CH2:26][CH2:25]1>>[CH3:28][O:24][C:25]1[CH:26]=[CH:18][C:19]2[O:21][C:1](=[O:2])[NH:8][C:12]=2[CH:11]=1
Reactant: O=C(O)C(F)(F)F
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CC#N
Product: COc1ccc2oc(=O)[nH]c2c1
Temperature: 70 °C
Yield: 82 %

Procedure:
2-amino-4-(methyloxy)phenol, HCl salt (1.0 g, 5.7 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran under argon. The mixture was heated to reflux (70° C.) and then 1,1′-carbonyldiimidazole (1.2 g, 7.4 mmol) was slowly added in small portions over a one hour period. After the addition was complete, the reaction continued to reflux for another 2.5 hours, before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=1.0 min and m/e 166 [M+1]+. The mixture was allowed to cool to room temperature before all volatiles were removed by rotary evaporation. The crude residue was dissolved in 100 mL of ethyl ether and washed with water (3×30 mL) and brine (3×30 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give 5-(methyloxy)-1,3-benzoxazol-2(3H)-one (0.78 g, 4.7 mmol, 82%) as an orange amorphous solid. MS (ES) m/e 166 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2].[C:19](/[CH:24]=[C:25]1\[CH2:26][C:27]([CH3:33])([CH3:32])[CH2:28][C:29](O\1)=[O:30])([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1>[C:19]([CH:24]=[C:25]1[N:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:1]([O:3][CH3:4])=[O:2])=[CH:18][CH:17]=2)[C:29](=[O:30])[CH2:28][C:27]([CH3:32])([CH3:33])[CH2:26]1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: COC(=O)c1ccccc1-c1ccc(CN)cc1
Reactant: CCOC(=O)/C=C1\CC(C)(C)CC(=O)O1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CC(C)(C)CC(=O)N1Cc1ccc(-c2ccccc2C(=O)OC)cc1

Procedure:
Compound (i) of Example 9 (1.2 g, 0.005 mole) and compound (b) of Example 2 (1.1 g, 0.005 mole) are combined in toluene (50 mL) and refluxed for 5 hours. The toluene is removed in vacuo and the residue is chromatographed on silica gel using hexane/ethyl acetate as the mobile phase. The title compound is isolated as a colorless oil (1.2 g, 52%). Mass Spec. (DCI) m/z 436 (M+H). Analysis-calc'd for C26H29NO5 : C, 70.96; H, 6.76; N, 3.18; found: C, 70.76; H, 7.11; N, 2.77.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:27][C:24]1[N:25]=[CH:26][C:21]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=2)=[CH:22][N:23]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CNC(=O)c1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNC(=O)c1ccc(-c2cnc(N)nc2)cc1F
Temperature: 110 °C
Yield: 91.4 %

Procedure:
A mixture of 4-bromo-2-fluoro-N-methylbenzamide (900 mg, 3.9 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (710 mg, 3.2 mmol), tetrakis(triphenylphosphine)palladium (100 mg, 0.1 mmol) and potassium carbonate (1.3 g, 9.7 mmol) in toluene (6.0 mL) and ethanol (3.0 mL) and water (3.0 mL) was heated at 110° C. for 2 hours. After cooling to RT, the reaction mixture was quenched with water and extracted with diethyl ether. The solid was filtered and washed with water and diethyl ether to afford the desired product (720 mg).
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:12]=2[C:13]=1[CH2:14][C:15]([OH:17])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[CH2:34]([NH:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH3:37].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[C:1]([C:9]1[O:10][C:11]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:12]=2[C:13]=1[CH2:14][C:15]([N:38]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:34][CH2:35][CH2:36][CH3:37])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCNCCCC
Reactant: COc1ccc2oc(C(=O)c3ccccc3)c(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCN(CCCC)C(=O)Cc1c(C(=O)c2ccccc2)oc2ccc(OC)cc12
Temperature: 25 °C

Procedure:
To a mixture of 10.6 mg (2-benzoyl-5-methoxy-1-benzofuran-3-yl)acetic acid from the Step B above, 7.8 mg HOBt and 13.1 mg EDC were added 6.6 mg dibutylamine and 0.5 mL DMF followed by 21 μL DIEA. After stirring at room temperature over night, it was heated in a 55° C. oil bath for 8 hours. It was purified directly on RP-HPLC using 60-95% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. 1H NMR (CDCl3, 500 MHz) 8.10˜8.13 (m, 2H), 7.62˜7.66 (m, 1H), 7.53˜7.57 (m, 2H), 7.45 (d, J=8.9 Hz, 1H), 7.275 (d, J=2.7 Hz, 1H), 7.14 (dd, J=2.7 & 9.1 Hz, 1H), 4.39 (s, 2H), 3.89 (s, 3H), 3.43˜3.47 (m, 2H), 3.37˜3.40 (m, 2H), 1.51˜1.61 (m, 4H), 1.26˜1.38 (m, 4H), 0.94 (t, J=7.3 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H). LC-MS: 4.24 min. (m/Z=422.3, 444.3).