Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][C@@H:11]([C@@H:13]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:14][C:15]([CH3:27])([CH3:26])[CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:10][C:9]1=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(N)CCC>[CH2:13]([NH:28][C:9](=[O:36])[C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:12][C@H:11]([OH:10])[C@@H:13]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:14][C:15]([CH3:26])([CH3:27])[CH2:16][CH2:17][O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:11][CH2:12][CH3:8]
Reactant: CC(C)(CCOCc1ccccc1)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1C[C@@H](Cc2ccccc2)C(=O)O1
Solvent: CCCCN
Product: CCCCNC(=O)[C@H](Cc1ccccc1)C[C@H](O)[C@H](CC(C)(C)CCOCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
A solution of 502 mg of 3(R)-benzyl-5(S)-[5-benzyloxy-1 (S)-tert-butoxycarbonylamino-3,3-dimethyl-pentyl]-2-oxo-tetrahydrofuran in 8.5 ml of butylamine is stirred at room temperature for 20 h and concentrated and the residue is purified by chromatography over silica gel (mobile phase A): Rf (A)=0.47; FAB-MS: (M+H)+ =569.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27]C)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([O:22]C)[CH:15]=2)[CH2:9][CH2:8]1.Br.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O>[OH:22][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[OH:20])[CH2:13][N:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:26]([OH:27])=[C:3]([OH:2])[CH:4]=2)[CH2:12][CH2:11]1
Reactant: COc1ccc(CN2CCN(Cc3ccc(OC)c(OC)c3)CC2)cc1OC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1ccc(CN2CCN(Cc3ccc(O)c(O)c3)CC2)cc1O
Temperature: 145 °C

Procedure:
1,4-Bis(3,4-dimethoxybenzyl)piperazine (5 g, 12.95 mmol) was combined with hydrobromic acid (50 ml of 48% w/w solution in water) and the solution heated slowly over 1 hour to 145° C. Reaction was maintained at 145° C. for 12 h at which time TLC revealed disappearance of starting material. The cooled solution was diluted with water (200 ml), carefully neutralized with saturated aqueous sodium hydrogen carbonate, and ethyl acetate (100 ml) added. The crude aqueous solvent mixture was filtered through Celite and the ethyl acetate layer separated. The aqueous layer was extracted with ethyl acetate (2×50 ml), and the combined extracts washed with water (50 ml), and dried (Na2SO4). The solvent was removed under reduced pressure and the residue recrystallized from toluene and methyl ethyl ketone to afford the product, DC-0009, 100 mg (98%, pure by HPLC analysis).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[OH:20][C:21]1[CH:34]=[CH:33][C:24]2[C:25]([C:29]([O:31][CH3:32])=[O:30])=[C:26]([CH3:28])[O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:19][O:18][CH:15]1[CH2:16][CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:20][C:21]3[CH:34]=[CH:33][C:24]4[C:25]([C:29]([O:31][CH3:32])=[O:30])=[C:26]([CH3:28])[O:27][C:23]=4[CH:22]=3)[CH:8]=2)=[O:12])[CH2:14]1
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: COC(=O)c1c(C)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1c(C)oc2cc(Oc3ccnc4cc(C(=O)N5CCC(OC)C5)sc34)ccc12
Yield: 58.5 %

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4b (707 mg, 2.38 mmole) with methyl 6-hydroxy-2-methyl-benzofuran-3-carboxylate 89c (565 mg, 2.74 mmole) and Cs2CO3 (3.10 g, 9.53 mmole) in a manner as previously described for example to give 650 mg (58%) of an off-white solid. 1H NMR (DMSO-d6) δ8.57 (1H, d, J=5.3 Hz), 8.07 (1H, s), 7.96 (1H, d, J=8.6 Hz), 7.75 (1H, d, J=2.0 Hz), 7.31 (1H, dd, J=8.6, 2.0 Hz), 6.74 (1H, d, J=5.6 Hz), 4.10-3.85 (3H, m), 3.90 (3H, s), 3.65-3.45 (2H, m), 3.25 (3H, d, J=12.6 Hz), 2.77 (3H, s), 2.15-1.95 (2H, m).
Reaction SMILES: [CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([NH2:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[CH3:21][S:22](Cl)(=[O:24])=[O:23].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([NH:19][S:22]([CH3:21])(=[O:24])=[O:23])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nc(-c2ccc(Cl)c(N)c2)c2ccccc2c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1nc(-c2ccc(Cl)c(NS(C)(=O)=O)c2)c2ccccc2c1=O
Reaction time: 8 h
Yield: 78 %

Procedure:
To a mixture of 2-methyl-4-(3-amino-4-chlorophenyl)-1-(2H)-phthalazinone (38.72 g, 0.136 mol), CH2Cl2 (380 mL) and pyridine (75 mL) at 0° C. was added methanesulfonyl chloride (15.75 mL) in CH2Cl2 (75 mL). The reaction mixture was stirred overnight, poured into 1N HCl (400 mL) and stirred for 45 minutes. The mixture was filtered and the filtrate layers were separated. The solid thus obtained was treated with saturated NaHCO3, filtered, stirred with hexane, then filtered, stirred with hot methanol, then filtered and finally stirred with hot ethyl acetate and filtered to afford 38.8 g (78%) of 2-methyl-4-(3-methylsulfonylamino-4-chlorophenyl)-1-(2H)-phthalazinone, m.p. 234°-236° C.
Reaction SMILES: [O:1]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(NC2CCCCC2)CCCCC1>>[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][C:8]([CH3:14])([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(C)Oc1ccccc1
Agent: C1CCC(NC2CCCCC2)CC1
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccccc1
Yield: 40.2 %

Procedure:
In a similar manner to that described in Reference example 7(c), a reaction was carried out using ethyl 2-phenoxypropionate (6.15 g), 4-benzyloxybenzyl chloride (9.62 g) and dicyclohexylamine (5.78 g) instead of diisopropylamine and the reaction mixture was treated to afford the desired compound (4.97 g) as a syrup.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH:7]([N:15]([C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[Cl:38])[CH2:16][C:17]1[S:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:38][C:32]1[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:31]=1[C:30]([N:15]([CH2:16][C:17]1[S:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:23]=[C:24]([F:29])[CH:25]=[C:26]([F:28])[CH:27]=1)[CH:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:6]([OH:40])=[O:5])=[O:39]
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1)N(Cc1sccc1-c1cc(F)cc(F)c1)C(=O)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(Cc1ccccc1)N(Cc1sccc1-c1cc(F)cc(F)c1)C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a stirred solution of 2-{(2,4-Dichloro-benzoyl)-[3-(3,5-difluoro-phenyl)-thiophen-2-ylmethyl]-amino}-3-phenyl-propionic acid tert-butyl ester (37.63 mg, 0.0625 mmol.) in dichloromethane (1 ml.), was added trifluoroacetic acid (1 ml.). The reaction mixture was stirred at room temperature during 1 hr. TLC monitored the progress of the reaction. When the reaction was completed, the mixture was concentrated under reduced pressure on a rotary evaporator, followed by silica chromatography using 90% ethylacetate, 10% methanol and 1 drop of acetic acid, afforded 2-{(2,4-Dichloro-benzoyl)-[3-(3,5-difluoro-phenyl)-thiophen-2-ylmethyl]-amino}-3-phenyl-propionic acid in 85% yield. 1H NMR (Varian 400 MHz, CDCl3) δ(ppm), 7.22 (m, 8H, ArH), 7.00 (m, 2H, ArH), 6.82 (m, 2H, ArH), 6.50 (m, 1H, ArH), 4.95 (m, 0.5H, NCH2), 4.65 (m, 0.5H, NCH2), 4.10 (m, 1H, NCH2), 3.60 (m, 1H, CHCH2), 3.20 (m, 1H, CHCH2), 3.05 (m, 1H, CHCH2). MS, 546.00 found.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18].[H-].[Na+].[CH3:28]I>CN(C)C=O.CCOCC>[CH3:28][O:18][CH:17]([C:5]1[N:4]([CH2:3][CH:2]([CH3:25])[CH3:1])[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CI
Reactant: CC(C)Cn1c(C(O)c2ccccc2)nc2cnc3ccccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(c1ccccc1)c1nc2cnc3ccccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
1-(2-Methylpropyl)-α-phenyl-1H-imidazo[4,5-c]quinoline-2-methanol (5.0 g; 15 mmol, Example 45) was dissolved in N,N-dimethylformamide (25 mL) then added to a cooled (0-5° C.) suspension of sodium hydride (0.5 g; 16.6 mmol) in N,N-dimethylformamide (100 mL). The reaction mixture was stirred at room temperature for about one hour then combined with methyl iodide (1.4 mL; 22.6 mmol). Stirring was continued until the reaction was complete as indicated by thin layer chromatography. The reaction mixture was diluted with ether then quenched with water. The ether layer was separated, washed twice with water, dried over magnesium sulfate then evaporated under vacuum. The residue was triturated with methylene chloride/hexane to provide 4.5 g of a solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[I:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.C(O)(=O)C.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[I:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(I)c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(OCc2ccccc2)c(I)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
Iron powder (12.5 g, 224 mmol) was added to a suspension of 2-benzyloxy-5-nitroiodobenzene (Description 13; 10 g, 28 mmol) in water (300 ml) and acetic acid (75 ml) and the mixture was stirred at 80° C. for 12 hours. The mixture was allowed to cool to room temperature and filtered through Hyflo™, washing with 4:1 water:acetic acid and ethyl acetate. The filtrate was extracted with ethyl acetate, and the organic extract was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure to give the title compound as a brown oil (9 g, 99% yield). 1H NMR (360 MHz, CDCl3) δ 7.49−7.47 (2H, m), 7.40−7.28 (3H, m), 7.19 (1H, d, J 2.4 Hz), 6.70 (1H, d, J 8.6 Hz), 6.62 (1H, dd, J 2.4, 8.6 Hz), and 5.04 (2H, s). m/z (ES+) 326 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][CH2:17][OH:18])=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][CH:17]=[O:18])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCCCC1CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ncccc1CN1CCCCC1CC=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 4.2 g of pyridine-sulfurtrioxide complex dissolved in dimethyl sulfoxide (DMSO) was added dropwise into a solution of 3 g of 2-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]-1-ethanol and 7.3 ml of triethylamine dissolved in 15 ml of DMSO, while keeping the bulk temperature at 20° C. or less. After completing the dropwise addition, the mixture was stirred at room temperature for one hour. An aqueous sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. After drying over sodium sulfate, the solvent was evaporated. The residue was purified by silica gel chromatography (methanol), to give 2.5 g of a red brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]=[O:13].[H-].[Na+].CI.[C:18](=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:18])[CH:7]=[C:6]2[CH:12]=[O:13]
Reactant: O=C([O-])O
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(C=O)cn2C
Yield: 99 %

Procedure:
5-Methoxyindole-3-carboxaldehyde (300 mg, 1.71 mmol) was added in portions over 5 min to a suspension of sodium hydride (82 mg, 2.05 mmol, 60% dispersion in mineral oil) in DMF (8 mL) stirring under argon. The mixture was stirred for 30 min, methyl iodide (0.13 mL, 2.05 mmol) was added and the mixture was stirred for 1 h. Sodium bicarbonate (10%, 40 mL) was added and the mixture was extracted with EtOAc (4×). The combined organic layers were washed with sodium bicarbonate (10%, 2×) and saturated NaCl, dried (MgSO4), filtered and evaporated. Column chromatography of the crude product (50:50 EtOAc:hexanes) afforded 43 (320 mg, 99%) as a light yellow solid; Rf=0.35 (50:50 EtOAc:hexanes); mp=130-132° C.; lit mp=132-133° C.53; 1H NMR (CDCl3): δ 9.95 (s, 1H), 7.79 (d, 1H, J=2.4 Hz), 7.62 (s, 1H), 7.25 (d, J=8.8 Hz), 6.96 (dd, 1H, J=2.4 and 8.9 Hz), 3.90 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[Cl-].C([Al+]CC)C.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[C:24]([C:7]1[C:8]2[C:13](=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CCCCn1ccc2ccc(C(=O)OC)cc21
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCn1cc(C(C)=O)c2ccc(C(=O)OC)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl 1-butyl-1H-indole-6-carboxylate (4.53 g) was dissolved in dichloromethane (25 ml). The mixture was cooled to 0° C. Diethyl aluminum chloride was added dropwise (29.5 mL) and the mixture was allowed to stir at 0° C. for 30 min. A solution of dichloromethane (25 mL) and acetyl chloride (2.1 mL) was added dropwise, and the mixture was stirred for 2 h at 0° C. The mixture was then partitioned between dichloromethane, water, and brine, dried over sodium sulfate, filtered, and concentrated. The concentrate was chromatographed on silica gel using ethyl acetate/heptane (40/60) to give methyl 3-acetyl-1-butyl-1H-indole-6-carboxylate (3.38 g). MS (ESI+) for C16H19N1O3+H1 m/z 274.14 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]2[NH:9][C:10]3[C:16]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH2:44]Br)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:44][CH2:43][CH2:42][CH:39]3[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:35])[CH2:37][CH2:38]3)[C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:10]=3[N:9]=2)=[CH:25][CH:26]=1
Reactant: Clc1ccc(OCc2nc3cccc(OCc4ccccc4)c3[nH]2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCc4ccccc4)cccc32)CC1
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of 2-(4-chlorophenoxymethyl)-4-benzyloxy-benzimidazole (720 mg, 1.97 mmol, 1.0 eq) in dry N,N-dimethylformamide (8 ml, 0.25 M) was treated with sodium hydride (60% in mineral oil, 57 mg, 2.30 mmol, 1.2 eq). The resulting mixture was stirred at room temperature for thirty minutes and then 3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl bromide (7.24 mg, 2.36 mmol, 1.2 eq) was added to the reaction mixture. The resulting mixture was stirred at 70° C. for three hours. The reaction was quenched by the addition of water (1×30 ml). The aqueous fraction was extracted with diethyl ether (1×30 ml). The organic fractions were combined, washed with water (1×30 ml), then brine (1×30 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by flash chromatography to provide a white foam in 38% yield.
Reaction SMILES: [CH:1]([N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][NH:8][CH2:9]2)[CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].O>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:20]([N:8]1[CH2:9][CH:10]2[CH2:12][CH:6]([CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:11]2)[CH2:7]1)=[O:21]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CC(C)N1CC2CNCC(C2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)N2CC3CC(C2)CN(C(C)C)C3)cc1OC
Reaction time: 3 h
Yield: 73.3 %

Procedure:
A 25-mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer, a standard condenser with a N2 inlet, a 10-mL addition funnel, and two glass stoppers. To a mixture of the amine (31, 0.60 g, 3.57 mmol) in CH2Cl2 (5 mL) and 10% NaOH (3.58 g, 8.93 mmol) was added dropwise a solution of 3,4-dimethoxybenzoyl chloride (0.80 g, 3.92 mmol) in CH2Cl2 (10 mL) over 15 min. Stirring of the mixture was continued for an additional 3 h under N2. An aqueous mixture, formed upon addition of H2O (30 mL), was extracted (CH2Cl2, 4×25 mL). Combined extracts were dried (Na2SO4, 2 h), filtered and concentrated to give a viscous yellow oil. Chromatography of the oil was performed on neutral alumina (74 g, 1.7 cm×32 cm) using 60:40 ethyl acetate/hexanes as eluant. Fractions (Rf = 0.31) were saved and concentrated (rotary evaporator then vacuum pump, overnight, RT/0.2 mm Hg) to give 0.87 g (73.1%) of off-white solid (34); mp 67.5°-69.5° C. IR (KBr) cm-1 3055 (Ar C--H), 2950, 2915, 2845, 2820, 2770, 2750, 2710 (C--H), 1625 (C=O); 1H NMR (DCCl3) δ0.96 (d, 3H, CH3, J=6.4 Hz), 1.06 (d, 3H, CH3, J=6.5 Hz), 1.62-1.75 [m, 3H, H(5) and H(9)], 1.96 [bs, 1H, H(1)], 2.43 [bd, 1H, H(4)ax, J=9.7 Hz], 2.51 [bd, 1H, H(6)ax, J=10.5 Hz], 2.62 [heptet, 1H, CH(CH3)2, J=6.4 Hz], 2.74 [bd, 1H, H(6)eq, J=9.9 Hz], 3.00-3.09 [m, 2H, H(4)eq and H(2)ax ], 3.32 [bd, 1H, H(8)ax, J=13.2 Hz], 3.83-3.94 [m, 7H, H(8)eq and OCH3 ], 4.77 [bd, 1H, H(2)eq, J=13.3 Hz], 6.84-6.94 (m, 3H, Ar--H); 13C NMR (DCCl3) ppm 16.46, 19.15 (CH3), 29.13 [C(1)], 29.86 [C(5)], 32.36 [C(9)], 46.71 [C(2)], 52.25 [C(4)], 52.65 [C(8)], 54.35 [CH(CH3)2 ], 54.68 [C(6)], 55.88, 55.93 (OCH3), 110.50, 119.64, 130.23, 148.78, 149.39 (Ar--C), 169.90 (C=O). Anal. Calcd. for C19H28N2O3 : C, 68.65; H, 8.49. Found: C, 68.58; H, 8.47.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.CCOC(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>[CH3:25][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(C(F)(F)F)c1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 102.6 %

Procedure:
Methyl 4-bromo-3-(trifluoromethyl)benzoate (6 g; 21.20 mmol; 1 eq.), o-tolylboronic acid (3.17 g; 23.32 mmol; 1.10 eq.), potassium carbonate (14.65 g; 105.99 mmol; 5 eq.), tetrakis(triphenylphosphine)palladium(0) (2.45 g; 2.12 mmol; 0.10 eq.) were taken up in Toluene (30 mL) and water (30 mL) under N2 atmosphere. The reaction mixture was purged with vacuum for 5 minutes, then degassed with N2 and then refluxed for 3 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene (200 mL). The filtrate was concentrated to afford brown oil which was taken in EtOAc (200 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 solution (50 mL), water (50 mL) and brine (50 mL), dried over MgSO4 and concentrated affording the title compound as a brown oil (6.4 g, quantitative). HPLC (Method A) Rt 5.33 min (Purity: 60.0%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[C:18](=[O:19])[CH2:17][N:16]([C:20](=[O:29])[CH2:21][O:22][C:23]4[S:24][C:25]([Cl:28])=[CH:26][CH:27]=4)[CH2:15][CH:14]3[C:30]([OH:32])=O)=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:33][N:34]1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.Cl>CN(C=O)C>[CH3:33][NH:34][C:30]([CH:14]1[CH2:15][N:16]([C:20](=[O:29])[CH2:21][O:22][C:23]2[S:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH2:17][C:18](=[O:19])[N:13]1[CH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1)=[O:32]
Reactant: CN1CCOCC1
Reactant: Nc1ncnc2cc(CN3C(=O)CN(C(=O)COc4ccc(Cl)s4)CC3C(=O)O)ccc12
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)C1CN(C(=O)COc2ccc(Cl)s2)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
Water (1 mL) is added to a solution containing (±)-1-(4-amino-quinazolin-7-ylmethyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-6-oxo-piperazine-2-carboxylic acid methyl ester (20 mg, 0.03 mmol), EXAMPLE 808, in a 1:1 mixture of THF/MeOH (2 mL). At ambient temperature, LiOH monohydrate (3 mg, 0.07 mmol) is then added. After 16 h, the reaction mixture is diluted with water and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 25 mg (>100%) of the associated acid as a white solid after lyophilization which is used directly in the next reaction. To a mixture containing (+/−)-1-(4-amino-quinazolin-7-ylmethyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-6-oxo-piperazine-2-carboxylic acid (12 mg, 0.02 mmol), N-methylmorpholine (19 mg, 0.19 mmol), and HATU (22 mg, 0.05 mmol) in anhydrous DMF (1 mL) is added MeNH2 hydrochloride (5 mg, 0.19 mmol). The reaction mixture is stirred 1 h at ambient temperature and then concentrated to dryness. The residue is dissolved in water and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 7 mg (58%) of the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][OH:11].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.[Cl-].[NH4+]>CN(C)C=O.O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:8][CH2:9][CH2:10][OH:11])=[CH:15][CH:14]=1
Reactant: OCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8.5 h

Procedure:
Potassium carbonate (12.0 g) and 3-bromo-1-propanol (5.1 mL) were added to a solution of 4-bromophenol (5.0 g) in N,N-dimethylformamide (200 mL) under ice-cooling, and the mixture was stirred at room temperature for 8.5 hours. The reaction solution was ice-cooled and a saturated ammonium chloride solution and water were added, followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1→4:1→3:1) to give 3-(4-bromophenoxy)propan-1-ol as a crude product.