Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:27]C(OC(C)(C)C)=O)[C:11]([O:13][C@H:14]([CH3:26])[C@H:15]([O:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH3:16])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[ClH:35]>O1CCOCC1>[ClH:35].[NH2:27][C@@H:10]([CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)[C:11]([O:13][C@H:14]([CH3:26])[C@H:15]([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])[CH3:16])=[O:12]
Reactant: C[C@@H](OC(=O)c1ccccc1)[C@@H](C)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](OC(=O)c1ccccc1)[C@@H](C)OC(=O)[C@@H](N)Cc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
(1R,2R)-1-Methyl-2-phenylcarbonyloxypropyl (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate (1.8 g, 2.7 mmol) was dissolved in 40 mL of 4M HCl in dioxane. The mixture was stirred at room temperature for 30 min. The dioxane was evaporated completely under reduced pressure. The resulting a white solid was dissolved in acetonitrile (5 mL) and ether added until the solution became slightly cloudy. The solution was refrigerated overnight and the product crystallized. The white, crystalline solid was collected and dried under vacuum to afford 1.0 g (87% yield) of the title compound (1). 1H NMR (400 MHz, CD3OD): δ 1.12 (d, J=6 Hz, 3H), 1.24 (d, J=6 Hz, 3H), 2.85 (dd, J=14, 8 Hz, 1H), 3.02 (dd, J=14, 5.2 Hz, 1H), 4.15 (t, J=5.6 Hz, 1H), 5.06 (m, 2H), 6.46 (dd, J=8, 2 Hz, 1H), 6.61 (d, J=2 Hz, 1H), 6.65 (d, J=8 Hz, 1H), 7.54 (t, J=7.6 Hz, 2H), 7.65 (t, J=7.6 Hz, 1H), 7.90 (m, 2H). MS (ESI) m/z 374.11 (M+H)+ and 372.08 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([N+:19]([O-:21])=[O:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2].[Br:22]Br>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([N+:19]([O-:21])=[O:20])=[CH:13][C:12]=3[Br:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])cc12
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc2c(cn1)[nH]c1c(Br)cc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.9 %

Procedure:
285 mg of 6-nitro-β-carbolin-3-carboxylic acid ethyl ester is introduced into 5.8 g of bromine and stirred for 2 days at room temperature. The mixture is then diluted with 15 ml of chloroform and filtered with suction. The residue is recrystallized from pyridine and chromatographed on silica gel with chloroform-methanol (9:1). 65 mg of 8-bromo-6-nitro-β-carbolin-3-carboxylic acid ethyl ester of melting point 291°-292° C. is obtained.
Reaction SMILES: O.[OH-].[Li+].C([O:6][P:7]([CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=1)([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[O:8])C>O.C(O)C>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([Cl:27])[CH:24]=1)[CH2:20][NH:19][CH2:18][CH2:17][CH2:16][P:7]([CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])(=[O:6])[OH:8]
Reactant: CCOC(OCC)P(=O)(CCCNCc1cc(Cl)cc(Cl)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(OCC)P(=O)(O)CCCNCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 0.36 g of lithium hydroxide monohydrate in 7 ml of water is added to a solution of 1.61 g of 3-(3,5-dichlorobenzylamino)propyl(diethoxymethyl)-phosphinic acid ethyl ester in 3 ml of ethanol and heated at 60° for 24 hours. The mixture is then cooled to room temperature and the solvent is removed under reduced pressure. The evaporation residue is taken up in water and rendered neutral with phosphoric acid. A white precipitate is formed. The precipitate is filtered off and the filtrate is concentrated to dryness by evaporation. The white evaporation residue is dried under reduced pressure and crystallised from toluene/diethyl ether. Filtration with suction and drying yield 3-(3,5-dichlorobenzylamino)propyl(diethoxymethyl)phosphinic acid having a melting point of 160°-161°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:12]#[C:13][CH2:14][CH3:15]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[C:12]([C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1)#[C:13][CH2:14][CH3:15]
Reactant: C#CCC
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCC#Cc1cc(C(=O)OC)ccn1
Temperature: 80 °C

Procedure:
A mixture of methyl 2-chloropyridine-4-carboxylate (3.32 g, 19.3 mmol), bis(triphenylphosphine)palladium(II) chloride (0.82 g, 1.1 mmol), copper(I) iodide (0.36 g, 1.9 mmol), triethylamine (30 mL), and n-but-1-yne (˜5 g) was heated in a sealed tube at 80° C. overnight. The product mixture was concentrated, and the residue was subjected to column chromatography on silica gel eluting with chloroform. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Br:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Cl:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Reactant: CC[C@H](COC)n1cc(Br)nc(Br)c1=O
Product: CC[C@H](COC)n1cc(Br)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 150-152° C.; 1H NMR (300 MHz, CDCl3): δ 7.18 (d, J=2.2 Hz, 1 H), 7.12 (s, 1 H), 7.10 (d, J=1.8 Hz, 1H), 4.95-4.90 (m, 1 H), 4.34 (t, J=8.1 Hz, 2 H), 3.67 (dd, J=10.6, 5.8 Hz, 1 H), 3.55 (dd, J=10.6, 3.5 Hz, 1H), 3.35 (s, 3 H), 3.12 (t, J=8.1 Hz, 2 H), 1.92-1.72 (m, 2 H), 0.93 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C17H19N3O2BrCl2 (M+H)+: 446.0038; found m/z 446.0008.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)[C:2]#[C:3]C.C([Li])CCC.[CH3:21][O:22][C:23]1[C:32]([CH:33]=[O:34])=[CH:31][C:30]([N+:35]([O-:37])=[O:36])=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:39])([CH3:38])[O:28]2.CCOCC>C1COCC1.O=[Mn]=O>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([O:5][CH2:1][C:2]#[C:3][C:33]([C:32]2[C:23]([O:22][CH3:21])=[C:24]3[C:29](=[C:30]([N+:35]([O-:37])=[O:36])[CH:31]=2)[O:28][C:27]([CH3:39])([CH3:38])[CH:26]=[CH:25]3)=[O:34])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: CC#CCOc1ccc(OC)c(OC)c1
Reactant: COc1c(C=O)cc([N+](=O)[O-])c2c1C=CC(C)(C)O2
Agent: O=[Mn]=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(OCC#CC(=O)c2cc([N+](=O)[O-])c3c(c2OC)C=CC(C)(C)O3)cc1OC
Reaction time: 0.5 h

Procedure:
To a solution of 4-but-2-ynyloxy-1,2-dimethoxybenzene (1.66 g, 8.66 mmol) in THF (75 mL) is added n-butyl lithium (5.54 ml of 1.6 M solution in THF, 8.86 mmol) at −78° C. After 30 min., 5-methoxy-2,2-dimethyl-8-nitro-2H-chromene-6-carbaldehyde (2.17 g, 8.25 mmol) in THF (50 mL) is added. The reaction is stirred for 1 h and then quenched with sat. NH4Cl and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over Na2SO4. The resulting crude material is dissolved in dichloromethane (20 mL) and MnO2 (5.3 g, 61 mmol) is added. After the reaction is stirred overnight at room temperature, ether is added and the suspension is filtered through a pad of celite and silica gel to afford 4-(3,4-dimethoxy-phenyoxy)-1-(5-methoxy-2,2-dimethyl-8-nitro-2H-chromen-6-yl)-but-2-yn-1-one.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH2:5][N:6]1[C:10](=O)[CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:8]([CH2:23][CH2:24][CH3:25])[C:7]1=[O:26].[CH3:31][Mg]Br.CCOCC>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH2:5][N:6]1[C:10]([CH3:31])=[C:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[N:8]([CH2:23][CH2:24][CH3:25])[C:7]1=[O:26]
Reactant: C[Mg]Br
Reactant: CCCN1C(=O)N(Cc2ccc(C)c(C)c2)C(=O)C1CCCc1ccc(OC)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCn1c(CCCc2ccc(OC)cc2)c(C)n(Cc2ccc(C)c(C)c2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A 0° C. solution of 3-(3,4-dimethyl-benzyl)-5-[3-(4-methoxy-phenyl)-propyl]-1-propyl-imidazolidine-2,4-dione (0.155 g, 0.379 mmol) in THF (6 mL) was treated dropwise with a 3 molar solution of methyl magnesium bromide in Et2O (0.76 mL, 2.28 mmol) and then stirred at 0° C. under N2 for 1 h. The reaction was quenched with 1 N HCl (5 mL) and stirred at room temperature for 15 minutes to effect elimination and then was worked up extractively with EtOAc and water. The organic layer dried (MgSO4), and the solvent removed in vacuo to afford 0.155 g (100%) 1-(3,4-dimethyl-benzyl)-4-[3-(4-methoxy-phenyl)-propyl]-5-methyl-3-propyl-1,3-dihydro-imidazol-2-one that was utilized without purification. MS (ES+) Calc'd for C26H35N2O2 (M+1) 407. Found m/z 407 (100%). 1H NMR.
Reaction SMILES: Br[CH2:2][C:3]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:16]1([Na])[CH:20]=[CH:19][CH:18]=[CH:17]1>CCOCC>[CH:19]1([CH2:2][C:3]2[C:15]3[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]=3[CH:6]=[CH:5][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:20]1
Reactant: BrCc1cccc2c1Cc1ccccc1-2
Reactant: [Na]C1C=CC=C1
Solvent: CCOCC
Product: C1=CC(Cc2cccc3c2Cc2ccccc2-3)C=C1
Reaction time: 2 h
Yield: 70 %

Procedure:
The ligand (cyclopentadienyl)(fluorenyl)methane was prepared as follows. To 0.4 mole dibromomethane dissolved in 200 mL pentane was added 0.2 mole fluorenyllithium powder. After the addition was complete, the reaction mixture was stirred for two hours. The reaction mixture was filtered and the filtrate washed with 100 mL of distilled water. The organic phase was dried with Na2SO4 and the solvent was stripped under vacuum. The residue was washed with 150 mL pentane to remove unreacted fluorene and dried under vacuum to yield pale yellow colored (bromo)(fluorenyl)methane. The yield was 80%. The (bromo)(fluorenyl)methane was dissolved in 20 mL ether and 19 mL (2 M in THF) cyclopentadienylsodium was added at a rate of 0.15 mL/min. The reaction mixture was stirred for two hours and washed with 50 mL distilled water. The organic phase was dried over Na2SO4 and the solvent removed under vacuum to yield pale yellow (cyclopentadienyl)(fluorenyl)methane. The yield was 70%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[N:22]=[CH:21][N:20](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:19]=4)[CH:16]=3)[N:11](C3CCCCO3)[N:10]=2)=[CH:5][CH:4]=1.C(Cl)Cl.ClC1C=C(C=CC=1)C(OO)=[O:56]>CCOC(C)=O>[NH:19]1[C:18]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:6]2[CH:7]=[CH:8][C:3]([S:2]([CH3:1])=[O:56])=[CH:4][CH:5]=2)=[N:22][CH:21]=[N:20]1
Reactant: CSc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)c1ccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.4 %

Procedure:
A mixture of 4-methylthio-1-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}benzene (136 mg, 0.214 mmol), 1.00 mL CH2Cl2, and 3-chloroperoxybenzoic acid (Aldrich, 77% purity, 48.1 mg, 0.214 mmol based on 77% purity, 1.00 equiv.) was stirred at room temperature for 30 minutes. The reaction was diluted with EtOAc, washed with 2× sat. aq. NaHCO3, dried (Na2SO4), filtered, and concentrated. The crude concentrate was heated in 5.00 mL of MeOH and 5.00 mL of 6.0 N aq. HCl at 65° C. for 17.5 h. The mixture was poured onto 6.0 N aq. NaOH and extracted with 2×EtOAc. The aqueous layer was neutralized to pH=6.0 with 6.0 N aq. HCl, and extracted with 2×EtOAc. The combined organics were dried (Na2SO4), filtered, and concentrated. Purification by prep HPLC afforded the title compound (7.2 mg, 10.4% yield): 1H NMR (CDCl3/CD3OD) δ 8.78 (s, 1H), 8.45-7.98 (m, 4H), 7.86 (d, 2H), 7.72 (d, 1H), 2.89 (s, 3H); ES-MS (m/z) 324 [M+1]4.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[H-].[Na+].[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[C:12]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][N:7]=3)[C:2]([O:1][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:3][C:4]2=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)CCCCCCc1ccccc1
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCCCCCc1ccccc1)Oc1cc(=O)n(-c2ccccc2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (953 mg, 4.0 mmol) in DMF (32 mL) was added sodium hydride (purity of about 60%, 176 mg, 4.4 mmol, 1.1 eq.), and the mixture was stirred at a room temperature for 40 minutes. Then, 7-phenylheptanoyl chloride (4.8 mmol, 1.2 eq.) was added thereto with cooling in an ice bath, and the mixture was stirred at a room temperature for 1.5 hours. Thereafter, the water was added to the reaction solution, and the precipitate was separated by filtration and dried to give 1-phenyl-4-(7-phenylheptanoyloxy)-1,8-naphthyridin-2(1H)-one as a form of crystal (1.52 g, yield 89%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[C:18]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])#[CH:19]>C(O)(C)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([C:18]#[CH:19])[CH:21]=1)(=[O:3])[CH3:2]
Reactant: C#Cc1cccc(N)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OC(C)=O)cc23)c1
Temperature: 83 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A suspension of 4-chloro-7-methoxyquinazolin-6-yl acetate (4.31 g), 3-ethynylaniline (3.00 g) and isopropanol (65 mL) was stirred at 83° C. overnight. The reaction mixture was cooled to room temperature and filtered, the residue was washed with 100 mL of isopropanol and dried to afford the desired compound as a solid (4.89 g, 85.90%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:18]2[C:13](=[C:14]([O:19]C)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[CH3:21].B(Br)(Br)Br.C(Cl)Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:18]2[C:13](=[C:14]([OH:19])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[CH3:21]
Reactant: COc1cccc2c1cc(C)n2Cc1c(Cl)cccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(O)cccc2n1Cc1c(Cl)cccc1Cl
Yield: 83.3 %

Procedure:
By the method used in Example 1, Part D, 1.08 g (3.38 mmol) of 1-[(2,6 dichlorophenyl)methyl]-4-methoxy-2-methyl-1H-indole was O-demethylated by treating it with 13.5 mL of 1M BBr3 /CH2Cl2 to give 862 mg (83% yield) of 1-[(2,6-dichlorophenyl)methyl]-4-hydroxy-2-methyl-1H-indole, after chromatography on silica gel (eluted with 20% EtOAc/hexane).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:27][CH3:28])[CH2:24][CH2:25][OH:26])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:32].O>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:27][CH3:28])[CH2:24][CH2:25][O:26][CH3:32])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCC(CCO)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CCOC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a solution of 3-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]pentan-1-ol (148 mg, 0.34 mmol) in N,N-dimethylformamide (5.0 mL) was added sodium hydride (60% dispersion in mineral oil, 27 mg, 0.675 mmol) at 0° C. After the mixture was stirred at 0° C. for 0.5 hr, iodomethane (0.064 mL, 1.03 mmol) was added to the reaction mixture at 0° C. The mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane to give the title compound (81.1 mg, 0.179 mmol, 53%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8](I)=[N:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2cnc(I)nc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: CN(C)C=O
Product: Brc1ccc2cncnc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a mixture of 7-bromo-2-iodoquinazoline (69 mg, 206 μmol), triphenylphosphine (5.4 mg, 21 μmol), and Pd(OAc)2 (3.2 mg, 14 μmol) in DMF (4.0 mL) was added TEA (72 μL, 515 μmol) and formic acid (9.5 μL, 247 μmol). The reaction mixture was stirred at 70° C. overnight. After cooling, the reaction mixture was concentrated, and the crude residue was dissolved in DCM and mixed with SiO2. The solvent was evaporated, and the residue was purified with flash column chromatography (pure DCM→3% MeOH in DCM) to obtain the desired product 7-bromoquinazoline (22 mg, 51%) as a white solid. LCMS (API-ES) m/z (%): 210.0 (100%, M++H).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]([C:12]([CH3:14])=[O:13])=[CH2:11].S(=O)(=O)(O)O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[C:1]1([CH:7]2[CH2:8][CH2:14][C:12](=[O:13])[CH:10]=[CH:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC(C)=O
Reactant: O=CCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1C=CC(c2ccccc2)CC1

Procedure:
A mixture of 19.5 cm3 of phenylacetaldehyde, 16.7 cm3 of methyl vinyl ketone, 0.17 cm3 of 36% sulphuric acid and 85 cm3 of toluene is heated for 1 hour at a temperature in the region of the reflux temperature. After cooling to a temperature in the region of 20° C., 50 cm3 of ethyl acetate are added to the reaction mixture. The resulting mixture is washed with 100 cm3 of saturated aqueous sodium bicarbonate solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography on a column of silica [eluent: cyclohexane/ethyl acetate (90/10)] to give 4.7 g of 4-phenylcyclohex-2-enone in the form of a yellow oil, the characteristics of which are as follows:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=1)=[CH:6]2.[CH:28]([N:31](C(C)C)[CH2:32]C)(C)C.CNC.O>CS(C)=O>[CH3:28][N:31]([CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=1)=[CH:6]2)[CH3:32]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(CCl)cc([N+](=O)[O-])c3[nH]2)=N1
Agent: CNC
Solvent: O
Solvent: CS(C)=O
Product: CN(C)Cc1cc([N+](=O)[O-])c2[nH]c(C3=N[C@H](COC(=O)C(C)(C)C)CS3)cc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.7 %

Procedure:
2,2-Dimethyl-propionic acid [(R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]methyl ester (1.0 g, 2.4 mmol) prepared in Preparation 41 was dissolved in dimethylsulfoxide (15 mL). Diisopropylethylamine (0.6 g, 4.9 mmol) and dimethylamine (0.2 g, 4.9 mmol) were added thereto, and the mixture was stirred for 6 h at room temperature. After completion of the reaction, water was added. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (0.7 g, Yield 71%).
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24]O>>[CH3:24][O:20][C:19](=[O:21])[CH2:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([Cl:22])=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Agent: Cl
Product: COC(=O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
A mixture of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2, 50 mg, 0.16 mmol) and 10% HCl in methanol (3 ml) was stirred for 3 h at room temperature. The mixture was concentrated and the residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1:5) to afford 23 mg (44%) of the title compound as white solids.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH2:12](Br)[C:13]#[CH:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:14]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[C:13]#[CH:12]
Reactant: C#CCBr
Reactant: O=C1NCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc2c(c1)C(=O)NC2
Yield: 68.7 %

Procedure:
The mixture of 6-hydroxyisoindolin-1-one ((73), 5.1 g, 34.2 mmol), propargyl bromide (80% solution in toluene, 5.70 ml, 51.3 mmol) K2CO3 (9.44 g, 68.4 mmol), KI (1.14 g, 6.8 mmol) in acetone was refluxed for overnight. The reaction mixture was filtered under vacuum and concentrated in vacuo to give the title compound (4.4 g, 68%) as a solid. MS (ES) m/z 188.1.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16]>O>[CH:1]([NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])=[O:3]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: O=CNc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (50 ml) was added to 98% formic acid (85 ml). The mixture was stirred at room temperature for 30 mins, then 3-aminobenzoic acid (10 g, 73 mmol) was added and the mixture was stirred for one hour at room temperature. Water (850 ml) was added and the mixture was stirred overnight at room temperature. The resultant white precipitate was collected (10.66 g, 88%).