Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:20]=1.I[CH3:22].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:22])[C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[N:20]=1
Reactant: CI
Reactant: CC1CN(c2ccccc2)c2nc(Cl)ncc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(c2ccccc2)c2nc(Cl)ncc2N(C)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To an ice cooled mixture of 0.46 g (0.0016 mole) of (rac)-2-chloro-7-methyl-9-phenyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-51), 0.15 mL (0.00239 mole) of iodomethane and 10 mL of dimethylformamide was added 0.10 g (0.00239 mole) of a 60% oil dispersion of sodium hydride. The mixture was stirred at 0 degrees for 2 hours, and then partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (100:0-60:40) to give 0.30 g of (rac)-2-chloro-5,7-dimethyl-9-phenyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-51) as white powder. HRMS (ES+) m/z Calcd for C15H15CLN4O+H [(M+H)+]: 303.1007. Found: 303.1006.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:33])=[C:12]([NH:14][C:15](=[O:32])[C:16]3[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]4[CH2:28][CH2:27][CH2:26][NH:25]4)[CH:19]=[CH:18][C:17]=3[N+:29]([O-])=O)[CH:13]=2)=[O:7])[CH2:4][CH2:3]1.[CH3:34]O>[Pd].C(O)C>[CH:2]1([NH:5][C:6](=[O:7])[C:8]2[CH:9]=[CH:10][C:11]([CH3:33])=[C:12]([N:14]3[C:15](=[O:32])[C:16]4[C:17](=[CH:18][CH:19]=[C:20]([O:22][CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][NH:25]5)[CH:21]=4)[N:29]=[CH:34]3)[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CO
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(OC[C@@H]2CCCN2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC[C@@H]3CCCN3)cc2c1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
N-{5-[(Cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitro-5-[(2S)-pyrrolidin-2-ylmethoxy]benzamide hydrochloride salt (2.05 g) and 10% palladium on carbon (0.2 g) were stirred in ethanol (40 ml) and methanol (20 ml) under an atmosphere of hydrogen gas for 19 hours at room temperature. The catalyst was removed by filtration through diatomaceous earth (Celite®) and the filtrate was concentrated. The residue was dissolved in ethanol (40 ml) and stirred with triethylorthoformate (2.16 ml) and glacial acetic acid (0.124 ml) at 80° C. for 3 hours and then concentrated. The residue was diluted with ethyl acetate and washed with saturated aqueous NaHCO3 solution, brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 20% methanol/ethyl acetate followed by 20% methanol/ethyl acetate+1% aqueous ammonia solution to give N-cyclopropyl-4-methyl-3-[4-oxo-6-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-3(4H)-yl]benzamide (AZ12299441) (0.837 g) as a cream coloured foam solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.70 (m, 2H), 1.49 (m, 1H), 1.61-1.76 (m, 2H), 1.85 (m, 1H), 2.15 (s, 3H), 2.85 (m, 3H), 3.42 (m, 1H), 3.95 (d, 2H), 7.52 (m, 2H), 7.58 (s, 1H), 7.73 (d, 1H), 7.84 (s, 1H), 7.91 (d, 1H), 8.19 (s, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 419.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]3[CH:14]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[NH:16][C:12]=3[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1>CN(C=O)C.O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][N:16]2[C:12]3[CH:11]=[CH:10][N:9]=[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=4)[C:13]=3[CH:14]=[C:15]2[C:17]([O:19][CH3:20])=[O:18])=[CH:28][CH:29]=1
Reactant: Clc1ccc(OCCBr)cc1
Reactant: COC(=O)c1cc2c(-c3ccnc(F)c3)nccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2c(-c3ccnc(F)c3)nccc2n1CCOc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 81.8 %

Procedure:
To a solution of methyl 4-(2-fluoropyridin-4-yl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (67 mg, 0.247 mmole) in DMF (1.2 mL) was added NaH (60% dispersion in mineral oil, 13 mg, 0.325 mmole) at RT. After gas evolution had ceased 1-(2-bromoethoxy)-4-chlorobenzene (76 mg, 0.321 mmole) was added and the mixture was heated to 60° C. After 3 hr the mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine, dried (MgSO4), filtered, and concentrated. Flash column chromatography (Biotage-SNAP-10 g SiO2, 35% EtOAc/hexanes) gave the title compound (86 mg, 82%) as a white foam. 1H NMR (400 MHz, CDCl3): δ 8.58 (d, J=5.9 Hz, 1 H); 8.39 (d, J=5.2 Hz, 1 H); 7.79 (d, J=5.4 Hz, 1 H); 7.60-7.51 (m, 3 H); 7.18-7.15 (m, 2 H); 6.72-6.67 (m, 2 H); 5.02-4.96 (m, 2 H); 4.39-4.33 (m, 2 H); 3.97 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:24]([OH:26])=[O:25]>>[F:1][C:2]1[CH:3]=[C:4]([C:22]2[C:21]([F:20])=[C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCC(C)C(=O)c1ccc(O)cc1F
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1F
Product: CCCCCCCCCCOc1ccc(C(=O)O)c(-c2ccc(C(=O)C(C)CCCCCCC)c(F)c2)c1F

Procedure:
The same procedure as in Example 20 was repeated, except that (+)-3-fluoro-4-(2-methylnonanoyl) phenol was used instead of (+)-3-fluoro-4-(2-methyloctanoyl) phenol in Example 20 and 3-fluoro-4-decyloxy benzoic acid was used instead of 3-fluoro-4-heptyloxy benzoic acid in Example 20, to obtain an objective compound having the aforementioned physical and chemical properties.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.N1C=CC=CC=1>O>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(Cl)c1ccccc1Oc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(c1ccccc1Oc1ccccc1)N1CCCC1
Reaction time: 5 h

Procedure:
7.7 parts of 2-phenoxybenzoyl chloride was added dropwise to a solution of 2.5 parts of pyrrolidine in 20 parts of pyridine at 0°. When the addition was complete the mixture was stirred for 5 hours. The temperature was then allowed to rise to room temperature and the reaction mixture was poured into 100 parts of water. The aqueous solution was then extracted with chloroform, and washed with water. The chloroform layer was dried over magnesium sulfate, removal of the magnesium sulfate by filtration and concentration of the filtrate gave 6.4 parts of N-(2-phenoxybenzoyl)pyrrolidine, NMR (CDCl3) 1.8δ(m,4H,CH2), 3.4δ(m,4H-N-CH2), 7.1δ(m,9H,Aromatic H). The following compounds can be prepared from the 2-substituted benzoyl chloride and the appropriate secondary amine as described above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][NH:16][C:17]([C:19]1[CH:24]=[C:23]([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH:22]=[CH:21][N:20]=1)=[O:18]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([O:25][C:23]3[CH:22]=[CH:21][N:20]=[C:19]([C:17](=[O:18])[NH:16][CH3:15])[CH:24]=3)=[CH:32][CH:31]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Reaction time: 22 h
Yield: 93.2 %

Procedure:
A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (14.60 g, 65.90 mmol) in CH2Cl2 (35 mL) was added dropwise to a suspension of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH2Cl2 (35 mL) at 0° C. The resulting mixture was stirred at room temp. for 22 h. The resulting yellow solids were removed by filtration, then washed with CH2Cl2 (2×30 mL) and dried under reduced pressure (approximately 1 mmHg) to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as an off-white solid (28.5 g, 93%): mp 207-209° C. ; 1H-NMR (DMSO-d6) δ2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, 1H), 7.62 (m, 4H), 8.11 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 465 ((M+H)+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[N:7]3[C:14]4[CH:15]=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[C:27]([CH2:26][CH2:25][CH2:24][N:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:22])[N:7]2[C:14]2[CH:15]=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=[CH:18][C:13]1=2)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=3)([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOc1ccc2[nH]c3nc4cc(C)ccc4c(=O)n3c2c1
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCn1c2ccc(OCC)cc2n2c(=O)c3ccc(C)cc3nc12

Procedure:
6-(Carboethoxypropyl)-3-methyl-9-ethoxybenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 3-methyl-9-ethoxybenzimidazo[2,1-b]quinazolin-12(6H)one and ethyl 4-bromobutyrate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:32]2[CH2:33][CH2:34][CH:30]([C:24]3[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH2:31]2)=[CH:4][CH:3]=1
Reactant: COc1cc(OC)cc(C2CCNC2)c1
Reactant: Fc1ccc(C(OCCBr)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)cc(C2CCN(CCOC(c3ccc(F)cc3)c3ccc(F)cc3)C2)c1
Yield: 46.5 %

Procedure:
Proceeding as in Example 9, using 14.8 g (45 mmole) of 1-[bis(4-fluorophenyl)methoxy]-2-bromoethane, 9.4 g (45 mmole) of 3-(3,5-dimethoxyphenyl)pyrrolidine and 12 g (86 mmole) of potassium carbonate, there was obtained after silica gel column chromatography (eluent chloroform-methanol, 9/1), 9.5 g (yield: 46%) of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-3-(3,5-dimethoxy phenyl)pyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:15][C:16](=O)[CH3:17].[I-].[Na+]>CO>[NH2:12][C:10]1[N:11]2[CH:15]=[C:16]([CH3:17])[N:1]=[C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C:9]=1[Cl:13]
Reactant: CC(=O)CBr
Reactant: COC(=O)c1cc(Cl)c(N)nc1N
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)n2cc(C)nc12
Reaction time: 24 h
Yield: 59 %

Procedure:
A mixture of methyl 2,6-diamino-5-chloronicotinate (Example 2, Step 3, 15 g, 74.4 mmol), bromoacetone (10.4 mL, 112 mmol) and sodium iodide (16.7 g, 112 mmol) in methanol (700 mL) was stirred under reflux for 22 h. Another 2.5 mL (33 mmol) of bromoacetone was added and the stirring was continued for 24 h. The reaction mixture was quenched with saturated aqueous sodium carbonate and removed methanol in vacuo. The residue was extracted with ethyl acetate (250 mL×10) adding a small amount of methanol to dissolve the organic solid. The organic extracts were dried over sodium sulfate and concentrated. Purification by column chromatography on silica gel eluting with dichloromethane/methanol (20:1) gave a dark brown solid, which was washed with ethyl acetate and filtered to afford 10.5 g (43.9 mmol, 59%) of the title compound as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH2:12]CCl)=[CH:8][S:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH2:12][O:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cscc1NC(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a solution of 4-(3-chloro-propionylamino)-thiophene-3-carboxylic acid methyl ester ([51486-30-7], 0.1 g, 0.43 mmol) in dimethylformamide (1.5 mL) was added potassium carbonate (0.88 g, 0.64 mmol) and 4-hydroxybiphenyl (0.087 g, 0.514 mmol) and the reaction mixture was then stirred overnight at 90° C. After such time the reaction mixture was allowed to cool to room temperature, water was added (in excess of 5 mL) leading to precipitation. The precipitate was then filtered, washed with water and dried in vacuo to yield the title compound as a white solid (0.16 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][S:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([S:16][CH3:15])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CSc1ccc(N)cc1
Product: CSc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and 4-(methylthio)aniline (3.33 g) was treated in the same manner as described in Preparation Example 37 to give white powder of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)=[O:22]>C(O)C.O.O>[C:1]([O:5][C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:22])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)C=Cc1ccc(C=CC(=O)c2ccc(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
3-(4-formyl-phenyl)-acrylic acid tert-butyl ester (150 mg, 0.64 mmol) and KOH (72 mg, 1.28 mmol)) were dissolved in ethanol/water (1:1, 5 ml) and 3,4-difluoroacetophenone (83.2 μl, 0.64 mmol) was added to the resulting solution. The resulting mixture was stirred at room temperature overnight and then diluted with H2O. The precipitate was filtered and dried under vacuo to give 210 mg of 3-{4-[3-(3,4-difluoro-phenyl)-3-oxo-propenyl]-phenyl}-acrylic acid tert-butyl ester.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:10]([OH:14])=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]=1.Br[CH2:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CN(C)C=O.C(OC(=O)C)C>[NH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:14][CH2:16][C:17]2[S:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH:5]=1
Reactant: Nc1ccc2c(O)cccc2c1
Reactant: BrCc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc2c(OCc3nc4ccccc4s3)cccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.9 %

Procedure:
Sodium hydride (1.05 g) is added to a cooled solution of 2-Amino-5-naphthol (4.18 g) in dimethylformamide (100 mL). Stir at room temperature 15 minutes and cool mixture. 2-Bromomethylbenzothiazole (6.00 g) is added and mixture to allowed to warm slowly and stir for 24 hours. Remove dimethylformamide in vacuo. Redilute with ethylacetate and absorb onto silica gel. Chromatograph (ethyl acetate/hexane) to give a brown solid (1.20 g, 15%) which was used directly in the next step., m.p. 141-143° C. 1H NMR (DMSO-d6, 400 MHz): d 5.43 (br s, 2H), 5.69 (s, 2H), 6.72 (d, 1H), 6.80 (s, 1H), 6.95 (d, 1H), 7.12-7.20 (m, 2H), 7.45 (t, 1H), 7.54 (t, 1H), 7.97 (d, 1H), 8.02 (d, 1H), 8.14 (d, 1H). MS [EI, m/z]: 306 [M]+. Anal. Calcd. for C18H14N2OS: C, 70.56; H, 4.61; N, 9.14. Found: C, 70.38; H, 4.42; N, 9.25.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[CH:42][C:43]([Cl:55])=[C:44]([CH:54]=2)[O:45][CH2:46][CH2:47][CH2:48]OS(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[CH:42][C:43]([Cl:55])=[C:44]([O:45][CH2:46][CH2:47][CH2:48][N:65]3[CH2:70][CH2:69][O:68][CH2:67][CH2:66]3)[CH:54]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(OCCCOS(C)(=O)=O)c2)n1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(OCCCN3CCOCC3)c2)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 34.1 %

Procedure:
A solution of Intermediate 76a (214 mg, 0.27 mmol) and DIPEA (95 μL, 0.54 mmol) in THF (5 mL) was treated with morpholine (47 μL, 0.54 mmol). The mixture was stirred at 50° C. for 18 h in a sealed vial. The volatiles were concentrated in vacuo and the product was purified by MDAP purification (Method 7) to give the title compound (72 mg, 34%). LCMS (Method 5): Rt 3.60 min, m/z 782.6 [MH+].+]. 1H NMR (400 MHz, d6-DMSO): 1.28 (9H, s), 1.57-1.65 (2H, m), 1.68-1.77 (4H, m), 1.80-1.94 (4H, m), 1.99-2.17 (2H, m), 2.24-2.32 (3H, bs), 2.36-2.42 (2H, t, J=6.9), 3.11-3.17 (4H, m), 3.48-3.52 (4H, m), 4.09-4-15 (2H, t, J=6.52 Hz), 4.76-4.84 (1H, m), 5.54 (1H, t, J=4.3 Hz), 6.34 (1H, s), 7.03-7.11 (2H, m), 7.16 (1H, dd, J=2.0, 9.9 Hz), 7.21-7.41 (5H, m), 7.54 (1H, d, J=8.5 Hz), 7.59-7.65 (2H, m), 8.14 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)=[CH:5][CH:4]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:41])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:41])[NH:13]3)=[CH:7][CH:8]=1
Reactant: CC(=O)O
Reactant: COc1ccc(-c2cccc3[nH]ccc23)cc1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Temperature: 27 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To the suspension of 4-(4-methoxy-phenyl)-1H-indole (1.84 g, 8.24 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (99 mL) was added pyridinium tribromide (90% purity from Aldrich, 8.78 g, 24.72 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (40 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (1.66 g, 84%) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:12])[NH:5][CH:6]=[N:7]2.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Cl:1][C:2]1[C:11]([N+:13]([O-:15])=[O:14])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:12])[NH:5][CH:6]=[N:7]2
Reactant: O=c1[nH]cnc2cccc(Cl)c12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1[nH]cnc2ccc([N+](=O)[O-])c(Cl)c12
Reaction time: 1 h

Procedure:
A solution of the above quinazolinone (1.26 g, 7.0 mmol) in conc. H2SO4 (7 mL) was cooled to −20° C., and 90% HNO3 (0.49 g, 7.0 mmol) was added with stirring. Stirring continued for 1 h at −20° C., and 2 h at room temperature. The mixture was poured onto ice, filtered, washed with water and dried to give 5-chloro-6-nitroquinazolin-4-one, along with the 8-nitro isomer in a 4:1 ratio. Three recrystallizations from EtOH gave the product as a 6:1 ratio of isomers (0.85 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[N:27]=[C:26]([CH:35]([CH3:37])[CH3:36])[C:25]=2/[CH:38]=[CH:39]/[CH:40]=[O:41])=[CH:20][CH:19]=1>C1COCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[N:27]=[C:26]([CH:35]([CH3:37])[CH3:36])[C:25]=2/[CH:38]=[CH:39]/[CH:40]([OH:41])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8])=[CH:20][CH:19]=1
Reactant: CC(C)c1nn(-c2cnccn2)c(-c2ccc(F)cc2)c1/C=C/C=O
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)/C=C/c1c(C(C)C)nn(-c2cnccn2)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
To a hexane washed suspension of NaH (0.90 g, 22.5 mmol) in THF (30 ml) at 0° C. under an inert atmosphere, was added a solution of ethyl acetoacetate (2.69 ml, 21.1 mmol) in THF (30 ml). The resulting clear solution was stirred at 0° C. for 15 minutes before n-BuLi (9.6 ml, 21.1 mmol) was added dropwise. The orange solution was stirred at 0° C. for 15 minutes before it was cooled to -78° C. and a solution of the unsaturated aldehyde (4.73 g, 14.1 mmol, Step E) in THF (80 ml) was added dropwise. This was stirred at -78° C. for two hours and then it was quenched by adding~5 ml HOAc and removing the cooling bath. The reaction was partitioned between Et2O and 5% K2CO3 (aq). The organics were dried (MgSO4) and evaporated to give a yellow oil. Elution from a 4-inch silica column gave 3.17 g (48%) of product as a yellow foam.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O1CCO[CH2:19][CH2:18]1>O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:18]([C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1)=[CH2:19]
Reactant: C1COCCO1
Reactant: COC(=O)c1ccc(Br)o1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1ccc(C(=O)OC)o1
Yield: 58 %

Procedure:
A solution of methyl 5-bromo-2-furancarboxylate (2.5 g, 12.19 mmol), potassium carbonate (8.43 g, 61.0 mmol), bis(tri-t-butylphosphine)palladium(0) (0.312 g, 0.61 mmol) and 2,4,6-trivinylcycloboroxane-pyridine complex (1.47 g, 6.10 mmol) in 1,4-dioxane (50 ml) and water (10 ml) was stirred at 80° C. in a sealed tube for 2 h. The reaction contents were partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 5-ethenyl-2-furancarboxylate (1.3 g, 7.09 mmol, 58% yield) as a yellow oil: LCMS (ES) m/z=153 (M+H)+.