Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]([CH2:32][CH2:33][C:34]([F:37])([CH3:36])[CH3:35])[CH2:5][CH:6]([O:28][C:29](=[O:31])[CH3:30])[CH:7]([NH:15][C:16]([C:18]1[CH:27]=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[NH2:2].CO[CH:40](OC)[N:41]([CH3:43])[CH3:42]>C(Cl)Cl.O>[CH3:40][N:41]([CH:43]=[N:2][C:1]([CH:4]([CH2:32][CH2:33][C:34]([F:37])([CH3:36])[CH3:35])[CH2:5][CH:6]([O:28][C:29](=[O:31])[CH3:30])[CH:7]([NH:15][C:16]([C:18]1[CH:27]=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:3])[CH3:42]
Reactant: CC(=O)OC(CC(CCC(C)(C)F)C(N)=O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC(CC(CCC(C)(C)F)C(=O)N=CN(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of acetic acid 3-carbamoyl-6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-heptyl ester (522 mg, 1.03 mmol) in N,N-dimethylformamide dimethyl acetal (2 mL) was heated to 50° C. for two hours, cooled to ambient temperature and diluted with methylene chloride and water. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated to give the title compound as a white foam (580 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].C(N(CC)C(C)C)(C)C.[CH3:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=1[C:32]1[N:33]([CH3:37])[N:34]=[CH:35][CH:36]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:29][C:28]1[CH:30]=[CH:31][C:25]([O:24][CH2:23][CH2:22][O:21][CH3:20])=[C:26]([C:32]2[N:33]([CH3:37])[N:34]=[CH:35][CH:36]=2)[CH:27]=1)=[O:6]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: COCCOc1ccc(N)cc1-c1ccnn1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1ccc(NC(=O)c2cccc(Br)c2)cc1-c1ccnn1C
Yield: 99.5 %

Procedure:
A solution of 3-bromobenzoyl chloride (0.06 mmol), N,N-diisopropylethylamine (14 μL, 0.08 mmol), and 4-(2-methoxyethoxy)-3-(2-methyl-2H-pyrazol-3-yl)aniline (0.05 mmol) in 0.28 mL DMF was agitated on a mechanical shaker for 2 hours. The product was isolated by RP-HPLC and lyophilized to give the title compound (21.4 mg, 96%). LCMS m/z (%)=432.3 (M+H, 81Br 100.0), 430.3 (M+H, 79Br 87.6).
Reaction SMILES: C[C:2]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[CH2:4][CH2:3]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][CH:3]=[CH:2]2
Reactant: COc1ccc2c(c1)C(C)(O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C=CC2
Temperature: 90 °C

Procedure:
Step AA (2): To a solution of crude methyl 6-methoxy-2,3-dihydro-1H-inden-1-ol from Step AA (1) (24.3 g) in benzene (100 mL) was added pTSA (250 mg), and the resulting solution was heated at 90° C. for 3 h with a Dean-Stark trap to remove water. Saturated sodium bicarbonate was added, the aqueous layer was extracted with EtOAc (×3), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product was distilled under vacuum to provide 5-methoxy-1H-indene as a colorless liquid (10 g). 1H NMR (400 MHz, CDCl3): 7.33 (1H, d), 6.96 (1H, d), 6.81 (1H, m), 6.75 (1H, m), 6.56 (1H, m), 3.82 (3H, s), 3.33 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([O:35][CH3:36])[C:33]=1[CH3:34])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:12][C:11]=1[NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:7].Br[CH2:38][C:39]([O:41]C)=[O:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([O:35][CH3:36])[C:33]=1[CH3:34])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:12][C:11]=1[N:22]([CH2:38][C:39]([OH:41])=[O:40])[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:7]
Reactant: COC(=O)CBr
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCc2ccccc2)cc(OC)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N(CCc2ccccc2)CC(=O)O)cc(OC)c1C
Temperature: 80 °C
Reaction time: 4 h
Yield: 61.9 %

Procedure:
A solution of compound 9a (45 mg, 0.092 mmol), methyl bromoacetate (0.053 mL, 0.56 mmol), and potassium carbonate (38 mg, 0.27 mmol) in DMF (1 mL) was sealed in a pressure tube and heated at 80° C. overnight and at rt for two days. Additional methyl bromoacetate (0.060 mL) and potassium carbonate (42 mg) was added and the reaction was heated at 100° C. for 5 h. The reaction mixture was filtered and concentrated on a rotary evaporator. The residue was purified by preparative tlc. This compound was dissolved in a mixture of THF (1 mL) containing several drops of MeOH and 10% LiOH (1 mL). The reaction mixture was stirred at rt for 4 h, neutralized, and concentrated on a rotary evaporator. The residue was dissolved in ethyl acetate, washed with water, dried, and concentrated to give compound 22a (31 mg, 62%). ESI-MS m/e 545.4 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(=O)([O-])O.[Na+]>CN(C=O)C>[Si:16]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 133.1 %

Procedure:
5-Hydroxyindole (209 mg, 1.57 mmol) was dissolved in DMF (6 mL), and the solution was added with imidazole (132 mg, 1.93 mmol) and tert-butyldimethylsilyl chloride (333 mg, 2.21 mmol) at 0° C. followed by stirring at room temperature for 3.5 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution at 0° C. and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 5-(tert-butyldimethylsilyloxy)indole (517 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[C@H:26]([CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[CH:3][C:4]=3[CH3:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3C)CC2)c(C)c1
Yield: 9.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (822 mg) described in Preparation Example 67 and (R)-4-methyloxazolidin-2-one (364 mg) described in Preparation Example 25, the title compound (82 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC#N>[CH2:18]([O:10][C:9]1[C:2]([F:1])=[CH:3][C:4]([CH:5]=[O:6])=[CH:7][C:8]=1[F:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
3,5-Difluoro-4-hydroxy-benzaldehyde obtained in Step A was dissolved in CH3CN (15 mL), and Cs2CO3(6.3 g, 19.23 mmol) was added to the solution. The mixture was cooled to 0˜5° C. Benzylbromide (1.1 mL, 9.23 mmol) was added slowly thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was filtered and then concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex=1/7) to obtain the title compound (1.76 g, 92%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:26][N:27]=[C:28]=[O:29]>C1COCC1.CN(C=O)C>[CH3:26][NH:27][C:28](=[O:29])[O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CN=C=O
Reactant: O=C(Nc1ccc(-c2ccc(CO)cc2)cc1)[C@H]1CN2CCC1CC2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)OCc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
35 mg (0.10 mmol) of (3R)-N-[4′-(hydroxymethyl)-1,1′-biphenyl-4-yl]-1-azabicyclo-[2.2.2]octane-3-carboxamide are dissolved in 1 ml of a 1:1 THF/DMF mixture. 12 mg (0.21 mmol) of methyl isocyanate are added, and the mixture is stirred at 60° C. overnight. The solvent is removed under reduced pressure, and the crude product is purified by preparative HPLC. 20 mg (49% of theory) of the title compound are obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([S:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>O1CCCC1>[C:7]1([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:22][CH:23]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)c1ccc(CSc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(CSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
To a suspension of lithium aluminum hydride (1.95 g, 51.3 mmol) in tetrahydrofuran (50 mL) was added dropwise a tetrahydrofuran solution of 4-phenylsulfanylmethyl-benzoic acid (5 g, 20.5 mmol) described in Manufacturing Example 206-1-1, which was stirred for 30 minutes at room temperature. This mixture was cooled with ice water, and water was carefully added. The mixture was filtered through a Celite bed, and the filtrate was combined. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (2.01 g). The title compound was used in the following reaction without any further purification.
Reaction SMILES: CS(C)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14][C@@H:13]1[CH2:26][OH:27])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>>[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:15][CH2:14][C@@H:13]1[CH:26]=[O:27])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)CC[C@@H]1CO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)CC[C@@H]1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add sulfur trioxide pyridine complex (0.27 g, 1.7 mmol) in dimethylsulfoxide (0.95 mL, 13.0 mmol) to (2R, 5R)-5-Benzyloxy-2-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.27 g, 0.84 mmol) in triethylamine (0.70 mL, 5.0 mmol) at 10° C. and stir at room temperature for 30 minutes. Quench with water and extract with diethyl ether. Combine the organic layers, wash with 5% aqueous citric acid followed by saturated aqueous sodium chloride, dry over magnesium sulfate and concentrate. The residue may be used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[Na].Br[CH2:10][CH2:11][CH2:12][Cl:13]>C1(C)C(C)=CC=CC=1>[Cl:13][CH2:12][CH2:11][CH2:10][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7]
Reactant: ClCCCBr
Reactant: O=C1CCCCN1
Agent: [Na]
Solvent: Cc1ccccc1C
Product: O=C1CCCCN1CCCCl
Reaction time: 6 h

Procedure:
A mixture of 2-piperidone (1.19 g, 12.0 mmcl) and fnely pulverized sodium metal (0.28 g, 12.0 mmol) in dry xylene (70 ml) was heated at 110° C. with vigrous stirring, 1-bromo-3-chloropropane (1.89 g, 12.0 mmol) was added to the stirred reaction mixture after 3 hours and the heating at 110° C. was continued for 6 hours. The reaction mixture was filtered and xylene was removed under reduced pressure. The residue was chromatographed on silica gel usinq hexane and chloroform as eluant to get 3 (n=2), B.P. 91° C./0.01 mm., yield 1.33 g (63.33%). IR (Neat): 3862, 3298, 2950, 2474, 2324, 1640, 1478, 1432, 1336, 1184, 1096, 754. 1H NMR (CDCl3): 1.79-2.36(m, 8H), 3.15-3.67(m,6H). MS: m/z 175 (M+).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][C:18](=O)[CH:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=1>C(O)(=O)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:1]([C:3]3[CH:8]=[N:7][CH:6]=[CH:5][N:4]=3)[N:2]=[C:18]([CH:19]([CH3:21])[CH3:20])[CH:17]=2)=[CH:12][CH:11]=1
Reactant: CC(C)C(=O)CC(=O)c1ccc(F)cc1
Reactant: NNc1cnccn1
Solvent: CC(=O)O
Product: CC(C)c1cc(-c2ccc(F)cc2)n(-c2cnccn2)n1
Yield: 62.1 %

Procedure:
The hydrazino pyrazine (20.20 g, 183 mmol, prepared as in J. Orq. Chem., 27, 3243 (1962)) was added in portions to the 1,3-diketone (34.7 g, 167 mmol, prepared in Example 1, Step A) in glacial acetic acid (400 mL). The reaction was refluxed for 2 hours, concentrated, and partitioned between EtOAc and K2CO3 (aq). The organics were dried (MgSO4) and evaporated to give a brown solid. Recrystallization from hexanes afforded 29.27 g (62%) of a cream colored solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:27]=[C:26]([S:28][CH3:29])[CH:25]=[CH:24][C:4]=2[S:5][C:6]=1[C:7]([NH:9][CH:10]=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8].[OH:30]O>C(O)(=O)C>[OH:1][C:2]1[C:3]2[CH:27]=[C:26]([S:28]([CH3:29])=[O:30])[CH:25]=[CH:24][C:4]=2[S:5][C:6]=1[C:7]([NH:9][CH:10]=[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:8]
Reactant: CSc1ccc2sc(C(=O)NC=C(c3ccccc3)c3ccccc3)c(O)c2c1
Reactant: OO
Solvent: CC(=O)O
Product: CS(=O)c1ccc2sc(C(=O)NC=C(c3ccccc3)c3ccccc3)c(O)c2c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A mixture of 3-hydroxy-5-methylthio-N-(2,2-diphenylethenyl)-benzo[b]thiophene-2-carboxamide (0.42 g, 0.0010 moles) and 30% H2O2 (0.80 ml) in acetic acid (10 ml) was stirred at 75° for 30 minutes. The reaction was cooled to 0° and the yellow precipitate was filtered, acetic acid washed and dried under vacuum, to afford 0.38 g (88%) of 3-hydroxy-N-(2,2-diphenyl)ethenyl-5-methylsulfinylbenzo[b]thiophene-2-carboxamide. MS gave Mol ion at 433.
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:18][C:9]3=[N:10][CH:11]=[C:12]([C:14]([O:16]C)=[O:15])[CH:13]=[C:8]3[CH2:7]2)[C:5](=[O:19])[NH:4][C:3]1=[O:20].[OH-].[Li+].Cl>C1COCC1.O>[CH3:1][N:2]1[C:6]2([CH2:18][C:9]3=[N:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=[C:8]3[CH2:7]2)[C:5](=[O:19])[NH:4][C:3]1=[O:20]
Reactant: COC(=O)c1cnc2c(c1)CC1(C2)C(=O)NC(=O)N1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)NC(=O)C12Cc1cc(C(=O)O)cnc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3′-methyl-2′,5′-dioxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-imidazolidine]-3-carboxylate (25 mg, 0.091 mmol) in THF (0.5 mL) and H2O (0.3 mL) was added 1 N aqueous lithium hydroxide (0.27 mL, 0.27 mmol). The reaction was stirred at ambient temperature for 1 h, acidified by addition of 1 N hydrochloric acid, and concentrated in vacuo to provide the title compound. MS: m/z=262.1 (M+1). 1H NMR (500 MHz, CDCl3) δ 8.99 (s, 1H), 8.31 (s, 1H), 3.55 (m, 2H), 3.44 (d, 1H, J=18.3 Hz), 3.42 (d, 1H, J=17.6 Hz), 2.72 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([Cl:19])[C:13]([CH2:17]Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([Cl:19])[C:13]([CH2:17][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CBr)ccc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CN3C(=O)c4ccccc4C3=O)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A mixture of 316 (16.1 g, 0.0467 mol) and potassium phthalimide (26.1 g, 0.141 mol) in anhydrous DMF (150 mL) was stirred at 80° C. overnight. The cooled reaction mixture was diluted with EtOAc and the organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (5 to 20% EtOAc) to afford 10.8 g (56%) of tert-butyl-4-chloro-5-((1,3-dioxoisoindolin-2-yl)methyl)-1H-indole-1-carboxylate (318) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.2 Hz, 1H), 7.88-7.86 (m, 2H), 7.74-7.72 (m, 2H), 7.62 (d, J=3.7 Hz, 1H), 7.27-7.25 (m, 2H), 5.12 (s, 2H), 1.65 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[C:4]([CH3:18])[CH:3]=1.CCN(C(C)C)C(C)C.Cl.[CH2:29]([O:31][NH2:32])[CH3:30]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:32][O:31][CH2:29][CH3:30])=[O:13])=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(Br)ccc1Nc1cnccc1C(=O)O
Reactant: CCON
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCONC(=O)c1ccncc1Nc1ccc(Br)cc1C
Reaction time: 2 h
Yield: 77 %

Procedure:
3-[(4-Bromo-2-methylphenyl)amino]isonicotinic acid 2b (320 mg, 1.04 mmol) was dissolved in 15 ml dry DMF followed by the addition of DIPEA (2.08 mmol, 373 μl), ByBOP (1.25 mmol, 651 mg) and O-ethylhydroxylamine hydrochloride (2.08 mmol, 203 mg). The mixture was stirred for 2 h and the volatiles were removed in vacuo. The crude material was purified by flash chromatography using silica gel and a gradient of 0-5% methanol in DCM as eluent to give 280 mg (800 μmol; 77% yield) of pure desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([F:46])([F:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:34]([C:47]([F:50])([F:49])[F:48])[CH:33]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CC(=O)OCC>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][C:39]([F:45])([F:46])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:34]([C:47]([F:48])([F:49])[F:50])[CH:33]=3)=[O:28])=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[CH3:2]
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Reactant: CCOC(=O)C(F)(F)Cc1ccc(N)cc1C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)Cc1ccc(NC(=O)Cc2ccc(-c3cnc(OCc4ccc(OC)cc4)c(OCC)c3)cc2F)cc1C(F)(F)F
Temperature: 20 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
To a mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (150 mg, 0.365 mmol) in pyridine (2 mL) were added ethyl 3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-difluoropropanoate (108 mg, 0.365 mmol) and T3P® (EA solvate) (464 mg, 0.729 mmol). The mixture was stirred at 20° C. for 1 h. LCMS and TLC (PE/EA=1:1, Rf=0.5) showed the reaction was finished. The mixture was concentrated and then purified by TLC (PE/EA=1:1, Rf=0.5) to give ethyl 3-(4-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-difluoropropanoate (120 mg, 0.150 mmol, 41.2% yield): 1H NMR (400 MHz, CD3OD-d4) δ 8.08-8.02 (m, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.78 (s, 1H), 7.54-7.33 (m, 7H), 6.90 (d, J=8.8 Hz, 2H), 5.35 (s, 2H), 4.26 (q, J=7.3 Hz, 2H), 4.13 (q, J=7.1 Hz, 2H), 3.81 (s, 2H), 3.78 (s, 3H), 3.63-3.52 (m, 2H), 1.41 (t, J=7.1 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H); ES-LCMS m/z 691 (M+H).
Reaction SMILES: Cl.[N+:2]([C:5]1[C:6]([CH2:19][O:20][CH3:21])=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]1[NH:15][C:16](=[O:18])[CH2:17][N:9]1[CH2:8]2)([O-])=O.Cl.[H][H]>C(O)C.[Pd]>[NH2:2][C:5]1[C:6]([CH2:19][O:20][CH3:21])=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]1[NH:15][C:16](=[O:18])[CH2:17][N:9]1[CH2:8]2
Reactant: COCc1c([N+](=O)[O-])ccc2c1CN1CC(=O)NC1=N2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COCc1c(N)ccc2c1CN1CC(=O)NC1=N2

Procedure:
To a suspension of 9.18 g. (3.4 × 10-2 mole) of 7-Nitro-6-methoxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one hydrochloride in 95% ethanol (300 ml.) is added 10 ml. of concentrated hydrochloric acid and 0.45 g. of 10% Pd/C catalyst. The mixture is placed on a Paar hydrogenator, shaken until theoretical hydrogen is absorbed, removed and water (150 ml.) added to effect dissolution of the precipitate. The mixture is filtered under suction, the catalyst washed with 95% ethanol and the mixture evaporated to dryness yielding the title product as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[CH3:11][C:10]([NH:9][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:12]
Reactant: COc1ccccc1N
Reactant: CC(=O)OC(C)=O
Product: COc1ccccc1NC(C)=O
Temperature: 45 °C

Procedure:
To 100 ml of acetic anhydride was added dropwise with stirring 100 g (0.813 mole) of o-anisidine, the temperature rising to about 60° C. during addition. The reaction mixture was heated on a steam bath for 15 minutes, allowed to cool to 45° C. and was poured onto 500 g of crushed ice. The white solid that precipitated was collected, washed free of acid with water and air dried to give 100 g, m.p. 84°-86° C., of product.
Reaction SMILES: [CH2:1]([N:13]=[C:14]=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:16]([OH:19])[CH2:17][OH:18]>O1CCCC1>[CH2:1]([NH:13][C:14](=[O:15])[O:18][CH2:17][CH2:16][OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN=C=O
Reactant: OCCO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)OCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.2 ml dodecyl isocyanate and 2.4 ml of ethylene glycol are combined in tetrahydrofuran at room temperature and stirred overnight at room temperature. The resultant material is evaporated under reduced pressure (<30° C.), dried in vacuo, and purified by chromatography on a silica gel column using ethyl acetate as elutant. Fractions 74-94 are combined (Rf 0.75 TLC Silica gel ethyl acetate iodine detection), evaporated under reduced pressure (<30° C.) and dried in vacuo to yield 546 mg of title product.