Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([OH:48])=[C:43]([O:49][CH3:50])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1>C(O)=O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([OH:48])=[C:43]([O:49][CH3:50])[CH:42]=3)[C:19](=[O:20])[N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1
Reactant: COc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc(C)c1O
Solvent: O=CO
Product: COc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCNCC3)CC2)cc(C)c1O

Procedure:
A solution of 220 mg (0.29 mmol) (R)-2-[4-(1-tert-butoxycarbonyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3-methoxy-5-methyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 10.4) in 3 mL formic acid was stirred for 4 h at RT and then concentrated by evaporation i.vac. at 40° C. The crude product was purified by preparative HPLC-MS.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[S:40]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41]1>O1CCCC1.O>[F:3][C:4]1[C:9]([C:10]2[N:14]([S:45]([C:42]3[CH:43]=[CH:44][S:40][CH:41]=3)(=[O:47])=[O:46])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH:11]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccsc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To a suspension of sodium hydride (97.9 mg, 60% in oil) in tetrahydrofuran (10 mL) were added a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (311 mg) in tetrahydrofuran (3 mL), 15-crown-5 (449 mg), and thiophene-3-sulfonyl chloride (280 mg) under ice-cooling. The mixture was stirred at room temperature for 30 min, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:1) to give the title compound as a pale-yellow oil (yield 433 mg, 94%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH2:16][C:17]#[C:18][CH3:19])[N:3]=[CH:4][N:5]=1
Reactant: CC#CCO
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 280 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 96 mg of 2-butyn-1-ol, to which 55 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 212 mg of 4-(2,3-difluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (83)).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][C:34]=1[OH:35])[C:9]([NH:11][NH:12][C:13]([C:15]1[O:16][CH:17]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:14])=[O:10].C(N(C(C)C)C(C)C)C>O1CCOCC1>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][C:34]=1[OH:35])[C:9]([NH:11][NH:12][C:13]([C:15]1[O:16][CH:17]=[C:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:14])=[O:10])(=[O:3])[CH3:2]
Reactant: Nc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O
Reactant: CC(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 216 h

Procedure:
Acetyl chloride (0.17 ml) was added to a mixture of the compound of Example 42 (0.83 g), ethyldiisopropylamine (1.05 ml) and dioxane (10 ml) at 0° C., allowed to be warmed to 25° C. and stirred for 9 days. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate and washed with 1 M hydrochloric acid and saturated brine. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) and recrystallized from ethyl acetate/hexane, thereby giving 0.25 g of the desired compound. Melting point: 233-235° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6](N)[CH:5]=1.[N-]=[N+]=[N-].[Na+].[OH2:22]>Cl.CO.CCOCC>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([OH:22])[CH:5]=1
Reactant: O
Reactant: COC(=O)c1cc(N)cc(N2CCCC2=O)c1
Agent: Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Temperature: 90 °C
Yield: 67 %

Procedure:
3-Amino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D4a) (1.50 g, 6.4 mmol, 1 equiv) was dissolved in a mixture of 2N aqueous HCl solution (25 ml) and MeOH (50 ml) at 0° C. and treated portionwise with NaN3 (950 mg, 13.8 mmol, 2.2 equiv) over 20 min. H2O (50 ml) was added and the resulting mixture was heated at 90° C. for 45 min then cooled to room temperature and diluted with Et2O (300 ml). The two layers were separated and the organic phase was dried over MgSO4 and concentrated in vacuo to give 3-hydroxy-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D37) (1.0 g, 67%) as a tan solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[C:9](=[CH:11][S:12][CH:13]=2)[N:10]=1.C(N(CC)CC)C>C(O)C>[Cl:4][C:5]1[N:6]=[C:7]([N:2]([CH3:3])[CH3:1])[C:8]2[C:9](=[CH:11][S:12][CH:13]=2)[N:10]=1
Reactant: CNC
Reactant: Clc1nc(Cl)c2cscc2n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)c1nc(Cl)nc2cscc12
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of 50% aqueous dimethyl amine (0.13 g) in ethanol (5 mL) were added 2,4-dichlorothieno[3,4-d]pyrimidine (0.20 g) and triethylamine (0.10 g) at room temperature, and the mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure and diluted with chloroform and water, and then the aqueous layer was extracted with chloroform. The organic layer was washed with 1 M hydrochloric acid and saturated brine, then the organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was crystallized with diethyl ether to obtain 2-chloro-N,N-dimethylthieno[3,4-d]pyrimidin-4-amine (0.16 g). (2) To a mixture of 2-chloro-N,N-dimethylthieno[3,4-d]pyrimidin-4-amine (0.156 g), Pd2(dba)3 (0.033 g), (±)-BINAP (0.068 g), 1-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.27 g), and 1,4-dioxane (8 mL) was added sodium t-butoxide (0.21 g) under nitrogen atmosphere, and the mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with ethyl acetate and water, the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, ethyl acetate) to obtain light yellow amorphous 1-((3R,4R)-3-(4-dimethylaminothieno[3,4-d]pyrimidin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.037 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:29]1[CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27][CH2:28]1)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1CCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)CC1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 4-methylpiperidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.90 minutes; C22H22Cl2N4O2 (445.35); mass spectrum: (M+H)+=445.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:18](=[O:20])[NH:17][CH:16]=[N:15][C:14]=2[N:13]([CH3:21])[C:12](=[O:22])[CH:11]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:33]=1[N+:41]([O-:43])=[O:42]>CN(C=O)C>[N+:38]([C:35]1[CH:34]=[C:33]([N+:41]([O-:43])=[O:42])[CH:32]=[CH:37][C:36]=1[N:17]1[C:18](=[O:20])[C:19]2[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[CH:11][C:12](=[O:22])[N:13]([CH3:21])[C:14]=2[N:15]=[CH:16]1)([O-:40])=[O:39]
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)[nH]cnc21
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(-c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])cnc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 5F (41 mg, 0.1 mmol, 1 eq) and catalytic amount of potassium iodide in DMF (1 mL) was added potassium carbonate (21 mg, 0.15 mmol, 1.5 eq). The reaction mixture was stirred at ambient temperature for 5 minutes. 1-Chloro-2,4-dinitrobenzene (22 mg, 0.11 mmol, 1.1 eq) was then added and the reaction mixture was irradiated with microwave at 80° C. for 30 minutes and then at 100° C. for 30 minutes. The reaction mixture was filtered and the filtrate was purified by preparatory LC/MS (50-75% CH3CN in H2O) to give 3-(2,4-dinitrophenyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione compound 24A as a yellow solid (18 mg, 31% yield). 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3H) 6.09 (s, 1H) 7.17-7.24 (m, 1H) 7.52 (d, J=8.34 Hz, 2H) 7.72-7.80 (m, 1H) 8.23 (s, 1H) 8.75 (dd, J=8.46, 2.65 Hz, 1H) 9.12 (d, J=2.53 Hz, 1H) 9.83 (s, 1H). [M+H] calc'd for C20H12FIN6O6, 579. found, 579.
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][CH2:8][N:9]([CH2:11][CH2:12][CH:13]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:10])(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH:15]1[C:14]2[CH:13]([CH2:12][CH2:11][N:9]([CH3:10])[CH2:8][CH2:7][C:6]([OH:26])=[O:5])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: CN(CCC(=O)OC(C)(C)C)CCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCC(=O)O)CCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 119 %

Procedure:
A solution of 3-{[2-(9H-fluoren-9-yl)-ethyl]-methyl-amino}-propionic acid tert-butyl ester (11.4 g) in 20 ml dichloromethane is cooled to 0°. Trifluoroacetic acid (20 ml) is added and the solution stirred at room temperature over night. To this mixture a 1 M aq. NaHCO3 solution (262 ml) is added dropwise under vigorous stirring. The phases are separated, the water phase acidified with 14 ml 2N HCl and extracted several times with dichloromethane. The combined extracts are dried over sodium sulfate, filtered and evaporated to afford 11.4 g (100%) of a light brown foam which is used without purification. TLC (silicagel, dichloromethane/methanol 85:15): rf 0.3.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[S:11]([CH2:21][N+:22]#[C-:23])([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[C-]#N.[Na+]>>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C@H:1]1[O:10][CH:23]=[N:22][C@@H:21]1[S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: COc1ccccc1C=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [C-]#N
Agent: [Na+]
Product: COc1ccccc1[C@H]1OC=N[C@@H]1S(=O)(=O)c1ccc(C)cc1

Procedure:
In a manner analogous to Preparation 1, 0-anisaldehyde (053 mL, 5.25 mmol), tosylmethylisocyanide (0.98 g, 5.0 mmol) and NaCN (24.5 mg, 0.50 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 332.0 (M+H+).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH2:5]([N:8]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[N:10]([C:16]2[C:17]([Cl:34])=[CH:18][C:19]([F:33])=[C:20]([N:22]3[C:31](=[O:32])[C:26]4[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=4[C:23]3=[O:24])[CH:21]=2)[C:9]1=[O:35])[CH:6]=[CH2:7].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([N:12]1[C:13](=[O:14])[N:8]([CH2:5][C:6]#[CH:7])[C:9](=[O:35])[N:10]([C:16]2[C:17]([Cl:34])=[CH:18][C:19]([F:33])=[C:20]([N:22]3[C:31](=[O:32])[C:26]4[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=4[C:23]3=[O:24])[CH:21]=2)[C:11]1=[O:15])[CH:2]=[CH2:3]
Reactant: C#CCBr
Reactant: C=CCn1c(=O)[nH]c(=O)n(-c2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCn1c(=O)n(CC=C)c(=O)n(-c2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)c1=O
Reaction time: 7 h
Yield: 55.2 %

Procedure:
Propargyl bromide (0.37 mL, 3.36 mmol) is added to a mixture of N-[5-(3-allylhexahydro-2,4,6-trioxo-s-triazin-1-yl)-4-chloro-2-fluorophenyl]-1-cyclohexene-1,2-dicarboximide (1.00 g, 2.24 mmol), and potassium carbonate (0.62 g, 4.48 mmol) in N,N-dimethylformamide. The reaction mixture is stirred for 7 hours, and poured into ethyl acetate. The organic solution is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a yellow oil. Flash column chromatography of the oil using silica gel and an ethyl acetate/hexanes (1:4) solution gives the title product as a white solid (0.60 g, mp 107°-114° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12](I)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.C(OC([N:28]1[C:32](B(O)O)=[CH:31][C:30]([CH3:36])=[N:29]1)=O)(C)(C)C>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:32]4[NH:28][N:29]=[C:30]([CH3:36])[CH:31]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: NC(=O)c1nc2n(c1I)CCOc1cc(F)c(Br)cc1-2
Reactant: Cc1cc(B(O)O)n(C(=O)OC(C)(C)C)n1
Product: Cc1cc(-c2c(C(N)=O)nc3n2CCOc2cc(F)c(Br)cc2-3)[nH]n1

Procedure:
10-bromo-9-fluoro-3-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2-tert-butoxycarbonyl-5-methyl-pyrazol-3-yl)boronic acid similarly to as described in Example 4 to produce crude 10-bromo-9-fluoro-3-(3-methyl-1H-pyrazol-5-yl)-5,6dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide. 10-bromo-9-fluoro-3-(3-methyl-1H-pyrazol-5-yl)-5,6dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol via General Procedure E to afford 5.8 mg (6.6%) 9-fluoro-10-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]-3-(3-methyl-1H-pyrazol-5-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase purification. M+1=478.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12]O>Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(Br)cc1C
Yield: 100 %

Procedure:
A solution of 4-bromo-2-methyl benzoic acid (1.0 g, 4.7 mmol) in methanol (24 mL) was treated with 20 drops of HCl, heated at reflux for 6 hours, and concentrated to provide the desired product (1.07 g, 100%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N+:10]([O-:13])=[C:9]([CH3:14])[C:8]=1[CH3:15].Cl[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>O1CCCC1>[CH3:14][C:9]1[C:8]([CH3:15])=[C:7]([O:6][CH2:5][CH2:4][O:3][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=[CH:11][N+:10]=1[O-:13]
Reactant: ClCc1ccccn1
Reactant: Cc1c(OCCO)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(OCCOCc2ccccn2)cc[n+]([O-])c1C
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
0.39 g of 60% sodium hydride was added to a suspension of 1.20 g (6.5 mmol) of 4-(2-hydroxyethoxy)-2,3-dimethylpyridine N-oxide in 40 ml of tetrahydrofuran under cooling with ice in a nitrogen atmosphere to obtain a mixture. This mixture was stirred for 0.5 hour, followed by the addition of 0.83 g (6.5 mmol) of 2-chloromethylpyridine. The obtained mixture was heated under reflux for 8 hours, cooled and filtered. The filtrate was concentrated and purified by silica gel column chromatography (solvent:ethyl acetate/n-hexane=4:1~CHCl3 /MeOH=19:1) to obtain 0.61 g of 2,3-dimethyl-4-(2-pyridylmethoxyethoxy)pyridine N-oxide.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:3][CH:4]=2)[C:8](=[O:12])[CH:7]=1
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1C=C(Br)c2ccccc21

Procedure:
5-methoxyindanone of formula 20 is dissolved in CCl4, N-bromosuccinimide (2 to 2.2 eq) and 2,2′-azobisisobutyronitrile (0.2 to 0.3 eq) are added thereto. The resulting mixture is further irradiated by a tungsten lamp (375W) for 3 to 5 h with stirring, to obtain the 3-bromoindenone of formula 21.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([O:15][C:16]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[S:18][CH:17]=3)[CH:12]=[C:11]([O:25][C:26]3C=C(C(F)(F)F)SC=3)[N:10]=2)=[CH:5][CH:4]=1.O(C)[Na].CO.Cl>CN(C)C=O>[CH3:26][O:25][C:11]1[CH:12]=[C:13]([O:15][C:16]2[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[S:18][CH:17]=2)[N:14]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:35])([F:1])[F:36])=[CH:8][CH:7]=2)[N:10]=1
Reactant: FC(F)(F)c1ccc(-c2nc(Oc3csc(C(F)(F)F)c3)cc(Oc3csc(C(F)(F)F)c3)n2)cc1
Agent: CO[Na]
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(Oc2csc(C(F)(F)F)c2)nc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 60 °C
Yield: 51 %

Procedure:
A solution of 2-(α,α,α-trifluoro-p-tolyl)-4,6-di{[5-(trifluoromethyl)-3-thienyl]oxy}pyrimidine (1.50 g, 2.70 mnol) in dimethylformamide is treated with 25% NaOCH3 in methanol (0.58 g, 2.70 mmol), heated to 60° C. for 1.5 hours, cooled to room temperature, poured onto water and acidified to pH 5 with 6N HCl. The resultant reaction mixture is extracted with ether. The ether extracts are combined, washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to give a solid residue. The residue is chromatographed (silica gel, ethyl acetate/hexanes, 3/97) to afford the title product as a white solid, 0.58 g (51% yield), mp 91-93° C., identified by 1HNMR, 13CNMR, 19FNMR, mass spectral and elemental analyses.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[C:11]([C:16]3[CH:17]=[C:18]([CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=O)[CH:19]=[CH:20][CH:21]=3)[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1>C1COCC1>[NH:7]1[C:15]2[C:10](=[C:11]([C:16]3[CH:17]=[C:18]([CH2:22][CH2:23][N:25]([CH3:26])[CH3:27])[CH:19]=[CH:20][CH:21]=3)[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: CN(C)C(=O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 134.5 %

Procedure:
To a suspension of LAH (276 mg, 7.2 mmol) in THF (20 mL) under nitrogen at rt was added dropwise a solution of 2-[3-(1H-indol-4-yl)-phenyl]-N,N-dimethyl-acetamide (500 mg, 1.8 mmol) in THF (10 mL). After stirring at rt for 6 hours, the reaction was quenched with water (0.6 mL) dropwise. The precipitate was filtered off, washed with ethyl acetate (3×), the filtrate was concentrated t give 640 mg of {2-[3-(1H-indol-4-yl)-phenyl)-ethyl}-dimethyl-amine.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][CH2:10][CH:11]([CH2:13][OH:14])[O:12][C:7]=2[C:6]=1[CH3:17])=[O:4].O.[OH-].[Ba+2].[OH-]>CO>[OH:14][CH2:13][CH:11]1[CH2:10][O:9][C:8]2[CH:15]=[CH:16][C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:17])[C:7]=2[O:12]1
Reactant: COC(=O)c1ccc2c(c1C)OC(CO)CO2
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)ccc2c1OC(CO)CO2
Yield: 79.9 %

Procedure:
To a round bottom flask equipped with magnetic stirring was added 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester (6.40 g, 26.9 mmol), barium hydroxide monohydrate (25.44 g, 134.3 mmol), and methanol (108 mL). This mixture was stirred at room temperature for 24 hours. The methanol was evaporated. The resulting slurry was taken up in water and washed once with ether. The aqueous layer was acidified by pouring into iced concentrated HCl. This was extracted twice with ethyl acetate. The ethyl acetate extracts were combined, dried over magnesium sulfate, filtered and evaporated to give a yellow solid, 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid, (4.82 g, 21.5 mmol) in 80% yield. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 2.45 (s, 3H), 3.85 (m, 2H), 4.12 (m, 1H), 4.24 (m, 1H), 4.41 (m, 1H), 6.76 (d, 1H), 7.51 (d, 1H); TLC: Rf=0.32 (1:1 ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[C:14]([CH:18]=C)[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:20])[C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].CSC.C[OH:25]>ClCCl>[NH2:20][C:9]1[C:8]2[N:7]=[CH:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:17]=2[C:16]2[CH:15]=[C:14]([CH:18]=[O:25])[CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: C=Cc1ccc2nc(N)c3ncn(CC(C)C)c3c2c1
Reactant: CO
Solvent: CSC
Solvent: ClCCl
Product: CC(C)Cn1cnc2c(N)nc3ccc(C=O)cc3c21
Temperature: 25 °C

Procedure:
A solution of 1-isobutyl-8-vinyl-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.9 mmol) in dichloromethane (30 mL) and methanol (5 mL) was cooled to −78° C. Ozone was bubbled through the solution for 10 minutes. While still cold, the reaction was purged with oxygen for 15 minutes and dimethyl sulfide (0.7 mL, 9.4 mmol) was added. The reaction was warmed to ambient temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and washed with 1% aqueous sodium carbonate (2×15 mL). The combined aqueous fractions were extracted with chloroform (3×20 mL) and sequentially dried (MgSO4), filtered, and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a gradient of 0-6% methanol in dichloromethane) to provide 237 mg of 4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline-8-carbaldehyde as an off-white solid. MS (ESI) m/z 269 (M+H)+.