Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([CH2:43][B-](F)(F)F)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].[K+]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:43][N:40]5[CH2:41][CH2:42][N:37]([C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])[CH2:38][CH2:39]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCN(C[B-](F)(F)F)CC1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Agent: [K+]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCN(C(=O)OC(C)(C)C)CC3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and potassium (4-tert-butoxycarbonyl-piperazin-1-yl)methyltrifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 1): tR=1.26 min; Mass spectrum (ESI+): m/z=591 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:11](Cl)=[N:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])#[N:2].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[C:16]#[CH:17].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:11]2[CH:17]=[C:16]([C:15]([O:19][CH2:20][CH3:21])=[O:18])[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])#[N:2]
Reactant: COc1ccc(C(Cl)=NO)cc1C#N
Reactant: C#CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(OC)c(C#N)c2)no1
Temperature: 40 °C

Procedure:
3-Cyano-N-hydroxy-4-methoxybenzenecaboximidoyl chloride, ethyl propiolate and triethylamine were dissolved in a THF solution, followed by stirring at 40° C. to obtain ethyl 3-(3-cyano-4-methoxyphenyl)-5-isoxazolecarboxylate. AP: 295.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18](Cl)(=[O:21])[CH2:19][CH3:20]>>[C:18]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:21])[CH2:19][CH3:20]
Reactant: CCC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 103.6 %

Procedure:
Beginning with 2.0 gm (8.7 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.91 mL (10.4 mMol) propionyl chloride, 2.58 gm of the title compound were prepared as a crude brown foam essentially by the procedure described in Example 4. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing 10% methanol and 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure. This residue was crystallized from ethanol:water to provide 1.74 gm (70%) of the title compound in two crops.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4](Cl)=[C:5]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][N:9]([CH3:18])[CH2:8][CH2:7][C:6]=12>[Pd].C(O)(=O)C>[Cl:1][C:2]1[S:3][CH:4]=[C:5]2[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][N:9]([CH3:18])[CH2:8][CH2:7][C:6]=12
Reactant: CN1CCc2c(Cl)sc(Cl)c2C(c2ccccc2)C1
Agent: [Pd]
Solvent: CC(=O)O
Product: CN1CCc2c(csc2Cl)C(c2ccccc2)C1
Reaction time: 24 h

Procedure:
A mixture of 1,3-dichloro-6-methyl-4-phenyl-5,6,7,8-tetrahydro-4H-thieno[3,4-d]azepine (73 mg) and 10% palladium on carbon (20 mg) in acetic acid (2 ml) was hydrogenated for 24 hours at 60 p.s.i. The mixture was filtered and the filtrate evaporated to a yellow oil. Chromatography on silica (1% methanol-ammonia in dichloromethane) gave the title product as an oil.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[F:20].COCCOC.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:36].[Na+]>O>[F:20][C:13]1[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=1[C:3]1[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]=1[I:36]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(N)c1
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(I)c1
Reaction time: 0.33 h
Yield: 58 %

Procedure:
To a stirred solution of T10.3 (1.00 g, 3.6 mmol) in DME (10.00 mL, 96 mmol) at 23° C. was added sulfuric acid (0.19 mL, 3.6 mmol) in water (8 mL), followed by dropwise addition of a solution of sodium nitrite (0.38 g, 5.4 mmol) in water (2 mL) at 0° C. over 30 minutes. The reaction was then stirred for 20 minutes. To the mixture was added a solution of sodium iodide (3.0 g, 20 mmol) in water (7 mL) at 0° C. The resulting mixture was then stirred for 1 hour. The reaction was quenched with sodium thiosulfate and extracted three times with diethyl ether. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was purified on silica gel (0-40% EtOAc in hexanes) to yield a colorless solid T10.4 (0.820 g, 58% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[Al]>O.CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:20]2[CH2:21][CH2:22][CH:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:18][CH2:19]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Al]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 190 °C
Reaction time: 0.08 h
Yield: 86.3 %

Procedure:
An oven-dried 20 mL microwave tube was charged with 4-fluoronitrobenzene (0.752 mL, 7.02 mmol), 4-phenylpiperidine (1.166 g, 7.02 mmol), and potassium carbonate (0.970 g, 7.02 mmol) under nitrogen, anhydrous DMSO (7 mL) was added, the tube was sealed with an aluminum crimp cap, and heated in a microwave reactor (Personal Chemistry, 300 W, 2.4 bar) at 190° C. for 10 minutes. TLC (SiO2, 5% EtOAc/hexanes) showed complete reaction. The reaction was poured into water (50 mL), stirred for 5 minutes, and vacuum filtered in a Büchner funnel. The collected yellow solids were washed with water (2×10 mL) and Et2O (5 mL), and the bright yellow solid was dried in vacuo to provide the title compound (1.712 g, 6.06 mmol, 86%). 1H NMR (400 MHz, CDCl3) δ ppm 1.73-1.90 (m, 2 H), 2.00 (d, J=13.34 Hz, 2 H), 2.73-2.86 (m, 1 H), 3.02-3.17 (m, 2 H), 4.10 (d, J=13.23 Hz, 2 H), 6.87 (d, J=9.43 Hz, 2 H), 7.23 (t, J=7.75 Hz, 3 H), 7.33 (t, J=7.43 Hz, 2 H), 8.14 (d, J=9.33 Hz, 2 H); MS (ESI+) m/z 283 (M+H)+.
Reaction SMILES: Cl[Si](C)(C)C.Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[F:15][C:16]1[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]([F:25])[C:17]=1[CH:18]=[O:19]>O1CCCC1.[Zn]>[F:15][C:16]1[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]([F:25])[C:17]=1[CH:18]([OH:19])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(F)c(C=O)c1F
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1ccc(F)c(C(O)CC(=O)OC(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.8 %

Procedure:
To a suspension of zinc (1.256 g, 19.21 mmol) in dry tetrahydrofuran (18 mL) was added chlorotrimethylsilane (1.228 mL, 9.61 mmol). After 20 min, tert-butyl 2-bromoacetate (1.420 mL, 9.61 mmol) was added. The reaction was stirred at rt for 10 min, then heated at 40° C. for 20 min. The reaction mixture was cooled to 0° C. under Ar, and 2,6-difluoro-3-methylbenzaldehyde (1.5 g, 9.61 mmol) in 3 mL of dry THF was added. The reaction was allowed to warm to rt and stirred overnight. The reaction mixture was quenched with 5% aqueous NaHCO3, filtered, and rinsed with EtOAc. The filtrate was washed with water and brine, dried over MgSO4, filtered, concentrated and purified by silica gel chromatography to yield the desired product (1.46 g, 56%). MS (ESI) m/z: 295.1 (M+Na)+.
Reaction SMILES: [CH:1]1([C@@H:7]([NH:20][C:21]([C:23]2[C:24]([OH:34])=[N:25][C:26]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)=[N:27][CH:28]=2)=[O:22])[C:8]2[CH:13]=[CH:12][C:11]([P:14]([CH3:19])(=[O:18])[O:15]CC)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCOCC1>[CH:1]1([C@@H:7]([NH:20][C:21]([C:23]2[C:24]([OH:34])=[N:25][C:26]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)=[N:27][CH:28]=2)=[O:22])[C:8]2[CH:13]=[CH:12][C:11]([P:14]([CH3:19])(=[O:15])[OH:18])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOP(C)(=O)c1ccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CP(=O)(O)c1ccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)C2CCCCC2)cc1
Temperature: 80 °C

Procedure:
A solution of 26-f (0.98 g, 2.03 mmol) in 15 ml of dioxane was treated with 2 ml of 5N NaOH and heated at 80° C. for 2 hour. The reaction solution was cooled to room temperature and then concentrated under vacuum and the residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with conc. HCl to pH=1 and the resulting solids were collected via filtration to give 26-1 (170 mg 38.4%). 1H NMR (300 MHz, DMSO-d6): δ 10.06 (s, 1H), 8.60 (s, 1H), 8.37 (s, 1H), 8.04 (s, 1H), 7.70 (m, 2H), 7.50 (m, 2H), 6.70 (s, 1H), 4.87 (m, 1H), 1.52 (m, 9H), 1.15 (m, 5H). (M+H)+=456.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:13][C@H:12]1[CH2:22][OH:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:25].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.Cl>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:13][C@H:12]1[C:22]([OH:25])=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: O=C(OCc1ccccc1)N1C[C@H](C2CCCCC2)C[C@H]1CO
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1C[C@@H](C2CCCCC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
To a solution of (2S-trans)-1-[(benzyloxy)carbonyl]-4-cyclohexyl-2-pyrrolidinemethanol (0.65 g) in dimethylformamide (10 ml) was added pyridinium dichromate (2.1 g). The mixture was stirred at room temperature for 16 hours and poured into crushed ice and hydrochloric acid (25 ml). Extraction with ethyl acetate followed by solvent evaporation yielded 0.4 g of (trans)-1-[(benzyloxy)carbonyl]-4-cyclohexyl-L-proline as a thick oil. The compound can be deprotected using catalytic hydrogenation as described in Method V.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=[O:13].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C(Cl)(Cl)Cl>>[N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:12][CH:11]=2)[C:6](=[O:13])[NH:7][CH:8]=1
Reactant: COc1ccc2nc[nH]c(=O)c2c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Product: O=c1[nH]cnc2ccccc12
Temperature: 25 °C
Reaction time: 3.75 h
Yield: 36.5 %

Procedure:
The Dihydro-(2H)-2-[3-(4-methoxyphenoxy)phenyl]-3-)4-trifluoromethyl benzyl)-6-methoxyquinazoline-4-one, above, was treated with 1.0 mL (0.05 mmol) of 0.05 molar DDQ/CHCl3 suspension and the mixture shaken at room temperature for 3.5-4 hr. The oxidation product was then purified by resin capture (with about 80 mg of VHL aminomethyl polystyrene resin) overnight. The reaction flask was covered with Teflon film. The resin solution was filtered through 30-50 mg of silica gel, washed with 0.5 mL of chloroform. The product was further purified by Prep TLC eluted with 30% ethyl acetate-hexane to give 9.5 mg (36.5%) of the subject quinazolin-4-one as a white solid. 1H-NMR (300 MHz, CDCl3) δ3.82 (s, 3 H), 3.96 (s, 3 H), 5.33 (s, 2 H), 6.80-7.73 (m, 15 H). MS m/z 533 (M+H, 100%).
Reaction SMILES: [C:1]([C:5]1[O:9][NH:8][N:7]([C:10]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](Cl)=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=1[NH2:23].C(N(CC)CC)C.O>O1CCCC1>[C:1]([C:5]1[O:9][NH:8][N:7]([C:10]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:23][C:22]2[CH:24]=[CH:25][C:26]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:27][C:21]=2[CH3:20])=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CN(c2c(Cl)cccc2C(=O)Cl)NO1
Reactant: Cc1cc(OC(F)(F)F)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OC(F)(F)F)ccc1NC(=O)c1cccc(Cl)c1N1C=C(C(C)(C)C)ON1
Reaction time: 1 h
Yield: 29 %

Procedure:
0.5 Gram of 2-(5-t-butyloxadiazol-3-yl)-3-chlorobenzoyl chloride was dissolved in 30 ml of tetrahydrofuran, and 0.3 g of 2-methyl-4-trifluoromethoxyaniline and 0.2 g of triethylamine were added thereto, the reaction was carried out for 1 hour under stirring. After completion of the reaction, the reaction mixture was poured into water, after extraction of the objective product with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, the residue thus obtained was purified by a silica gel column chromatography to obtain 0.22 g (yield: 29%) of the objective product.
Reaction SMILES: Cl.Cl[S:3]([CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:5])=[O:4].[CH3:13][O:14][C:15](=[O:37])[C@H:16]([CH2:33][CH2:34][S:35][CH3:36])[NH:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:13][O:14][C:15](=[O:37])[C@H:16]([CH2:33][CH2:34][S:35][CH3:36])[NH:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:8]2[C:7]([CH:6]=[S:3](=[O:5])=[O:4])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:21][C:20]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=S(=O)(Cl)Cc1cccnc1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(Nc2ncccc2C=S(=O)=O)cc1-c1ccccc1

Procedure:
A mixture of 3-chlorosulfonylmethylpyridine hydrochloride (1.0 equivalent) and (4-amino-2-phenylbenzoyl)methionine methyl ester (1.0 equivalent) in dichloromethane is treated with triethylamine (2.2 equivalents). When judged complete by TLC analysis, the reaction is diluted with ethyl acetate, and then is washed with pH 4 water, saturated NaHCO3, and brine. The mixture is dried and concentrated to give the crude title compound which is purified by chromatography on silica gel.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:12]([O:17][C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:23][CH:24]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CCCCCOc1ccc(N)cc1
Product: CCCCCOc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-pentyloxyaniline to yield 2-[(4-pentyloxyphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.C1C(=O)N([Br:22])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1>[Br:22][CH2:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: COC(=O)c1cccc2oc(C)nc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: COC(=O)c1cccc2oc(CBr)nc12
Yield: 20 %

Procedure:
453 mg (2.37 mmol) of methyl 2-methylbenzoxazole-4-carboxylate (prepared by the method in J. Heterocyclic Chem. 27, 335 (1990)) are dissolved in 40 ml of chlorobenzene, 421 mg (2.37 mmol) of NBS and 20 mg of benzoyl peroxide are added, and the resulting mixture is refluxed for 2 hours. It is concentrated, and the residue is taken up in ethyl acetate, extracted by shaking with saturated NaHCO3, 10 % strength Na2SO3 and saturated NaCl solution and dried over Na2SO4. Concentration and chromatography on SiO2 with n-heptane-ethyl acetate (2:1) yields 128 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([OH:11])=[C:4]([N+:12]([O-])=O)[C:3]=1[CH3:15]>C(O)C.[C].[Pd]>[NH2:12][C:4]1[C:3]([CH3:15])=[CH:2][CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[C:5]=1[OH:11]
Reactant: Cc1c(Cl)cc(C(C)C)c(O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(C)C)c(O)c1N
Temperature: 60 °C
Reaction time: 3 h
Yield: 122.3 %

Procedure:
To a solution of 4-chloro-6-isopropyl-3-methyl-2-nitrophenol (1.82 g, 7.92 mmol) obtained in Example 97 in ethanol (40 ml) was added 10% palladium carbon catalyst (1.8 g) and the mixture was stirred under hydrogen atmosphere at 60° C. for 3 hours. After the reaction was over, the reaction solution was filtered with celite and the filtrate was concentrated to provide 1.60 g of 2-amino-6-isopropyl-3-methylphenol (yield 99%) as pale brown solid. To a solution of this aminophenol (1.65 g, 7.92 mmol) in ethanol (25 ml) was added potassium O-ethyl dithiocarbonate (1.52 g, 9.50 mmol) and the mixture was heated to reflux for 8 hours and the solvent was evaporated. The resulting residue was dissolved in water, acidified to pH, 3-4 with 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, a saturated sodium chloride solution successively, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was crystallized from ethyl acetate-hexane to provide 0.99 g (yield 60%) of 7-isopropyl-2-mercapto-4-methylbenzoxazole as pale yellow needles.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[O:7].Cl>O.C1COCC1>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=2)=[CH:19][CH:18]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 71.9 %

Procedure:
Lithium hydroxide monohydrate (874 mg, 20.8 mmol) was added to a suspension of the ester 28a (2.00 g, 4.17 mmol), 50 ml water, and 200 ml THF. The mixture was refluxed for 48 hours and then was acidified with concentrated HCl. Water (150 ml) was added and the solution was cooled. The resulting tan precipitate was filtered and washed with water. The tan precipitate was dissolved in 100 ml hot THF and hexanes were added until the solution remained cloudy with stirring. After cooling, crystals were filtered to yield 1.4 g of a light yellow solid, and a second crop of crystals was isolated for a total yield of 1.67 g (86%). The product was used without further purification.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15].[Br:16][C:17]([CH3:22])([CH3:21])[C:18](Br)=[O:19].O>C(Cl)Cl>[Br:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15])=[O:19]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Nc1cccc(Br)c1O
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(Br)C(=O)Nc1cccc(Br)c1O
Temperature: 25 °C

Procedure:
Pyridine (1.8 ml, 22.3 mmol) was added to a solution of 2-Amino-6-bromo-phenol (4.198 g, 22.3 mmol) in dry CH2Cl2 (200 ml). The mixture was cooled in ice and then a solution of 2-bromo-2-methyl-propionylbromide (2.8 ml, 22.6 mmol) was added slowly. The mixture was stirred at the room temperature for an hour and was poured into CH2Cl2 and water. The organic layer was washed with water, dried and concentrated in vacuo to yield crude 2-bromo-N-(3-bromo-2-hydroxy-phenyl)-2-methyl-propionamide, which was used directly in step 2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30](Cl)=[O:31]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30]([C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=3)=[O:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc2ccccc2c1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-naphthoyl chloride were combined to provide N2-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-naphthamide as a white powder, m.p. 257.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ8.85 (broad s, 2H), 8.69 (broad s, 1H), 8.57 (s, 1H), 8.38 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 7.99-7.80 (m, 5H), 7.75-7.50 (m, 4H), 4.75 (t, J=6.9 Hz, 2H), 3.39 (m, 2H), 1.98 (quintet, J=7.2 Hz, 2H), 1.68 (quintet, J=7.2 Hz, 2H); MS (EI) m/e 409.1909 (409.1903 calcd for C25H23N5O).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.[OH:14][C:15]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[C:24]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[C:20]([O:19][C:17]([C:16]1[C:15]([OH:14])=[C:27]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:25][C:24]=1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:36][CH:35]=1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)C(O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)ccc(C(F)(F)F)c1O
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(C(O)C(=O)O)cc3)cc2)ccc(C(F)(F)F)c1O

Procedure:
According to a method similar to Example (31) and Example (17-4), from methyl (4-bromophenyl)(hydroxy)acetate (100 mg, 0.41 mmol) and tert-butyl 2-hydroxy-6-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}-3-(trifluoromethyl)benzoate (170 mg, 0.34 mmol) obtained in Example (22-4), the title compound was obtained as a grayish white powder (14 mg, yield: 8%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=[O:12])[NH:6]2>C1(C)C=CC=CC=1.C(OC(N(C)C)OC(C)(C)C)(C)(C)C>[C:3]([O:12][C:11]([C:5]1[NH:6][C:7]2[C:3]([CH:4]=1)=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=2)=[O:13])([CH3:7])([CH3:4])[CH3:2]
Reactant: O=C(O)c1cc2c(Br)cccc2[nH]1
Agent: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc2c(Br)cccc2[nH]1

Procedure:
To 7 g 4-Bromo-1H-indole-2-carboxylic acid in 150 ml toluene, 28 ml Di-tert-butoxymethyl-dimethyl-amine were added dropwise at 80° C. The reaction mixture was heated under reflux for additional 12 h. After removal of the solvents under reduced pressure the residue was dissolved in 200 ml DCM and washed with sat. aqueous NaHCO3 solution (2×50 ml). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate 9:1. The fractions containing the product were collected and concentrated under reduced pressure. Yield: 6.5 g . MS (ESI+): m/e=297.