Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].C1(C)C=CC=CC=1.[SH:17][CH2:18][C:19](O)=O.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:19][CH2:18][SH:17])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)CS
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: SCCNc1ccc(Cl)c(Cl)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 125.3 %

Procedure:
A 3-necked 2 L round bottomed flask equipped with an overhead stirrer, temperature probe and reflux condenser with Dean-Stark trap was charged with 100.0 grams (0.617 mol) of 3,4-dichloroaniline and 500 mL of toluene. The resulting solution was then treated with 64.4 mL (0.927 mol, 1.5 equivalents) of mercaptoacetic acid. The solution was heated to reflux (130° C.), while collecting water in the Dean-Stark trap for 20 hours, then cooled to room temperature. Ethyl acetate (250 mL) was then added followed by 123 mL of 1N hydrochloric acid. The layers were separated and the organic layer washed with 250 mL of water then 500 mL of saturated aqueous sodium bicarbonate and concentrated under vacuum to a volume of approximately 200 mL. After addition of 200 mL of toluene, the solution was again concentrated to approximately 200 mL, diluted with 1 L of tetrahydrofuran and filtered. This filtrate was added dropwise to a nitrogen-purged 3-necked 5 L round bottomed flask containing 1.73 L (1.73 mol, 2.80 equivalents) of 1N borane-tetrahydrofuran complex while maintaining a temperature of 10-15° C. Some gassing was observed. The reaction mixture was warmed to room temperature and stirred overnight then cooled to 10° C. A solution of 252 grams (6.91 mol, 11.2 equivalents) of anhydrous hydrogen chloride in 840 mL of ethanol was added at 10-15° C. during which time significant gas evolution was observed and solids precipitated. After stirring for 1 hour at 5-10° C. the solids were collected by filtration, washed with tetrahydrofuran, and dried under vacuum to yield 100.0 grams (62.6% yield) of the title compound as a white solid, mp 185-188° C. 1H NMR (DMF-d7) δ7.20 (d, J=8.7 Hz, 1H), 7.01 (d, J=2.7 Hz, 1H), 6.78 (dd, J=2.7, 8.7 Hz, 1H), 3.18 (dd, J=6.4, 7.7 Hz, 2H) 2.61 (br s, 2H), 2.37 (br s, 1H). 13C NMR (DMF-d7) δ146.02, 132.94, 134.90, 122.70, 118.09, 117.19, 50.05, 23.07. HRMS (FAB) calcd for C8H9Cl2NS: 221.9911; found: 221.9893.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].IC.[C:16](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([CH3:16])[C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:13])[CH3:12]
Reactant: CCOC(=O)CC(=O)c1ccco1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)C(C)C(=O)c1ccco1

Procedure:
In a flask were placed ethyl 3-(2-furyl)-3-oxopropanoate (0.5 g), iodomethane (0.14 ml), finely ground potassium carbonate (0.75 g) and acetone (5 ml). The mixture was stirred at reflux for 2 h. A further portion of iodomethane (0.9 mmol, 0.056 ml) and potassium carbonate (0.9 mmol, 0.12 g) were added and the mixture stirred at reflux for 1 h. The reaction mixture was filtered and concentrated under vacuum. Yield (0.5 g, 93%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.Cl.[CH3:29][C:30]1([OH:34])[CH2:33][NH:32][CH2:31]1.Cl>O1CCCC1>[OH:34][C:30]1([CH3:29])[CH2:33][N:32]([S:2]([C:5]2[CH:14]=[C:13]3[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]3=[O:15])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:31]1
Reactant: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)Cl)ccc12
Reactant: CC1(O)CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(O)CN(S(=O)(=O)c2ccc3c(C(=O)O)c[nH]c(=O)c3c2)C1

Procedure:
7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1 g), diisopropylethylamine (3 ml) and 3-methylazetidin-3-ol hydrochloride (0.8 g) in tetrahydrofuran (8 ml) were heated at 55° C. for 3 days. The mixture was acidified with hydrochloric acid and then filtered to yield 7-[(3-hydroxy-3-methylazetidin-1-yl)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid as a pale pink solid.
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)(O)=[O:2].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:25])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:2])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Reactant: Nc1ccccc1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)Nc1ccccc1
Yield: 42 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.20 g) obtained in Example 9 and aniline to give Compound 27 (0.10 g, 42%) as a white solid.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[I-:18].[Na+]>C(#N)C>[I:18][CH2:2][O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: [I-]
Reactant: O=C(CCC(=O)OCc1ccccc1)OCCl
Agent: [Na+]
Solvent: CC#N
Product: O=C(CCC(=O)OCc1ccccc1)OCI

Procedure:
3-Benzyloxycarbonylpropionic acid chloromethyl ester (2 g, 1.38 mmole) was dissolved in acetonitrile (30 ml). Sodium iodide (1.6 g, 10.9 mmole) was added to the solution. After reaction at 70° C. for 3 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (20 ml) and refiltered. The solution was dried and gave intermediate 3-benzyloxycarbonylpropionic acid iodomethyl ester in quantitative yield. This intermediate is bonded to an accessible function of a drug, such as a ring hydroxy or carboxy function using conventional alkylation/acylation conditions as described generally herein. Following deprotection of the terminal carboxy, a di/trifunctional linker bearing R2, such as 1,3-bis-O-(L-valyl)glycerol or iodomethyloxy-L-valyl is acylated/alkylated thereon or R2 amide bonded thereon by conventional techniques as described herein, such as with DCC coupling agent.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1[C:29]2[C:24](=[CH:25][N:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30](O)=[O:31]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30]([C:21]1[CH:22]=[CH:23][C:24]2[C:29](=[CH:28][CH:27]=[N:26][CH:25]=2)[N:20]=1)=[O:31]
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2cnccc2n1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with [1,6]naphthyridine-2-carboxylic acid. MS: 416.4 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:21][O:22]/[N:23]=[C:24](/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)\[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]O)=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[CH3:21][O:22]/[N:23]=[C:24](/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)\[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)=[CH:29][CH:28]=1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: CCOC(=O)CC(c1ccccc1)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(c1ccccc1)c1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.17 %

Procedure:
To a 100 mL of two neck RB flask was charged ethyl 3-(4-hydroxyphenyl)-3-phenylpropanoate (0.6 g, 2.2 mmol) and (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.6 g, 2.2 mmol) in 20 mL of THF. To this added triphenyl phosphine (0.755 g, 2.88 mmol) at 0° C. and added DIAD (0.59 g, 2.88 mmol) portion wise over a period of 15 min at 0° C. After 12 h of stirring at RT, the mixture was diluted with Ethyl acetate, washed with water and brine solution successively. Organic phase was dried over anhydrous Na2SO4 and concentrated to afford yellow oil as product (0.6 g, yield: 52.17%); 1H NMR (300 MHz, DMSO-d6): δ 7.57-7.60 (m, 2H), 7.06-7.31 (m, 12H), 6.84-6.86 (m, 4H), 5.12 (s, 2H), 4.84 (s, 2H), 4.39-4.45 (t, 1H), 3.86-4.01 (m, 5H), 2.92-2.95 (d, 2H), 1.00-1.05 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27])[CH3:24].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:31]3[CH:32]=[CH:33][C:28]([C:26]([O:25][CH2:23][CH3:24])=[O:27])=[CH:29][CH:30]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[O:22])[CH2:8][C@@H:9]1[CH3:21])(=[O:20])[CH3:19]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Temperature: 105 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see intermediate 100), (39.0 g, 106 mmol), {4-[(ethyloxy)carbonyl]phenyl}boronic acid (22.5 g, 116 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.83 g, 1.58 mmol) were mixed in DME (430 mL) and the resulting mixture was treated with 2N aqueous Na2CO3 (210 mL, 420 mmol). The mixture was degassed under house vacuum with several quenches with nitrogen and then stirred at 105° C. under nitrogen for approximately 6 h before being allowed to cool to room temperature. The mixture was partitioned between AcOEt and water and the layers were separated. The aqueous phase was extracted with AcOEt and the combined organic phases were washed with brine. The organic phase was then filtered through a 70 g silica cartridge, washing the cartridge with AcOEt. The combined filtrate and washings were concentrated in vacuovacuo. The residue was triturated with Et2O then filtered off. The solid obtained was air dried to give ethyl 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (35.2 g, 80.2 mmol, 76%) as a grey solid. The filtrate was concentrated in vacuo and the residue obtained triturated with Et2O (approximately 30 mL). The solid formed was isolated by filtration and air dried, to give ethyl 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoate as a grey solid (5.96 g, 13.5 mmol, 13%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[C:25]([C:29]([OH:31])=O)[NH:26]3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[CH3:32][NH:33][CH3:34].O1CCCC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[C:25]([C:29]([N:33]([CH3:34])[CH3:32])=[O:31])[NH:26]3)=[CH:22][CH:21]=2)=[CH:6][CH:7]=1
Reactant: CNC
Reactant: O=C(O)c1cc2ccc(CC3c4ccc(O)cc4CCN3c3ccc(F)cc3)cc2[nH]1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2ccc(CC3c4ccc(O)cc4CCN3c3ccc(F)cc3)cc2[nH]1
Yield: 48 %

Procedure:
The title compound was prepared as described in Example 34.B using 6-{[2-(4-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinolyl]methyl}indole-2-carboxylic acid (0.25 g, 0.6 mmol) and 2.0 M solution of dimethylamine in tetrahydrofuran (1.0 mL, 2.0 mmol) to provide the title compound (0.127 g, 48% yield): 1H NMR (CDCl3) 9.05 (br, 1H), 7.52 (d, 1H), 7.26-6.76 (m, 7H), 6.61 (d, 1H), 6.57 (d, 1H), 6.50 (dd, 1H), 4.80 (t, 1H), 3.58 (m, 1H), 3.47 (m and s, 4H), 3.27 (dd, 1H), 3.20 (s, 3H), 3.03 (dd, 1H), 2.89 (m, 1H), 2.67 (dt, 1H); ES-MS m/z 444 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][CH:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C>[O:8]=[C:7]1[CH:6]=[CH:5][O:4][CH:3]=[C:2]1[O:1][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CBr
Reactant: O=c1ccocc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)COc1coccc1=O
Reaction time: 1.25 h

Procedure:
A mixture of 3-hydroxy-4H-pyran-4-one (1.12 g), ethyl 2-bromoacetate (1.7 g) and potassium carbonate (1.4 g) in ethanol (30 ml) was stirred at 67° to 70° C. for 75 minutes. The reaction mixture was allowed to stand at room temperature. An insoluble substance was filtereed off, and the filtrate was adjusted to pH 4 to 5 with conc. hydrochloric acid and the ethanol was removed. To the residue was added ethyl acetate, and the resultant mixture was washed with an aqueous solution saturated with sodium chloride and dried over magnesium sulfate. After removal of the solvent, the residue was chromatographed on silica gel (15 g) with an eluent (ethyl acetate:benzene= 1:5) to give crystals of ethyl 2-(4-oxo-4H-pyran-3-yloxy)acetate, mp 58° to 60° C.
Reaction SMILES: [CH:1]1([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[O:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.CN(C)P(N(C)C)(N(C)C)=O>C1COCC1>[OH:21][C:18]1([C:1]2([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]2)[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1
Reactant: N#CC1CCC1
Reactant: O=C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: N#CC1(C2(O)CCOCC2)CCC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 44.1 %

Procedure:
To a solution of cyclobutanecarbonitrile (405 mg, 5 mmol) in THF (7 mL) was added 2.0M lithium diisopropylamide (2.5 ml, 5 mmol) dropwise at −78° C. and the reaction solution was stirred at −78° C. for 40 minutes. A solution of dihydro-2H-pyran-4(3H)-one (550 mg, 5.5 mmol) in hexamethylphosphoramide (268 mg, 1.5 mmol) was added and the mixture was warmed up to room temperature, and stirred for 3 hours. The reaction mixture was quenched with 1N aqueous HCl solution and extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (eluted with petroleum ether: EtOAc=20:1) to obtain the title compound as a corloless oil (0.40 g, yield 44%). 1H NMR (400 MHz, CDCl3): δ 3.97 (dd, J=11.4, 4.2 Hz, 1H), 3.60-3.50 (m, 2H), 3.40-3.33 (m, 1H), 2.66-2.57 (m, 2H), 2.30-2.16 (m, 3H), 1.99-1.87 (m, 2H), 1.72 (dd, J=8.8, 3.6 Hz, 2H), 1.63-1.58 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[I-].[Mg+2].[I-].[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[CH:19]1[C:23](=[O:24])[CH:22]=[CH:21][C:20]1=[O:25]>ClCCl>[Br:1][C:2]1[CH:3]2[O:4][CH:5]([CH:6]=1)[CH:21]1[CH:22]2[C:23](=[O:24])[CH:19]([C:12]2[C:11]([CH3:10])=[CH:16][C:15]([CH3:17])=[CH:14][C:13]=2[CH3:18])[C:20]1=[O:25]
Reactant: Cc1cc(C)c(C2C(=O)C=CC2=O)c(C)c1
Reactant: Brc1ccoc1
Agent: [I-]
Agent: [Mg+2]
Solvent: ClCCl
Product: Cc1cc(C)c(C2C(=O)C3C4C=C(Br)C(O4)C3C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Bromofuran (5.2 g, 56 mmol) and magnesium iodide (1.5 g, 5.6 mmol) are added to 2-(2,4,6-trimethylphenyl)cyclopent-4-ene-1,3-dione (4.0 g, 18.7 mmol) and the mixture is stirred at room temperature for 2 days; small quantities of dichloromethane are added when required to aid stirring. The reaction mixture is allowed to stand at room temperature for 17 hours, then concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1RS, 2RS,6SR,7SR)-8-bromo-4-(2,4,6-trimethylphenyl)-10-oxatricyclo-[5.2.1.02,6]dec-8-en-3,5-dione.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[C:10]1([C:16]#[CH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:17]2
Reactant: Nc1ccc(Br)cc1I
Reactant: C#Cc1ccccc1
Product: Brc1ccc2[nH]c(-c3ccccc3)cc2c1
Yield: 60 %

Procedure:
The general procedure was used to convert 4-bromo-2-iodobenzenamine and phenylacetylene to the title product. Purification by flash chromatography gave the analytically pure product as a white solid, 60% yield. 1H NMR (300 MHz, DMSO) δ 11.77 (s, 1H), 7.88-7.85 (d, J=7.4, 2H), 7.72 (s, 1H), 7.50-7.45 (t, J=7.5, 2H), 7.39-7.35 (m, 2H), 7.23-7.20 (dd, J=8.5, 1.8, 1H), 6.89 (s, 1H). 13C NMR (75 MHz, DMSO) δ 139.06, 135.69, 131.54, 130.41, 128.88, 127.78, 125.09, 123.89, 122.04, 113.15, 111.78, 98.16. Anal. Calcd. for C14H10BrN: C, 61.79; H, 3.70; Br, 29.36; N, 5.15. Found C, 61.60; H, 3.74; N, 5.02.
Reaction SMILES: C1C(/C=C/C([O:11][C@H:12]2[C@H:17]([OH:18])[C@H:16]([OH:19])[CH2:15][C@@:14](O)([C:20]([OH:22])=[O:21])[CH2:13]2)=O)=CC(O)=C(O)C=1.[K]>O>[C:20]([OH:22])(=[O:21])[C:14]1[CH:15]=[C:16]([OH:19])[C:17]([OH:18])=[C:12]([OH:11])[CH:13]=1
Reactant: O=C(/C=C/c1ccc(O)c(O)c1)O[C@@H]1C[C@](O)(C(=O)O)C[C@@H](O)[C@H]1O
Agent: [K]
Solvent: O
Product: O=C(O)c1cc(O)c(O)c(O)c1

Procedure:
After 20 g of commercially available instant coffee (Nescafe Gold Blend Red Label) was dissolved in 1400 mL of distilled water (which solution will hereinafter be called “Coffee P”), 30 g of activated carbon “Shirasagi WH2c 28/42” (product of Japan EnviroChemicals, Ltd., having an average pore size of 4.2 angstrom) was added to the resulting solution. The resulting mixture was stirred for one hour and then, filtered through a membrane filter (0.45 μm) to yield a filtrate (which will hereinafter be called “Coffee Q”). The resulting filtrate was freeze dried, whereby 15.8 g of brown powder was obtained. The resulting brown powder was dissolved in distilled water and amounts of chlorogenic acids and HHQ were determined by HPLC analysis as in Example 1. As a result, the chlorogenic acid content was 4.12 wt. %, while the HHQ content was below the detection limit (in accordance with the analysis conditions B). In addition, the potassium content was measured by ICP emission spectrometry. The potassium content in each of the raw material instant coffee and coffee treated with activated carbon was about. 4.2 wt. %. Analysis results of coffee P, coffee Q and gallic acid by HPLC are shown by the respective charts in FIGS. 1 and 2. In coffee Q, a peak in the vicinity of a retention time of 6.8 minutes disappears and it does not have a peak substantially. In FIG. 1, a represents the chart of coffee P, b represents the chart of coffee Q and c represents a chart of gallic acid. In FIG. 2, b represents the chart of coffee P, c represents the chart of coffee Q and a represents the chart of gallic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[N:4]([CH:5]=[N:6][C:7]3[CH:13]=[CH:12][S:11][C:8]=32)[N:3]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)Cl>[Br:14][C:10]1[C:2]([CH3:1])=[N:3][N:4]2[C:9]=1[C:8]1[S:11][CH:12]=[CH:13][C:7]=1[N:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2c3sccc3ncn2n1
Solvent: ClCCl
Product: Cc1nn2cnc3ccsc3c2c1Br
Reaction time: 1 h

Procedure:
To a solution of 8-methylpyrazolo[1,5-c]thieno[2,3-e]pyrimidine (1.01 g, 5.34 mmol) in methylene chloride (30 mL) was added N-bromosuccinimide (0.959 g, 5.39 mmol). After stirring for 1 h, the reaction solution was concentrated, and the resultant residue was purified with flash chromatography (eluting with a gradient of 0-20% ethyl acetate in hexanes) to give the desired product as whited solid. 1H NMR (300 MHz, CD3OD) δ 9.11 (1H, s), 7.94 (1H, d, J=5.3 Hz), 7.52 (1H, d, J=5.3 Hz), 2.48 (3H, s) ppm. LCMS calculated for C9H7BrN3S (M+H)+: m/z=268.0. Found: 267.9.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[S:31]([CH3:30])(=[O:33])=[O:32])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1S(C)(=O)=O
Yield: 61 %

Procedure:
Using a similar procedure to that described in Example 29, 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-pyrrolidin-2-yl]methoxy}quinazoline hydrochloride (300 mg) was reacted with methane sulfonyl chloride to give the title product (200 mg, 61%); 1H NMR Spectrum: (DMSO d6) 1.88-2.17 (m, 4H); 2.98 (s, 3H); 3.38 (m, 2H); 3.93 (s, 3H); 4.02 (m, 1H); 4.15 (m, 2H); 7.20 (s, 1H); 7.20-7.30 (m, 1H); 7.42-7.53 (m, 2H); 7.81 (s, 1H); 8.37 (s. 1H); 9.62 (s, 1H); Mass Spectrum: (M+H)+ 481.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:17]([NH:18][C:19]([C:21]2[NH:22][C:23]([CH2:27][CH3:28])=[C:24]([Cl:26])[N:25]=2)=[O:20])[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:43]1[S:44][C:45]([C:49]([O:51][CH2:52][CH3:53])=[O:50])=[C:46]([CH3:48])[N:47]=1>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:17]([NH:18][C:19]([C:21]2[NH:22][C:23]([CH2:27][CH3:28])=[C:24]([Cl:26])[N:25]=2)=[O:20])[CH2:16][CH2:15][N:14]([C:43]2[S:44][C:45]([C:49]([O:51][CH2:52][CH3:53])=[O:50])=[C:46]([CH3:48])[N:47]=2)[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(=O)OCc2ccccc2)nc1Cl
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](NC(=O)OCc3ccccc3)C2)nc1C
Yield: 84.2 %

Procedure:
The same operation as in Example (1h) was performed using tert-butyl trans(±)-3-{[(benzyloxy)carbonyl]amino}-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidine-1-carboxylate obtained in Example (79d) (85 mg, 0.17 mmol), sodium carbonate (160 mg, 1.51 mmol) and ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (55 mg, 0.22 mmol), to obtain 82.3 mg of the title compound as a yellow solid (85%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[N+:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:18]([O-:20])=[O:19])[CH:26]=2)[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc([N+](=O)[O-])c2)cn1
Yield: 74.2 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.44 mmol) was converted, using 3-nitrophenylboronic acid (120 mg, 0.88 mmol) instead of 4-fluorophenylboronic acid, to the title compound (113 mg, 73%) which was obtained as a light yellow foam. MS: m/e=347.1 [M+H]+.