Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C:10](=[CH2:13])[C:9]2=[O:14])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.COCCOC>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:26]3[CH2:25][CH2:24][N:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][CH3:15])[CH2:28][CH2:27]3)[C:9]2=[O:14])=[CH:4][CH:3]=1
Reactant: C=C1CCN(c2ccc(Br)cc2)C1=O
Reactant: COc1ccccc1N1CCNCC1
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1N1CCN(CC2CCN(c3ccc(Br)cc3)C2=O)CC1
Yield: 81.4 %

Procedure:
1.31 g of 1-(4-bromophenyl)-3-methylene-2-pyrrolidinone and 2.00 g of 4-(2-methoxyphenyl)piperazine were mixed with 5 ml of ethylene glycol dimethyl ether. The mixture was refluxed for 2 hours and then cooled. Thereto was added water. The mixture was subjected to extraction with ethyl acetate twice. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to obtain an oily material. The oily material was purified by silica gel column chromatography using a mixed solvent of chloroform/methanol=40/1 to obtain 1.88 g of oily 1-(4-bromophenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]methyl-2-pyrrolidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([N:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([N:21]3[CH2:22][CH2:23][CH:24]([OH:27])[CH2:25][CH2:26]3)=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:28]([F:31])([F:29])[F:30]
Reactant: O=C1CCN(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(4-oxo-piperidine-1-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (20 mg), sodium borohydride (10 mg) in 1 mL of methanol was stirred at room temperature overnight. To the mixture was added water and the resulting mixture was extracted with ethyl acetate three times. The organic layer was washed with brine and dried. After the removal of solvents the residue was further purified by flash column (50% ethyl acetate in hexane) to afford the title compound as a white solid: 1H NMR: (CDCl3, ppm) δ 8.12 (d, 1H), 8.09 (d, 1H), 7.95 (dd, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 4.05 (m, 1H), 3.88 (m, 1H), 3.47 (m, 1H), 3.36 (m, 1H), 3.02 (m, 1H), 1.94 (m, 1H), 1.73 (m, 1H), 1.58 (m, 1H), 1.48 (m, 2H); MS: (M+H)/z=498.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:10]=1[C:11]1[C:12]([CH2:35][O:36][CH3:37])=[C:13]([CH:32]=[N:33][OH:34])[N:14]=[CH:15][C:16]=1[N:17]2S(C1C=CC(C)=CC=1)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)C[CH2:41][C:40]1=O.C[Si](C#C)(C)C.[OH-].[Na+]>C(Cl)Cl.O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:10]=1[C:11]1[C:12]([CH2:35][O:36][CH3:37])=[C:13]([C:32]3[CH:41]=[CH:40][O:34][N:33]=3)[N:14]=[CH:15][C:16]=1[NH:17]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCc1c(C=NO)ncc2c1c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Agent: C#C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COCc1c(-c2ccon2)ncc2[nH]c3cccc(OCc4ccccc4)c3c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
103 mg of 5-benzyloxy-4-methoxymethyl-9-tosyl-β-carboline-3-carbaldehyde oxime is combined in 5 ml of methylene chloride with 22 mg of N-chlorosuccinimide and agitated for one hour at room temperature. Subsequently 30 mg of trimethylsilylacetylene and 0.13 ml of triethylamine are added and the mixture stirred for 2 hours at room temperature. The mixture is then combined with 1 ml of 1N sodium hydroxide solution and agitated for one hour at room temperature, poured on 25 ml of water, extracted with 25 ml of methylene chloride, and the organic phase is dried, filtered, and concentrated. The residue is refluxed for 1.5 hours in 15 ml of methanol with 54 mg of sodium methylate. After concentration, the mixture is taken up in 25 ml of water and extracted with ethyl acetate. After drying and filtration, the organic phase is concentrated and the residue is chromatographed over silica gel with toluene+ethyl acetate in a ratio of 1:1 as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][CH:7]=1.C(O)C>C(OCC)(=O)C.[Pd].[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3](=[O:27])[CH:4]([O:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)C(Cc1ccc(O)cc1)Oc1ccccc1
Yield: 96 %

Procedure:
3-(4-Benzyloxyphenyl)-2-phenoxypropanoic acid methyl ester (0.47 g; 1.3 mmole) was hydrogenated in ethyl acetate (20 ml) using Pd/C (18 mg; 5%) as catalyst at atmospheric pressure and room temperature for 23 hours. As the reaction was very slow, the catalyst was changed to palladium hydroxide, ethanol (95%, 10 ml) was added and the pressure was raised to 4 bar. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give 0.34 g (yield 95%) of 3-(4-hydroxyphenyl)-2-phenoxypropanoic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[CH2:7][CH2:6]2.[CH2:14](N)[CH2:15][NH2:16].CC1C=CC(S(O)(=O)=O)=CC=1.O.Cl.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH2:14][CH2:15][N:16]=[C:8]1[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(=O)N2
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)CCC1=NCCN12
Temperature: 200 °C
Yield: 11.9 %

Procedure:
To a mixture of Compound 13 (0.50 g, 2.6 mmol) and ethylenediamine (0.88 ml, 13.1 mmol) was added p-TsOH.H2O (2.5 g, 13.1 mmol), and heated to 200° C. for 24 h. The cooled mixture was solved with 6N HCl, basified with NaOH aq., and extracted with CH2Cl2. The organic layers were combined, dried over MgSO4, filtered, and concentrated. This residue was purified by SiO2 chromatography to give Compound 14 (63 mg, 0.31 mmol, 12%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]([C:19](O)=[O:20])=[CH:17][C:12]3[C:13]([CH3:16])=[N:14][O:15][C:11]=3[C:10]=2[F:22])=[C:4]([Cl:23])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[CH:41]1([CH2:44][O:45][NH2:46])[CH2:43][CH2:42]1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[CH:41]1([CH2:44][O:45][NH:46][C:19]([C:18]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[Cl:23])=[C:10]([F:22])[C:11]3[O:15][N:14]=[C:13]([CH3:16])[C:12]=3[CH:17]=2)=[O:20])[CH2:43][CH2:42]1
Reactant: Cc1noc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc12
Reactant: NOCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCC3CC3)cc12
Reaction time: 144 h
Yield: 47.1 %

Procedure:
To a solution of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylic acid (9a) (50.0 mg, 0.125 mmol) in DMF (1 mL) was added HOBt (24.6 mg, 0.161 mmol), Et3N (0.060 mL, 0.43 mmol), O-cyclopropylmethyl-hydroxylamine (15.5 mg, 0.178 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (32.2 mg, 0.168 mmol) at room temperature. After 6 days, the reaction mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, concentrated in vacuo, and purified by flash column chromatography using the Biotage system (0.5% MeOH in CH2Cl2) to give 27.6 mg (47% yield) of the desired product (10a). MS APCI (−) m/z 466, 468 (M+, Br, Cl pattern) detected. 1H NMR (400 MHz, CD3OD) δ 7.82 (s, 1H), 7.57 (d, 1H), 7.31 (dd, 1H), 6.74 (dd, 1H), 3.73 (d, 2H), 2.60 (s, 3H), 1.16 (m, 1H), 0.55 (m, 2H), 0.28 (m, 2H). 19F NMR (376 MHz, CD3OD)−140.96 (s, 1F).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[I:13])=[N+:2]=[N-:3].[F:14][C:15]([F:19])([F:18])[CH2:16][NH2:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:17][CH2:16][C:15]([F:19])([F:18])[F:14])=[O:10])=[CH:6][C:5]=1[I:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1I
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1ccc(C(=O)NCC(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of 4-azido-3-iodobenzoic acid (5.00 g, 17.3 mmol) obtained in Example 379a) in DMF (80 ml) were added sequentially 2,2,2-trifluoroethylamine (2.5 g), triethylamine (3.6 ml), HOBt (1.3 g) and WSC (5.0 g), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/20 to 1/1) to give the title compound as a pale-yellow solid (2.93 g, 46%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:27]2[CH:28]=[C:29](OS(C(F)(F)F)(=O)=O)[CH:30]=[CH:31][CH:32]=2)([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:41][N:42](C=O)C>C(OCC)C.[C-]#N.[Zn+2].[C-]#N>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:26])=[CH:18][CH:19]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:41]#[N:42])[CH:28]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CCN(CC)C(=O)c1ccc(C2(c3cccc(OS(=O)(=O)C(F)(F)F)c3)CCCN(Cc3ccccc3)C2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: CCN(CC)C(=O)c1ccc(C2(c3cccc(C#N)c3)CCCN(Cc3ccccc3)C2)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-[1-benzyl-3-(4-diethylcarbamoyl-phenyl)-piperidin-3-yl]-phenyl ester (0.40 g, 0.69 mmol) in DMF (8 mL) was added zinc cyanide (0.057 g, 0.49 mmol) and tetrakis triphenylphosphine palladium (0.16 g, 0.14 mmol). The reaction was stirred under a nitrogen atmosphere at 90° C. for 5 hours. The mixture was cooled to room temperatures and it was diluted with diethyl ether (30 mL). The organic layer was washed with brine (5×10 mL), dried (MgSO4) and concentrated. Purification with hexanes/EtOAc (1:1) afforded 0.28 g of 4-[1-benzyl-3-(3-cyano-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[OH:21][CH:22]1[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C.CS(C)=O>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:24]4[CH2:25][CH:22]([OH:21])[CH2:23]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: OC1CNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC(O)C3)c(F)cc2c1=O
Yield: 79.9 %

Procedure:
A solution of 0.9 g (3.2 mmoles) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.7 g (6.4 mmoles) of 3-hydroxyazetidine, 1.6 g (16.0 mmoles) of triethylamine and 15 ml of DMSO is heated to 80° C. for 4 hours. It is allowed to cool, added to a mixture of ice and water, and adjusted to pH 5 giving a precipitate which is filtered and washed with water. The solid is dried under vacuum to yield 0.86 g (80%) of 1-cyclopropyl-6,8-difluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid melting at 286°-288° C. Spectroscopic data are identical to those of method C.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]([C:14]([C:16]2([CH3:31])[CH2:19][CH2:18][N:17]2[C:20](=[O:30])[NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=2)=[O:15])[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:36]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:14]([C:16]2([CH3:31])[CH2:19][CH2:18][N:17]2[C:20](=[O:30])[N:21]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=2)[CH3:36])=[O:15])[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:32][CH:33]=1
Reactant: CI
Reactant: Cc1cc(C)cc(NC(=O)N2CCC2(C)C(=O)N(CCCC(=O)O)Cc2ccc(Cl)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(N(C)C(=O)N2CCC2(C)C(=O)N(CCCC(=O)O)Cc2ccc(Cl)cc2)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of 4-{(4-chloro-benzyl)-[1-(3,5-dimethyl-phenylcarbamoyl)-2-methyl-azetidine-2-carbonyl]-amino}-butyric acid, compound 200 (1 eq.) in DMF was added NaH (3 eq.). The reaction was stirred for 1 h at 20° C., then MeI (2.5 eq.) was added. The reaction was stirred for 15 h at 20° C. The crude was partitioned between aqueous HCl (0.1N) and EtOAc. The organic layer was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by preparative LCMS to afford 4-((4-chloro-benzyl)-{1-[(3,5-dimethyl-phenyl)-methyl-carbamoyl]-2-methyl-azetidine-2-carbonyl}-amino)-butyric acid.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10])([CH3:5])[CH3:4])#[N:2].CO.O>O1CCCC1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: COC(=O)c1cccc(C(C)(C)C#N)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C#N)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a solution of methyl 3-(1-cyano-1-methylethyl)benzoate (2.8 g, 14 mmol) in tetrahydrofuran (30 mL) were added lithium hydroxide•monohydrate (0.98 g, 24 mmol), methanol (10 mL) and water (10 mL), and the mixture was stirred at room temperature for 18 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with water (15 mL). 1N Hydrochloric acid was slowly added to the mixture to adjust the pH to 3. The precipitated white precipitate was collected by filtration, washed with water, and dried to give the title compound (2.5 g, 98%) as a white powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][CH2:15][CH2:16][CH2:17][OH:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.O>ClCCl>[CH2:7]([O:14][CH2:15][CH2:16][CH:17]=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCCOCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CCCOCc1ccccc1
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
To a solution of 15.6 mL of oxalyl chloride in 420 mL of dichloromethane at −78° C. was added 24.0 mL of dimethyl sufoxide and stirred for 10 min, followed by addition of 19.95 g (0.12 mol) of 3-benzyloxy-1-propanol and stirred for 45 min. After adding 58.5 mL of triethylamine, the mixture was stirred in an ice bath for 20 min. 42 mL of water was added and the mixture was extracted with 660 mL of benzene/diethyl ether (1/1). The organic layer was washed with 5% hydrochloric acid (42 mL), water (42 mL) and brine (42 mL), dried over anhydrous sodium sulfate and concentrated. Distillation at 68-70° C./3 mmHg gave 17.0 g of a liquid in 86.3% yield. 1H NMR (CDCl3): δ 9.79 (t, J=1.8 Hz, 1H, CHO), 7.35-7.31 (m, 5H, ArH), 4.53 (s, 2H, ArCH2O), 3.81 (t, J=6.0 Hz, 2H, CH2O), 2.69 (td, J=6.0, 1.8 Hz, 2H, CH2C═O). 13C NMR (CDCl3): δ 201.08, 137.72, 128.35, 127.69, 127.62, 73.18, 63.75, 43.81. EIMS m/z 164 (M+), 107, 91, 79.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:15])[CH3:14].[C:16]1(C)[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:19]1([S:22]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13](=[O:15])[CH3:14])(=[O:24])=[O:23])[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)Nc1ccccc1OCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1OCCCOS(=O)(=O)c1ccccc1
Reaction time: 16 h

Procedure:
To a solution of N-[2-(3-hydroxypropoxy)phenyl]-acetamide (Example 113) (7.5 g, 36 mmol) in pyridine (90 ml), cooled to 0° C., was added p-toluenesulfonyl chloride (13.6 g, 56 mmol). After the tosyl chloride went into solution, the reaction was then allowed to stand at 5° C. for 16 hours. The reaction was poured onto ice, and a brown oil settled. The aqueous supernatant was decanted from the oil, and the residual oil taken up in diethyl ether. The diethyl ether was washed with cold (5° C.) 3N HCl and then with brine. The organic layer was dried (MgSO4), and concentrated to afford a thick, brown oil, 5.3 g.
Reaction SMILES: [OH-].[Al+3:2].[OH-].[OH-].[P:5]([CH2:9][NH:10][CH2:11][C:12]([OH:14])=[O:13])([OH:8])([OH:7])=[O:6]>O>[P:5]([CH2:9][NH:10][CH2:11][C:12]([OH:14])=[O:13])([OH:8])([OH:7])=[O:6].[Al:2]
Reactant: [Al+3]
Agent: O=C(O)CNCP(=O)(O)O
Agent: [OH-]
Solvent: O
Product: [Al]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminum hydroxide (1.17 grams, 0.015 mole) was combined with 7.5 grams (g) (0.045 mole) of N-phosphonomethylglycine in a 200 milliliters (ml) flask containing 60 ml of deionized water. The flask was equipped with a magnetic stirrer. This solution was heated at reflux temperature for one hour and then let stand overnight at room temperature. The reaction mixture the next day contained more solid material after cooling overnight. The solution was again heated at reflux for 3 more hours, and then cooled to room temperature. The material was then filtered to remove the solids and the aqueous filtrate was stripped at 30° C. and 1 mm of mercury. The residue was 8.0 g of a white powder which was water-soluble, having a melting point of 231° C. The white powder was subjected to standard analytical procedures and the subject compound was confirmed as one part aluminum and four parts of the N-phosphonomethylglycine anion.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:18]3[N:26]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=3)=[CH:14][NH:15]2)=[CH:11][C:10]=1[O:37][CH3:38])C1C=CC=CC=1.C[Si](I)(C)C>C(#N)C>[CH3:38][O:37][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:9]=1[OH:8])[NH:15][CH:14]=[C:13]2[C:18]1[N:26]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c[nH]c2cc1OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c[nH]c2cc1O
Reaction time: 16 h
Yield: 49.9 %

Procedure:
A solution of 2-(6-benzyloxy-5-methoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.52 g; 993 μmol), in acetonitrile (40 ml) is treated with trimethyl silyl iodide (0.353 ml; 2.483 mmol; 2.5 eq.) at 50° C. for 2 hours and then at 20° C. for 16 hours, in a 100 ml three-necked flask. After evaporation, the reaction mixture is taken up in a mixture of dichloromethane (50 ml) and water (50 ml) and is then separated by settling out. The aqueous phase is extracted with dichloromethane (250 ml); the extracts are combined, dried over magnesium sulfate, and evaporated to give a compound which is purified by chromatography on silica gel (10 g, 35 μm silica), elution being carried out with a mixture of cyclohexane and ethyl acetate (60/40 vol/vol). The fractions containing the expected compound are combined and evaporated, resulting in a solid which is triturated in diisopropyl ether so as to obtain 5-methoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-6-ol, (0.215 g; 50%), the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]([F:29])([CH:8](OS(C1C=CC(C)=CC=1)(=O)=O)[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.[C].[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:2]([F:1])([F:29])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(F)(F)C(OS(=O)(=O)c1ccc(C)cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.7 %

Procedure:
To a solution of ethyl 2,2-difluoro-3-{[(4-methylphenyl)sulfonyl]oxy}-3-(4-nitrophenyl)propanoate (1.06 g, 2.80 mmol) in ethyl acetate (30 mL) was added 10% palladium-carbon (50% water-containing product, 0.50 g), and the mixture was stirred at room temperature for 16 hr under a hydrogen atmosphere (balloon pressure). To the reaction mixture was added saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-50% ethyl acetate/hexane) to give the title compound (255 mg, yield 40%) as a pale-yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[I-].[Na+].[NH3:15]>CO>[NH:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[C:4]([CH2:3][CH2:2][NH2:15])=[CH:5]1
Reactant: ClCCc1c[nH]c2ncccc12
Reactant: N
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: NCCc1c[nH]c2ncccc12
Temperature: 60 °C

Procedure:
A mixture of 3-(2-Chloroethyl)-1H-pyrrolo[2,3-b]pyridine (4.0 g) and sodium iodide (3.2 g, 0.95 eq.) in a solution of ammonia in methanol (7 N, 20 mL) is heated to 60° C. in a Fischer-Porter sealed pressure bottle for 48 h. The bottle is cooled, opened cautiously and the solvent removed in vacuo. The resultant residue is recrystallized from THF to give the title ethylamine compound as a tan solid, 4.8 g, identified by HPLC and mass spectral analyses.
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9]([CH3:11])=[CH:8][C:6]=2[N:7]=1.[CH:13]1[C:18]2[CH2:19][NH:20][CH2:21][CH2:22][S:23](=[O:24])[C:17]=2[CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:24]=[S:23]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:18]=2[CH2:19][N:20]([C:2]2[NH:3][C:4](=[O:12])[C:5]3[S:10][C:9]([CH3:11])=[CH:8][C:6]=3[N:7]=2)[CH2:21][CH2:22]1
Reactant: Cc1cc2nc(Cl)[nH]c(=O)c2s1
Reactant: O=S1CCNCc2ccccc21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2s1
Yield: 81.1 %

Procedure:
2-Chloro-6-methylthieno[3,2-d]pyrimidin-4(3H)-one (3.01 g, 15 mmol) was dissolved in toluene (50 mL), followed by addition of 6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene-5-oxide (3.39 g, 18.7 mmol), triethylamine (6 mL, 43 mmol). Then the solution was heated to reflux overnight. The suspension was filtrated and the solid was washed by methanol to afford 4.2 g of 2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylthieno[3,2-d]pyrimidin-4(3H)-one (yield was 81.1%) as a slight brown solid. MS obsd. (ESI+) [(M+H)+] 346.