Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.CO>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:21]4[CH:25]=[CH:24][N:23]=[CH:22]4)[CH:13]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1
Reactant: CON=Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN1CCCC1=O
Product: CON=Cc1ccc2c(c1)ncn2-c1cccc(-n2ccnc2)c1

Procedure:
A mixture of 1-(3-bromophenyl)-5-formylbenzimidazol O-methyloxime (29a) from Example 8 (0.7 g, 2.13 mmol), imidazole (0.33 g, 4.85 mmol), potassium carbonate (0.29 g, 2.13 mmol) and a catalytic amount of copper-bronze in 5 ml N-methyl-2-pyrrolidone is heated to 140° C. under a stream of nitrogen for 24 hours. After cooling the mixture is poured into water. A small volume of methanol is added and the mixture is extracted with dichloromethane. The extract is dried over sodium sulfate and concentrated under reduced pressure. The residue is eluted through silica gel with a mixture of dichloromethane and ethanol (10:1) to yield pure 29b. Yield: 0.23 g (34%) Mp. 197-199° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[S:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[CH:14]([CH3:16])[CH3:15])(=[O:5])=[O:4].S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[F:18][C:2]([F:17])([F:1])[S:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N+:24]([O-:26])=[O:25])=[CH:9][C:8]=1[CH:14]([CH3:15])[CH3:16])(=[O:4])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C(C)C)c(OS(=O)(=O)C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc(OS(=O)(=O)C(F)(F)F)c(C(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-isopropyl-5-methylphenyl trifluoromethanesulfonate (Step 1, 1.3 g, 4.6 mmol) in acetic acid (10 mL) is slowly added conc. sulfuric acid and conc. nitric acid premixed solution (2 mL/0.5 mL) at 0° C. After stifling at room temperature for 2 hours, the mixture is poured into ice water. The mixture is extracted with ethyl acetate (3×20 mL). The combined organic phase is washed with sodium carbonate aqueous solution and brine, and dried over sodium sulfate. After concentration, the crude 2-isopropyl-5-methyl-4-nitrophenyl trifluoromethanesulfonate is used directly in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1>ClCCl>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:42])=[CH:36][CH:35]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 4-chloro-phenyl isocyanate (24 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 mins. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-chloro-phenyl)-amide as a white solid. (Yield 42 mg, 60%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:12].C(N(CC)CC)C.[CH3:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>ClCCl>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[CH3:20]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Oc1ccc2c(c1Br)CCCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Oc1ccc2c(c1Br)CCCC2
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-5,6,7,8-tetrahydro-2-naphthol (6.81 g) and triethylamine (4.2 ml) in dichloromethane (60 ml) was added 2-methylbenzoyl chloride (4.62 g) dropwise with ice-cooling. The mixture was stirred under ice cooling for 1 hour, after which it was washed with water and dried (MgSO4). The solvent was then distilled off to give 1-bromo-2-(2-methylbenzoyloxy)-5,6,7,8-tetrahydronaphthalene as oil in quantitative yield.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH3:21])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)(C)(C)C.Cl>C(OCC)(=O)C>[C:19]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([CH2:9][C@@H:8]([NH2:7])[CH3:21])[CH:11]=[CH:12]2)#[N:20]
Reactant: C[C@@H](Cn1ccc2cc(C#N)ccc21)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](N)Cn1ccc2cc(C#N)ccc21

Procedure:
The product obtained in step A] (500 mg) was treated with 2.2M HCl in ethyl acetate (15 mL) at RT for 60 minutes. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3 solution and brine, dried, filtered and evaporated. The crude product was purified by flash chromatography using CH2Cl2/MeOH/NH4OH 95:5:0.5 as an eluent. The fractions containing pure product were combined and evaporated to give the title compound as a colorless oil (251 mg).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15]O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>ClCCl>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][Cl:19])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(c1ccccc1)N1CCC(CO)CC1
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCC(CCl)CC1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
To 800 ml of the dichloromethane solution of N-benzoyl-4-hydroxymethylpiperidine (C) obtained in Example 2, which contains about 1 mol of N-benzoyl-4-hydroxymethylpiperidine, there was added dropwise 109 ml (1.5 mol) of thionyl chloride over 2 hours with keeping the reaction temperature at 25° to 30° C. Then the obtained reaction mixture was stirred at room temperature for 1 hour and at 35° C. for 8 hours. After the completion of the reaction, the solvent and the excess of thionyl chloride were removed by distillation to obtain 248.96 g of N-benzoyl-4-chloromethylpiperidine (D) as a yellowish brown oily matter. The NMR spectrum of the obtained compound was measured. The result is shown below.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[S:13][C:12]([CH3:18])([CH3:17])[CH2:11][C:10]2=[O:19])(=O)=O.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>C(N(CC)CC)C.CN(C)C=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C:12]1([CH3:18])[CH2:11][C:10](=[O:19])[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH:8]=2)[S:13]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC(=O)c2cc(OS(=O)(=O)C(F)(F)F)ccc2S1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)c2cc(C#C[Si](C)(C)C)ccc2S1
Temperature: 95 °C
Yield: 90.9 %

Procedure:
A solution of 2,2-dimethyl-4-oxothiochroman-6-yl trifluoromethanesulfonate (2.88 g, 8.50 mmol) in 10 mL triethylamine (Et3N) and 20.0 mL dimethylformamide (DMF) was sparged with argon for 10 minutes. To this solution was added trimethylsilylacetylene (4.15 g, 42.0 mmol) and bis(triphenylphosphine)-palladium(II) chloride (298.0 mg, 0.425 mmol). The solution was heated to 95° C. for 5 hours, cooled to room temperature, and diluted with H2O. Extraction with EtOAc was followed by washing the combined organic layers with H2O and saturated aqueous NaCl and drying over MgSO4. Concentration of the dry solution under reduced pressure and isolation of the product by column chromatography (3% EtOAc/hexanes) afforded 2.23 g (91%) of the 2,2-dimethyl-6-trimethylsilanylethynyl-thiochroman-4-one as an orange oil. 1H NMR (300 MHz, CDCl3) δ: 8.18 (1H, d, J=1.9 Hz), 7.34 (1H, dd, J=1.9, 8.1 Hz), 7.15 (1H, d, J=8.1 Hz), 2.85 (2H, s), 1.45 (6H, s), 0.23 (9H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Br:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1F
Reactant: c1c[nH]cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1-n1ccnc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 86.2 %

Procedure:
A mixture of 1-bromo-5-fluoro-4-nitro-2-(trifluoromethyl)benzene (16.0 g, 0.0556 mol), imidazole (4.0 g, 0.0588 mol) and N,N-diisopropylethylamine (10.1 mL, 0.0582 mol) in acetonitrile (160 mL) is stirred under nitrogen for 1.5 hour at 80° C. After concentration of the reaction mixture, the residue is partitioned between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate, the combined organic phases are washed in turn with a saturated solution of ammonium chloride, brine and dried over sodium sulfate. Concentration and purification by cake filtration over silica gel, eluting with a mixture of ethyl acetate and cyclohexane from 2/8 to 1/1 affords the title compound as a yellow solid (16.1 g, 86.2%)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])=[C:5]([CH3:14])[C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[OH-].[K+]>CCO.O.CCOCC.[Cl-].[Na+].O>[CH3:13][C:10]([O:9][C:7]([C:6]1[C:5]([CH3:14])=[C:4]([C:15]([OH:17])=[O:16])[S:3][C:2]=1[NH2:1])=[O:8])([CH3:11])[CH3:12]
Reactant: Cc1c(C(=O)OCc2ccccc2)sc(N)c1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: Cc1c(C(=O)O)sc(N)c1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a cold degassed solution of the compound prepared in Example 2 (22.6 g, 64.9 mmol) in EtOH (700 ml) was added 3M KOH (350 ml) dropwise over 30 minutes. When the addition was complete the reaction was warmed to room temperature. After 3 days the reaction was diluted with H2O, Et2O and brine. The layers were separated and the aqueous layer was further extracted with Et2O (2×). The combined Et2O layers were extracted with 0.1M KOH (1×). All of the aqueous basic layers were combined and cooled to 15° C. and acidified dropwise with 3M HCl (aq) (note: do not let the internal temperature rise above 18° C.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([OH:12])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH:4]([O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)CCCCC(O)CCCl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)OC(CCCl)CCCCC(=O)O
Reaction time: 0.5 h

Procedure:
The methyl ester of (-)-8-chloro-6-hydroxy-octanoic acid (-)-(VIII), (R=Me) (2.1 g, 10 mmoles) and 1.0 g (10 mmoles) of triethylamine were mixed in 40 ml of toluene. While cooling to an internal temperature of 10° to 15° C., 1.4 g (12 mmoles) of methanesulfonyl chloride were added slowly. Stirring was continued for 30 minutes. After the addition of 25 ml of water, stirring was continued for a further 30 minutes, after which the organic phase was removed and dried over magnesium sulfate. The solvent was then evaporated under vacuum. The methyl ester of (-)-8-chloro-6-methanesulfonyloxy-octanoic acid (-)-(II), (R=R'=Me) was obtained in a yield of 2.5 g (88% of the theoretical yield). [α]D20 =-31.3 (c=1; ethanol).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:15]=1[NH:21][C:22](=[O:26])OCC)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN(C)C=O>C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:12](=[O:13])[C:14]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:15]=2[NH:21][C:22]1=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Nc1sc(CC)cc1C(=O)NCCO[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CCO[Si](C)(C)C(C)(C)C)c(=O)[nH]c2s1
Temperature: 150 °C
Reaction time: 24 h
Yield: 45.2 %

Procedure:
A mixture of ethyl (3-{[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]carbonyl}-5-ethyl-2-thienyl)carbamate (0.35 g) and N,N-dimethylformamide (5 mL) was stirred at 150° C. for 1 day. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.14 g, 45%).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].O[CH2:11][C:12]1[CH:17]=[CH:16][N:15]2[N:18]=[C:19]([CH3:38])[C:20]([C:21]3[C:22](=[O:37])[NH:23][C:24](=[O:36])[C:25]=3[C:26]3[C:34]4[C:29](=[C:30]([CH3:35])[CH:31]=[CH:32][CH:33]=4)[NH:28][CH:27]=3)=[C:14]2[CH:13]=1.C(N(CC)CC)C.O>C1COCC1>[CH3:38][C:19]1[C:20]([C:21]2[C:22](=[O:37])[NH:23][C:24](=[O:36])[C:25]=2[C:26]2[C:34]3[C:29](=[C:30]([CH3:35])[CH:31]=[CH:32][CH:33]=3)[NH:28][CH:27]=2)=[C:14]2[CH:13]=[C:12]([CH2:11][O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:17]=[CH:16][N:15]2[N:18]=1
Reactant: Cc1nn2ccc(CO)cc2c1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nn2ccc(COS(C)(=O)=O)cc2c1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonic anhydride (815 mg, 4.49 mmol, 4.3 equiv) is added at room temperature under an atmosphere of argon to a solution of 3-(5-hydroxymethyl-2-methyl-pyrazolo[1,5-a]pyridin-3-yl)-4-(7-methyl-1H-indol-3-yl)-pyrrole-2,5-dione (400 mg, 1.04 mmol) and of triethyl amine (0.314 ml, 2.25 mmol, 2.2 equiv) in anhydrous THF (10 ml). The reaction mixture is stirred for 1 hour at room temperature. Water is added, and the mixture is extracted three times with EtOAc. The combined organic layers are dried over Na2SO4, filtered, and concentrated in vacuo. The residue (450 mg, 94%) is used directly in the next transformation.
Reaction SMILES: CN(C=O)C.[I:6][CH2:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:11]=1)[OH:9].N1C=CN=C1.[CH2:34]([Si:36](Cl)([CH2:39][CH3:40])[CH2:37][CH3:38])[CH3:35]>CN(C)C1C=CN=CC=1.CCOC(C)=O.CCCCCCC>[I:6][CH2:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:11]=1)[O:9][Si:36]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:34][CH3:35]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CI)ccc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Yield: 100.6 %

Procedure:
To a stirred DMF (65 mL) solution containing (R)-2-iodo-1-[4-phenylmethoxy-3-[(methylsulfonyl)amino]phenyl]ethanol (12.7 g, 28 mmol), imidazole (5.25 g, 77 mmol), and 4-dimethylaminopyridine (0.30 g, 2.46 mmol) was added triethylsilyl chloride (5.0 mL, 29.8 mmol). After 15 minutes the completed reaction was diluted with EtOAc (200 mL) and heptane (70 mL). The organic phase was washed 1×100 mL H2O, 2×100 mL aq. sat. CuSO4, 1×100 mL H2O, 1×100 mL sat. brine, and dried over Na2SO4. The filtrate was concentrated in vacuo to give 15.81 g of tan solid which was dissolved in ~125 mL CH2Cl2 and diluted with 650 mL heptane. The mixture was concentrated in vacuo at 40°-42° C. until solids were seen (~105 mL distillate were collected), cooled to ~15° C. and filtered. The collected solids were washed with heptane and dried in vacuo at 45° C. to give 11.1 g (70%) of the title compound.
Reaction SMILES: [Na].Br[CH2:3][C:4]([O-:6])=[O:5].[K+].[CH3:8][O:9][CH2:10][CH2:11][OH:12]>>[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C([O-])CBr
Reactant: COCCO
Agent: [K+]
Agent: [Na]
Product: COCCOCC(=O)O
Temperature: 25 °C
Reaction time: 19 h
Yield: 70.5 %

Procedure:
Sodium (1.15 g.; 50.0 mmoles) was dissolved in 2-methoxyethanol (50 ml.; anhydrous) under N2 at room temperature. The temperature rose to 110° over about a 30 minute period. The pale yellow mixture was cooled to room temperature and to this was added powdered potassium bromoacetate (8.85 g.; 50.0 mmoles) under vigorous stirring. The mixture (suspension) was stirred at room temperature overnight (19 hrs.) under N2. The excess of methoxyethanol was removed in vacuo and the residue diluted with H2O (50 ml.) and neutralized with 1N HCl (50 ml.). After evaporation of water, the residue was extracted with CH2Cl2 (75 ml.×2) and the extracts were evaporated to dryness yielding 5.26 g. of yellowish oil. This oil was distilled under reduced pressure, yielding 2-methoxyethoxyacetic acid (4.72 g.; 35.2 mmoles; yield 70.5%) as a colorless oil: b.p. 98° C./0.3 mm Hg; nmr (CDCl3): δ ppm 3.45 (3H, s, -OCH3), 3.4-3.9 (4H, m, --OCH2CH2O-), 4.22 (2H, s, HO2CCH2O-), 9.74 (1H, br. s., -CO2H); ir (neat) 1750 cm-1 (νc=o --CO2H).
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[C:7]([NH:12][CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[O-]S([O-])(=O)=O.[Mg+2].[CH:32]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([OH:39])=[O:38])=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CO.C(Cl)Cl>[CH:2]1[C:11]2[C:6](=[C:7]([NH:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:32][C:34]4[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=4)[C:37]([OH:39])=[O:38])[CH2:14]3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: c1cc(NC2CCCNC2)c2ccncc2c1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1cccc(CN2CCCC(Nc3cccc4cnccc34)C2)c1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a solution of Intermediate 4 (10 g×2, 0.0379 mol×2) in DCE (400 mL×2) was added Et3N (9.2 g×2, 0.0910 mol×2) and MgSO4 (20×2, 0.139 mol×2), and stirred for 0.5 h at 30° C. 3-formylbenzoic acid (6.26 g×2, 0.0417 mol×2) and AcOH (5.46 g×2, 0.0910 mol×2) was added. The reaction mixture was stirred at 30° C. for 0.5 hours. NaBH(OAc)3 (24.1 g×2, 0.1137 mol×2) was added and the reaction mixture was stirred at 30° C. overnight. TLC (methylene dichloride:methanol=10:1) showed the reaction was complete. The reaction mixture was filtered. The filtered cake was washed with CH2Cl2, the filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo, and purified by preparative HPLC to give Intermediate 5 (10.2 g, 37.2%) as a yellow solid.
Reaction SMILES: [CH2:1]([C@H:3]1[O:5][CH2:4]1)Cl.ClCCCl.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[CH2:1]([O:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:3]1[O:5][CH2:4]1
Reactant: Oc1ccccc1
Reactant: ClC[C@@H]1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: c1ccc(OC[C@H]2CO2)cc1
Reaction time: 42 h
Yield: 79.6 %

Procedure:
To a reaction vessel were added (S)-epichlorohydrin (99% ee, 2.64 g, 29 mmol), benzyltrimethylammonium chloride (36 mg), 1,2-dichloroethane (6 ml) and water (6 ml), and the mixture was cooled with ice. After addition of phenol (1.78 g, 19 mmol), thereto 24% aqueous NaOH solution (4.10 g, 25 mmol) was dropped in a ten minute period under stirring. The mixture was stirred for 30 minutes under ice-cooling and then for 42 hours at room temperature. After the aqueous layer was removed, the organic layer was neutralized with 5% HCl and washed with water twice. The solvent was removed to give objective crude (R)-glycidylphenyl ether (2.27 g, yield 80%, optical purity 98% ee) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.C([O:33][C:34]1[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:36](Cl)=[O:37])(=O)C.[OH-].[Na+].Cl>C(Cl)Cl>[OH:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([NH:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:5])=[O:37]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: Nc1ccccc1C(=O)NCCCCC(=O)O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCCCNC(=O)c1ccccc1NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 1.61 g (6.81 mmol) of 5-(2-aminobenzoylamino)pentanoic acid in 20 ml of dry methylene chloride, add 1.41 g (11.94 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 0.88 g (8.73 mmol) of triethylamine and a solution of 1.15 g (5.82 mmol) of acetylsalicyloyl chloride dissolved in 5 ml of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 20 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization (EtOH/H2O). This yields 1.26 g (61%) of 5-[2-(2-hydroxybenzoylamino) benzoyl-amino]pentanoic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][C:11]([NH:14][C:15](=[O:20])C(F)(F)F)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(N2CC(C)C(NC=O)=N2)C=CC=1Cl>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][C:11]([NH:14][CH:15]=[O:20])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(NC1=NN(c2ccc(Cl)c(Cl)c2)CC1)C(F)(F)F
Agent: CC1CN(c2ccc(Cl)c(Cl)c2)N=C1NC=O
Solvent: O=CO
Product: O=CNC1=NN(c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 1 h

Procedure:
A mixture of 5.0 g. of 3-amino-1-(3,4-dichlorophenyl)-2-pyrazoline (prepared in Example 1) and 25 ml. of a mixture of formic acid and acetic anhydride (Example 15) is allowed to stand at room temperature for one hour. The resulting solid is collected by filtration and washed with hexane. The solid is dissolved in dichloromethane and is columnized and recrystallized as described in Example 5 to give 3.85 g. of the desired product as yellow prisms, m.p. 151°-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:18]=[O:19])[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:4][CH:3]=1.[CH3:20][Mg]Br.CCOCC>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:18]([OH:19])[CH3:20])[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-chloro-1-(3-fluorophenyl)-1H-indole-2-carbaldehyde (50 mg, 0.18 mmol) in tetrahydrofuran (5 mL) was added 3.0 M methylmagnesium bromide in ether (0.091 mL, 0.27 mmol). The reaction was stirred at room temperature for 1 hour, quenched with water, and then extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give the desired product (51 mg). The crude product was used directly in next step. LCMS calculated for C16H14ClFNO(M+H)+: m/z=290.1. Found: 289.7.