Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([CH2:16][OH:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=[O:20].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O.CCOCC>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([C:16]([OH:20])=[O:17])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)=O
Reactant: OCc1onc(-c2ccccc2)c1C(F)(F)F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(C)O
Product: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol (5.24 g, 21.6 mmol) in acetone (75 mL) at room temperature (immersed in a water bath) was added Jones' Reagent (43.8 mL, 53.9 mmol) via addition funnel slowly over 1.5 h. The dark reaction mixture was stirred at room temperature overnight. By HPLC, the reaction was 93% complete. An additional 0.5 equivalents (9 mL) of the Jones' Reagent was added. After 1 h, the reaction was 95% complete. After an additional 3h, the reaction was 96% complete. An additional 0.5 equivalents (9 mL) of the Jones' Reagent was added. The reaction mixture was stirred for an additional 2.5 h. By HPLC, the reaction was 97% complete. Isopropyl alcohol (6 mL) was added, and the mixture was stirred for 90 min, resulting in a dark green precipitate. The mixture was diluted with ether (600 mL), washed with a 2% aqueous solution of sodium hydrogen sulfite (5×100 mL), and the organic layer was collected. The aqueous layer was back-extracted with ether (2×100 mL). By HPLC, there was no additional product in the aqueous layer. The combined organic layers were washed with water (100 mL), washed with a saturated aqueous solution of brine (100 mL), and dried over anhydrous sodium sulfate. The aqueous layer was back-extracted with ether (100 mL), and the organic layer was added to the previous organic layers. The solution was concentration under reduced pressure to give 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid as an off-white solid. The solid was diluted with dichloromethane (200 mL), washed with a 2% aqueous solution of sodium hydrogen sulfite, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (3.84 g, 14.93 mmol, 69.3% yield) as a pale yellow solid. The product was 96% pure by HPLC with a ret. time=1.60 min.-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=258.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Br:28])[C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:25]([CH3:27])[CH3:26])[CH:19]=1)[CH2:5][P:6](=[O:13])([O:10]CC)[O:7]CC>Cl>[Br:28][C:15]1[CH:14]=[C:4]([CH:3]=[C:2]([Br:1])[C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:25]([CH3:26])[CH3:27])[CH:19]=1)[CH2:5][P:6](=[O:7])([OH:10])[OH:13]
Reactant: CCOP(=O)(Cc1cc(Br)c(Oc2ccc(O)c(C(C)C)c2)c(Br)c1)OCC
Agent: Cl
Product: CC(C)c1cc(Oc2c(Br)cc(CP(=O)(O)O)cc2Br)ccc1O
Yield: 53.6 %

Procedure:
A mixture of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy) benzyl phosphonic acid, diethyl ester (21 mg, 0.0392 mmol) in 2 ml of 6 M HCl was refluxed for 24 hours. The reaction mixture was concentrated and the residue was recrystallized with EtOH/water to give 10 mg (0.021 mmol, 53%) of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)-benzylphosphonic acid as white crystalls.
Reaction SMILES: [NH2:1]O.[F:3][C:4]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=O.[OH-].[Na+]>CO.C(O)(C(F)(F)F)=O.[Zn]>[F:3][C:4]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[NH2:1]
Reactant: O=C(CCC(F)(F)C(F)(F)F)c1ccccn1
Reactant: NO
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NC(CCC(F)(F)C(F)(F)F)c1ccccn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Hydroxylamine (0.216 mL, 3.53 mmol) was added to a solution of 4,4,5,5,5-pentafluoro-1-(pyridin-2-yl)pentan-1-one (0.894 g, 3.53 mmol) in MeOH (10.87 mL) and the resulting solution was stirred at 25° C. for 5 h. Another 1 eq. hydroxylamine was added and the reaction was stirred overnight. Another 2 eq hydroxylamine was added and the reaction was stirred overnight. The reaction mixture was concentrated in vacuo and the resulting residue was diluted with EtOAc and the resulting organic phase was washed with water and brine, then dried (Na2SO4) and concentrated in vacuo to give the crude oxime, as a colorless solid. This was redissolved in TFA (6.52 mL) and cooled to 0° C. Zinc (1.155 g, 17.66 mmol) was added in one portion. After 3 h at 0° C. the reaction mixture was poured into a mixture of ice and 5 N aq. NaOH. The pH was adjusted to pH 10. The mixture was extracted with DCM (3×). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the desired amine product. m/z=255.1 (M+H).
Reaction SMILES: O=[C:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][CH:3]1[C:17]([O:19][CH3:20])=[O:18].Cl.[CH3:22][O:23][NH2:24]>N1C=CC=CC=1>[CH3:22][O:23][N:24]=[C:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][CH:3]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CN(C(=O)OCc2ccccc2)CC1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
A solution of 1-benzyl 3-methyl 4-oxopyrrolidine-1,3-dicarboxylate (12 g, 43.2 mmol) in pyridine (50 mL) at 0° C. was added O-methylhydroxylamine hydrochloride (5.51 g, 66.0 mmol) which was stirred for 10 minutes, and then it was warmed up to RT and stirred for 16 hrs. The reaction mixture was concentrated to yield a crude product which was partitioned in 300 mL of 1N HCl and 300 mL of EtOAc. The organic layer was washed with 100 mL of brine. The combined aqueous phases were extracted with 200 mL of EtOAc. The combined organic phases were dried over Na2SO4. Filtration and concentration to yield the product (12.6 g, 95% yield).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]([CH2:18][OH:19])[CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1.C(=O)(O)[O-].[Na+].ClCCl>O1CCCC1>[C:1]([NH:9][C:10]([NH:12][C:13]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]([CH2:18][OH:19])[CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:14]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(N)(c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CO)C(NC(=S)NC(=O)c2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
Benzoyl isothiocyanate (81.37 μL, 603.33 mmol) is added to a 0° C. solution of tert-butyl 3-amino-4-(hydroxymethyl)-3-phenyl-pyrrolidine-1-carboxylate (0.168 g, 574.60 mmol) in tetrahydrofuran (2.3 mL). The mixture is warmed to room temperature and stirred overnight. Benzoyl isothiocyanate (15.50 μL, 114.92 mmol) is added and the mixture is stirred for 2 hr. Sodium bicarbonate solution and dichloromethane are added and the aqueous layer is separated, the aqueous mixture is extracted with dichloromethane (3×25 mL), dried over sodium sulfate, filtered, and concentrated to dryness. The crude product is purified via silica gel chromatography eluting with 0-100% ethyl acetate/hexanes to give the title compound (0.178 g, 68%). ES/MS (m/e): 454.3 (M−1).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:21]([OH:23])=[O:22])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[NH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].IC.[CH3:26]COC(C)=O>CN(C=O)C>[CH3:26][O:22][C:21](=[O:23])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[NH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)O
Reactant: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of BOC-5-hydroxy-tryptophan (5.9 g, 18.4 mmol) and iodomethane (3.43 mL) in DMF (80 mL) was added powered KHCO3 (3.68 g). The reaction mixture was stirred at rt for 4 hours. EtOAc (500 mL) was added and the mixture was washed with brine (500 mL) and water (500 mL). The organic phase was concentrated and the residual oil was triturated with CH2Cl2 (20 mL). The formed white solid was collected by filtration, washed with CH2Cl2 (20 mL) and dried to give the desired product (4.48 g, 73%). MS (DCI) m/z 335 (M+1)+.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[CH3:9][C:10]1[N:11]([CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[C:12]([CH3:36])=[C:13]([C:31]([O:33]CC)=[O:32])[CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[C:15]=1[C:16]([O:18]CC)=[O:17]>CC(C)=O.C1(C)C=CC=CC=1>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[CH3:36][C:12]1[N:11]([CH2:37][CH2:38][N:39]2[CH2:40][CH2:41][O:42][CH2:43][CH2:44]2)[C:10]([CH3:9])=[C:15]([C:16]([OH:18])=[O:17])[CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:28])[F:29])[C:13]=1[C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)C1=C(C)N(CCN2CCOCC2)C(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Agent: O=C(O)/C=C\C(=O)O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC1=C(C(=O)O)C(c2ccccc2C(F)(F)F)C(C(=O)O)=C(C)N1CCN1CCOCC1
Yield: 106.9 %

Procedure:
A solution of 1.2 g (0.010 mol) of maleic acid in 6 ml of acetone was poured into a solution of 5.1 g (0.010 mole) of diethyl 1,4-dihydro-2,6-dimethyl-1-[2-(4-morpholinyl)ethyl]-4-[2-(trifluoromethyl)phenyl]-3,5-pyridinedicarboxylate in 30 ml of toluene. The precipitated solid was collected, washed with toluene, and dried to yield 6.1 g (97%) of 1,4-dihydro-2,6-dimethyl-1-[2-(4-morpholinyl)ethyl]-4-[2-(trifluoromethyl)phenyl]-3,5-pyridinedicarboxylate maleate. This material was partitioned between 30 ml of toluene and 25 ml of 10% aqueous NaOH and the separated toluene phase was diluted with 60 ml of heptane. Chilling overnight yielded 3.4 g (67%) of diethyl 1,4-dihydro-2,6-dimethyl-1-[2-(4-morpholinyl)ethyl[4-[2-(trifluoromethyl)phenyl]-3,5-pyridinedicarboxylate. Recrystallization from 10 ml of 2-propanol yielded 2.9 g of the title compound which contained, as determined by HPLC, 0.19% of ##STR11##
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[CH2:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)[CH2:14][CH3:15].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=1
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Reactant: CCCc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)Nc2ccc3sc(C)nc3c2Cl)cc1
Yield: 52 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with 4-propylbenzoyl chloride (90 μL, 0.56 mmol) in presence of triethylamine (0.5 mL) according to method A gave N-(4-Chloro-2-methyl-benzothiazol-5-yl)-4-propyl-benzamide (44 mg, 0.13 mmol, 52% yield) as a orange powder after crystallisation in hexane and methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)([O-:10])=[O:9].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO.C1(C)C=CC=CC=1>[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=[N+]([O-])c1ccc(CNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
Combined aniline (6.16 g, 66.2 mmol) and 4-nitrobenzaldehyde (10.0 g, 66.2 mmol) in MeOH (165 mL) and toluene (165 mL), and heated to 60° C. for 3 h. Cooled the mixture to room temperature, added sodium borohydride (5.01 g, 132 mmol) portionwise, and then stirred at room temperature for 1 h. Added sat NaHCO3 and stirred for 1 h. Added water and extracted with EtOAc. Combined extracts were washed with brine, dried (MgSO4) filtered, and evaporated to an amber oil that was purified by chromatography on silica gel, eluting with CH2Cl2 to give the title compound (9.0 g, 59.6% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[N:9]2)=[CH:4][CH:3]=1.[C:24]([N:32]=C=O)(=[O:31])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:24]([NH2:32])=[O:31])[CH:14]=3)=[CH:11][C:10]([C:20]([F:21])([F:22])[F:23])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Nc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(F)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: NC(=O)Nc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(F)cc2)ccn1
Temperature: 50 °C
Yield: 14 %

Procedure:
4-[2-(4-Fluoro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-pyridin-2-ylamine (132 mg, 0.41 mmol) and benzoyl isocyanate (120 mg, 0.82 mmol) are mixed in DCM (4.0 mL) and the reaction mixture is heated at 50° C. for 16 hrs. After it is cooled down, the solvent is removed and the residue is dissolved in ethanol (2.5 mL). Potassium carbonate (70 mg, 0.49 mmol) is added and the reaction mixture is heated at 85° C. for 2 hrs before it is cooled down to room temperature. The solvent is removed and the residue is partitioned between water (30 mL) and EtOAc (50 mL). The organic layer is separated and concentrated to give the crude product. Purification by flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 21 mg of the titled product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:37])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]2[S:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[N:22][C:21]=2[CH3:35])=[CH:14][C:13]=1[CH3:36].I[CH2:39][CH3:40]>CS(C)=O.CCOCC>[CH3:7][O:8][C:9](=[O:37])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:39][CH3:40])[CH2:19][C:20]2[S:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)=[N:22][C:21]=2[CH3:35])=[CH:14][C:13]=1[CH3:36]
Reactant: COC(=O)COc1ccc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCN(Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1C)c1ccc(OCC(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 58.9 %

Procedure:
A suspension of potassium carbonate (76 mg, 0.55 mmol), and (2-methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid methyl ester (225 mg, 0.50 mmol, example 18.2) in DMSO (3 ml) was treated with iodoethane (0.04 ml, 0.53 mmol) in DMSO (0.5 ml) and stirred for 19 h at RT. Again iodoethane (0.34 ml, 4.20 mmol) in 2 portions over 7 h was added. The reaction mixture was taken up in ether and washed with KHSO4-solution (10%). The organic phase was washed with NaCl (10%), dried (Na2SO4) and evaporated. Purification by flash chromatography (SiO2, n-heptane/AcOEt=9/1) gave 141 mg of pure (4-{ethyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-2-methyl-phenoxy)-acetic acid methyl ester, MS: 479.5 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:22][C@H:23]2[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]1[NH:20][C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:22][C@H:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:11]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1CCCNC1
Yield: 44 %

Procedure:
Prepared according to Example 53, using tert-butyl (3S)-3-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-2-quinoxalinyl)amino)-1-piperidinecarboxylate (Ex. 51) and (2.5:1) DCM:TFA. Purification by reverse-phase preparative HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 80%) and free-base generation by elution of a solution of the product in MeOH through a pre-washed column of Si-carbonate (SiliaPrep, Silicyle) provided 2-(2-methyl-3-((3S)-3-piperidinylamino)-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (105 mg, 44%). 1H NMR (CDCl3) δ: 7.87-7.95 (m, 1H), 7.59-7.67 (m, 1H), 7.31-7.42 (m, 1H), 7.09 (s, 1H), 5.29 (s, 1H), 4.06 (br. s., 1H), 3.59-3.66 (m, 2H), 3.20-3.28 (m, 1H), 2.84-3.06 (m, 5H), 2.59 (s, 3H), 2.15-2.33 (m, 2H), 2.03 (m, 2H), 1.73-1.85 (m, 1H), 1.51-1.69 (m, 1H). m/z (ESI, +ve) 377.2 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[S:15])[CH:9]2[CH3:16])([O:3][CH2:4][CH3:5])=[O:2].[Cl:17]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:17][C:9]1([CH3:16])[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:7]=2)[NH:11][C:10]1=[S:15]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)C(=S)N2
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)C(C)(Cl)C(=S)N2

Procedure:
A solution of 5-carboethoxy-3-methylthiooxindole (1.50 g, 7 mmol) and N-chlorosuccinimide (1.25 g, 9.3 mmol) in methylene chloride (150 ml) was stirred at room temperature for 24 hours. The solvent was removed in vacuo, yielding crude 3-chloro-5-carboethoxy-3-methylthiooxindole and the residue was dissolved in tetrahydrofuran and added to a vigorously stirred slurry of red mercuric oxide (1.53 g, 7 mmol) and boron trifluoride etherate (1.00 g, 7 mmol) in 100 ml of 50 percent aqueous tetrahydrofuran. After stirring at room temperature for 1 hour, the red solution was extracted with chloroform. The organic extracts were dried over anhydrous magnesium sulfate, filtered, evaporated, and the residue was chromatographed on silica gel. Elution with chloroform gave 5-carboethoxyisatin (860 mg, 56%) as a yellow solid, mp 205°-207° (recrystallized from ether), ir (KBr) 3265 (NH), 1765 (ester C=O), 1750 (C=O), and 1700 cm-1 (amide C= O); nmr (DMSO-d6) τ-1.00 (1H, b s, NH), 1.80 (d of d, 1H, J4,6 =2 Hz, J6,7 =9 Hz, H6), 1.90 (d, 1H, J4,6 =2H3, H4), 3.20 (d, 1H, J6,7 =9 Hz, H7), 5.65 (q, 2H, CO2CH2CH3), and 8.60 (t, 3H, CO2CH2CH3); mass spectrum m/e obs. 219.0534 (calc. 219.0531).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:16])[N:3]=1.P(Cl)(Cl)([Cl:19])=O>CN(C)C1C=CC=CC=1>[Cl:19][C:6]1[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:16])[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CCc1c(C)nc(C)[nH]c1=O
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)CCc1c(C)nc(C)nc1Cl
Yield: 72 %

Procedure:
A mixture of ethyl 3-(2,6-dimethyl-3H-pyrimidin-4-on-5yl)propionate (3.87 g, 0.017 mol), phosphorus oxychloride (40 mL), and N,N-dimethylaniline (10 drops) was heated under reflux for 2 h. The mixture was concentrated, cooled, and ice water was added. Solid KOH was added to bring the pH to 6 and the mixture was extracted with ether. The extracts were dried (MgSO4) and concentrated to give 2.95 g (72%) of product as a brown oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([CH3:35])[CH:27]=1>>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:31])=[C:28]([CH3:35])[CH:27]=1
Reactant: COc1ccc(C(=O)O)c(C)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: COc1ccc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)c(C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Methoxy-2-methyl-benzoic acid. LC-MS (basic): tR=0.90 min; [M+H]+=476.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)[C:9]=2[F:29])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)[C:32]([OH:34])=[O:33]>ClCCl>[C:4]([O:34][C:32]([N:26]1[CH2:27][CH2:28][N:23]([C:19]2[CH:18]=[C:17]([CH2:16][C:10]3[C:9]([F:29])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:13]([O:14][CH3:15])=[CH:12][CH:11]=3)[CH:22]=[CH:21][N:20]=2)[CH2:24][CH2:25]1)=[O:33])([CH3:8])([CH3:5])[CH3:3]
Reactant: COc1ccc(Cc2ccnc(N3CCNCC3)c2)c(F)c1-c1cccc(Cl)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cc2ccnc(N3CCN(C(=O)OC(C)(C)C)CC3)c2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Synthesis of 1-[4-(3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-piperazine (P-515) In a 40 mL vial equipped with a stir bar was placed I-274 (360 mg, 0.703 mmol) and dichlormethane (2.3 mL). The solution was cooled in an ice-water bath for 10 minutes and then trifluoroacetic acid (522 μL, 7.03 mmol) was added. The solution was stirred at room temperature for 3 hours and then concentrated by a stream of nitrogen. To the oil was added water (50 mL), a saturated sodium bicarbonate solution (till pH 8) followed by extractions with dichloromethane (2×75 mL). The organic portions were combined, washed with brine (50 mL), dried (MgSO4) and concentrated. The residue was purified by column utilizing 10%, 15% and then 20% methanol/dichloromethane as the eluent to produce 120 mg of P-515 as an off-white solid in 41% yield. 1H NMR (400 MHz, DMSO-d6) δ 2.80 (t, J=5 Hz, 4H), 3.39 (t, J=5 Hz, 4H), 3.73 (s, 3H), 3.84 (s, 2H), 6.46 (d, J=5 Hz, 1H), 6.69 (s, 1H), 6.94 (d, J=8 Hz, 1H), 7.28 (bd, J=7 Hz, 1H), 7.32 (t, J=9 Hz, 1H), 7.36 (s, 1H), 7.41-7.47 (m, 2H), 7.98 (d, J=5 Hz, 1H) ppm. MS (APCI+): 412.1 (M+1); LC-MS: >99%.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1cc(O)nc2ccccc12
Product: O=C(O)c1cc(Cl)nc2ccccc12
Temperature: 0 °C

Procedure:
2-Hydroxyquinoline-4-carboxylic acid (34, 2.57 g, 13.6 mmol) and POCl3 (25 mL) were refluxed for 24 h. The reaction mixture was poured onto crushed-ice (300 g). The solid that separated was filtered, washed with water, and dried well under high vacuum afforded 2.47 g (87%) white flasks of desired product. 1H NMR (CDCl3, 300 MHz): δ 8.67 (d, 1H, J=8.4 Hz), 7.91 (d, 1H, J=8.1 Hz), 7.83 (s, 1H), 7.76 (t, 1H, J=7.2 Hz), 7.54 (t, 1H, J=7.2 Hz); LCMS (m/z): 208 (MH+).