Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7](B(O)O)[CH:8]=1)=[O:2].Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:16]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:7]2[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=2[O:12][CH3:13])[CH:1]=[O:2])=[CH:16][C:17]=1[S:22]([CH3:25])(=[O:23])=[O:24]
Reactant: CS(=O)(=O)c1cc(Br)ccc1F
Reactant: COc1ccc(C=O)cc1B(O)O
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C=O)cc1-c1ccc(F)c(S(C)(=O)=O)c1
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 108.1 %

Procedure:
To a solution of 5-Formyl-2-methoxyphenylboronic acid (324 mg, 1.8 mmol, 1.5 eq, Frontier Scientific, Inc., Logan, Utah, USA) in dioxane:H2O (2:1; 15 mL) was added 4-bromo-1-fluoro-2-(methylsulfonyl)benzene (300 mg, 1.2 mmol, 1.0 eq., Apollo Scientific Ltd., Stockport, Cheshire, UK), K2CO3 (496 mg, 3.6 mmol, 2 eq.) and Pd(PPh3)4 (30 mg). The mixture was stirred under nitrogen at 140° C. in a microwave for 40 min. Solvent was evaporated and the residue was dissolved in DCM and washed with water. The DCM layer was dried and evaporated. Purification via column chromatography (eluent: PE:EA=3:1) yielded 400 mg (72%) of 3-(4-fluoro-3-(methylsulfonyl)phenyl)-4-methoxybenzaldehyde (27).
Reaction SMILES: [CH:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16](OC)[O:17]C)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(OC)c1ccc(S(=O)(=O)C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(S(=O)(=O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 1112.1 %

Procedure:
To a solution of 1-(cyclohexylsulfonyl)-4-(dimethoxymethyl)benzene (117 mg, 0.392 mmol) in THF (4 mL) was added an aqueous solution of sulfuric acid (2% v/v, 2 mL) and the resulting mixture stirred for 18 hours at room temperature. Excess solid potassium carbonate was then added, and the mixture diluted with water. Finally, the aqueous solution was extracted with ethyl acetate (×3), and the combined organic phases dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give 4-(cyclohexylsulfonyl)benzaldehyde (1100 mg, quantitative yield) as a colourless oil.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH2:17][OH:18])([C:15]#[N:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C.CCOC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:18][CH2:17][C:12]2([C:15]#[N:16])[CH2:13][CH2:14][CH:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:10][CH2:11]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: N#CC1(CO)CCC(OCc2ccccc2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C#N)CCC(OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a solution of 4-(benzyloxy)-1-(hydroxymethyl)cyclohexanecarbonitrile (crude 770 mg, 1.0 equiv) in DCM (7 mL) was added p-toluenesulfonyl chloride (898 mg, 1.5 equiv), triethylamine (1.44 mL, 3.3 equiv) and DMAP (38 mg, 0.1 equiv). The solution was stirred at room temperature overnight. It was concentrated to give the residue. EtOAc (120 mL) was added. The organic solution was washed with saturated NaHCO3 (30 mL), H2O (30 mL) and HCl (1.0 N, 30 mL), brine (30 mL), dried over anhydrous Na2SO4 and then concentrated to give yellow solid which was purified by CombiFlash (24 g silica gel column, EtOAc/Hexane: 0-30%) to afford 450 mg (yield 36%) of (4-(benzyloxy)-1-cyanocyclohexyl)methyl 4-methylbenzenesulfonate as a white solid.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].Br[C:29]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[C:32]([NH2:33])=[C:31]([CH3:39])[CH:30]=1.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[CH3:39][C:31]1[CH:30]=[C:29]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[C:32]=1[NH2:33]
Reactant: C1COCCN1
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)cc([N+](=O)[O-])c1N
Temperature: 85 °C
Reaction time: 72 h

Procedure:
To a 800 ml pressure flask was added Tris(dibenzylideneacetone)dipalladium (2.64 g, 2.88 mmol), 2-(Di-t-butylphosphino)biphenyl (1.42 g, 4.75 mmol) and sodium tert-butoxide (17.5 g, 182 mmol). Then dry THF (500 mL), 4-bromo-2-methyl-6-nitroaniline (30.0 g, 130 mmol) and morpholine (34 ml, 390 mmol) were added. Argon was bubbled through the solution for 1 minute and the flask was sealed. The reaction mixture was stirred at 85° C. for 3 days. THF was evaporated in vacuo and the crude product was preabsorbed on silica and this then transferred on top of a silica gel column. Elution with hexane-ethyl acetate (6:4 to 4:6 to 0:1 gradient) gave, after evaporation of solvents, the title compound (15.2 g red-brown solid, 49.3%). LCMS (M+H)+ m/z 238 (t=0.64 min.) 1H NMR (500 MHz, DMSO-d6) δ 7.32 (1H, s), 7.22 (1H, s), 6.96 (2H, s), 3.72 (4H, broad s), 2.96 (4H, broad s), 2.21 (3H, s).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[K].[O:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].[I-].[Na+].O>CN(C)C=O>[N:15]1[CH:14]=[CH:13][N:12]2[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]3[C:20](=[O:22])[CH2:21][O:17][C:18]3=[O:23])=[CH:8][CH:9]=[CH:10][C:11]=12
Reactant: O=C1COC(=O)N1
Reactant: ClCCCCCc1cccc2nccn12
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COC(=O)N1CCCCCc1cccc2nccn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 15.59 g (70 mmol) of 5-(5-chloropentyl)imidazo[1,2-a]pyridine and 9.74 g (70 mmol) of oxazolidine-2,4-dione potassium salt in 300 ml of N,N-dimethylformamide, 10.49 g (70 mmol) of sodium iodide was added, followed by stirring at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate→ethyl acetate/ethanol=10/1) to yield 11.90 g (59.2%, light orange crystal) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]([O:17]CC)=O)=[N:10]2)[CH:5]=[CH:4][N:3]=1.[NH2:20][NH2:21].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]([NH:20][NH2:21])=[O:17])=[N:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1nc(C)n(Cc2ccnc(Cl)c2)n1
Reactant: NN
Solvent: CO
Solvent: O
Product: Cc1nc(C(=O)NN)nn1Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazole-3-carboxylate (218 mg, 0.81 mmol) in MeOH (4.5 mL) was added NH2NH2.H2O (122 μL, 1.22 mmol) and TEA (511 μL, 3.6 mmol). The reaction was allowed to stir overnight at RT. The solvent was then removed under reduced pressure and the crude material was spun down from toluene (3×) to give 1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazole-3-carbohydrazide as a white solid, which was used directly for the next step without further purification. MS (ES+) C10H11ClN6O requires: 266 found: 267[M+H]+.
Reaction SMILES: CN(C(ON1[N:17]=[N:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][CH:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[C:36]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[N:37][C:38]3[C:43]([C:44]=2[C:45](O)=[O:46])=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:30][CH2:29]1)[CH3:27].NN1CCCCCC1.CCN(CC)CC>C1COCC1.C(Cl)Cl>[N:16]1([NH:17][C:45]([C:44]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=[C:36]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:35]=2[CH2:34][N:31]2[CH2:32][CH2:33][N:28]([CH:26]([CH3:25])[CH3:27])[CH2:29][CH2:30]2)=[O:46])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:15]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)N1CCN(Cc2c(-c3ccccc3)nc3ccccc3c2C(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NN1CCCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)N1CCN(Cc2c(-c3ccccc3)nc3ccccc3c2C(=O)NN2CCCCCC2)CC1

Procedure:
O-Benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (156 mg, 0.41 mmol) was added to a stirred mixture of 3-(4-(1-methylethyl)-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid (100 mg, 0.26 mmol) [J. Med. Chem. 2001, 44, 1675-1689], 1-aminohomopiperidine (47 μL, 0.41 mmol) and Et3N (178 μL, 1.3 mmol) in THF (5 mL) and CH2Cl2 (1.5 mL), and the mixture was heated at reflux for 18 h under N2. The solvent was evaporated under reduced pressure, and the residue was dissolved in CH2Cl2 and washed with H2O, 0.5 N NaOH solution, and H2O. The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC affording, after basic work up, the desired hydrazide (28 mg, 17%). 1H NMR (CD3OD, 360 MHz), Major rotamer δ 8.05 (1H, d, J=8.3 Hz), 7.96 (1H, d, J=8.3 Hz), 7.83-7.75 (1H, m), 7.72-7.60 (1H, m), 7.55-7.43 (5H, m), 3.66 (2H, s), 3.24-3.17 (4H, m), 2.53 (1H, septet, J=6.5 Hz), 2.45-2.10 (8H, m), 1.86-1.72 (8H, m), 1.00 (6H, d, J=6.5 Hz). MS (ES+) C30H39N5O requires: 485, found: 486 (M+H+, 100%).
Reaction SMILES: [Cl-].[OH:2][NH3+:3].[OH-].[Na+].[CH3:6][O:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O>C(O)C>[CH3:6][O:7][CH2:8][C:9](=[N:3][OH:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [NH3+]O
Reactant: COCC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCC(=NO)c1ccccc1
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A mixture of hydroxylammonium chloride (10.0 g, 144 mmol) and sodium hydroxide (6.0 g, 150 mmol) in absolute ethanol (200 ml) was stirred for 1 h. The precipitated sodium chloride was filtered off and 2-methoxyacetophenone (10.0 g, 67 mmol) was added to the filtrate. The mixture was heated at reflux for 30 min. The precipitated compound was collected and recrystallised from n-heptane/ethanol 9/1 to give 7.1 g 2-methoxyacetophenone oxime.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>C(O)C.[Pd]>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C=Cc1ccc2c(c1)CCC2
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCc1ccc2c(c1)CCC2
Yield: 110.7 %

Procedure:
3-(2,3-Dihydro-1H-inden-5-yl)-propenoic acid (500 mg, 2.66 mmol) (available from Aldrich) was taken up in ethanol (40 ml) and hydrogenated at 15 psi H2 pressure with 40 mg of 10% Pd/C for 4 h. The mixture was filtered through a short plug of Arbocel and the filtrate evaporated to give the title product (560 mg, approx. quantitative) which was used with no further purification; 1HNMR (400 MHz, CDCl3) δ: 1.98-2.07 (m, 2H), 2.75 (t, 2H), 2.80-2.90 (m, 6H), 6.95 (d, 1H), 7.03 (s, 1H), 7.08 (d, 1H); LRMS: m/z ES-189 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:13])=[CH2:12])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.CCO>[Pt].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:13])[CH3:12])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: C=C(C)c1cc(Cl)cnc1C(=O)O
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)c1cc(Cl)cnc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A sealable vial was charged with 5-chloro-3-(prop-1-en-2-yl)picolinic acid (373 mg, 1.887 mmol) and EtOH (100 mL). The solution was purged with Nitrogen. Pt on activated carbon (479 mg, 0.245 mmol) was added, followed by glacial acetic acid (0.4 mL). The reaction mixture was evacuated, backfilled with hydrogen and stirred for 30 min at rt. The reaction mixture was filtered through a pad of celite to obtain the title compound as a white solid. The product contained minor amounts of dehalogenated product. The product was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:11])[C:7](=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1>>[OH:24][C:21]1([C:2]2[CH:13]=[CH:12][C:5]3[N:6]([CH3:11])[C:7](=[O:10])[N:8]([CH3:9])[C:4]=3[CH:3]=2)[CH2:22][CH2:23][C:18]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:19][CH2:20]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cn1c(=O)n(C)c2cc(Br)ccc21
Product: Cn1c(=O)n(C)c2cc(C3(O)CCC4(CC3)OCCO4)ccc21

Procedure:
The title compound was prepared as a white solid from 5-bromo-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (prepared by methylation of 5-bromo-1,3-dihydro-benzoimidazol-2-one from Pharmlab) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:11][CH2:12][CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>[Pd].C(O)C.C(OCC)(=O)C>[NH2:1][C:4]1[C:5]([N:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:11][CH2:12][CH2:13][N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1CCCN(c1ccccc1)c1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cccnc1N(CCCN1C(=O)c2ccccc2C1=O)c1ccccc1

Procedure:
2-[3-[(3-Nitro-2-pyridinyl)phenylamino]propyl]-1H-isoindole-1,3(2H)dione is reduced with hydrogen and palladium-on-carbon catalyst in ethanol-ethyl acetate mixtures to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:14]([OH:16])=O)=[CH:6]2.[CH2:17]([NH:19][C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:18]>>[CH3:18][CH2:17][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([C:14]([C:7]2[NH:8][C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=3)[CH:6]=2)=[O:16])[CH2:28][CH2:27]1
Reactant: COc1cc2cc(C(=O)O)[nH]c2cc1OC
Reactant: CCNc1cccnc1N1CCNCC1
Product: CCNc1cccnc1N1CCN(C(=O)c2cc3cc(OC)c(OC)cc3[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 16 and making non-critical variations but using 5,6-dimethoxyindole-2-carboxylic acid (0.50 g) and 1-[3-ethylamino-2-pyridinyl]piperazine (0.51 g), the title compound is obtained,
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][N:9]([C:18](=[O:28])[CH:19]=[C:20]1[C:24](=[O:25])[O:23]C(C)(C)[O:21]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl.C(#N)C>O1CCCC1.O>[C:1]([O:5][C:6]([CH2:7][O:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:18]([CH:19]=[C:20]([OH:21])[C:24]([OH:25])=[O:23])=[O:28])=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)O
Reaction time: 1 h
Yield: 41.7 %

Procedure:
A solution of [[2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-(4-fluorobenzyl)-aminooxy]-acetic acid tert-butyl ester (0.10 g, 0.24 mmol) in tetrahydrofuran (3 ml) was treated at 0° C. with 0.48 ml (0.48 mmol) of 1 M aqueous lithium hydroxide. After 1 h, the reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried (magnesium sulphate) and evaporated in vacuo. Chromatograpy of the residual solid on Premisphere 5 μC-8 (gradient of acetonitrile in water) gave 0.037 g (41% yield) of the title material as a white solid: mp 73° C. (dec). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.51 (9H, s t-Bu), 4.36 (2H, s, CH2), 4.95 (2H, s, CH2), 6.66 (1H, broad s, CH), 7.05 (2H, m, aromatics), 7.39 (2H, m, aromatics). HRMS (ES+) calculated for C17H21FNO7[M+H]+: 370.130206. Found: 370.129173.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[O:10][C:9]2=[O:25])=[CH:4][CH:3]=1.[C:26](O)(=[O:28])[CH3:27]>>[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[O:10][C:9]2=[O:25])=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: COC(=O)c1ccc(OCC2CN(c3ccc(N)cc3)C(=O)O2)cc1
Reactant: CC(=O)O
Product: COC(=O)c1ccc(OCC2CN(c3ccc(NC(C)=O)cc3)C(=O)O2)cc1
Reaction time: 1 h
Yield: 99 %

Procedure:
A 1.2 ml quantity of anhydrous acetic acid was added dropwise to an acetic acid (60 ml) solution of 3.0 g of methyl 4-[3-(4-aminophenyl)-2-oxooxazolidin-5-yl]methoxybenzoate obtained in Example 9 at room temperature, and the mixture was stirred at the same temperature for 1 hour. The crystals were collected by filtration and washed with ethanol to give 3.05 g of the title compound (compound 113) in a yield of 99%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[C:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([OH:30])=[O:29]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:35]=[CH:36][C:31]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:3][CH:4]=2)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[C:21]([CH3:27])[CH:22]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(/C(CC(c2ccc(Br)cc2)c2ccc(Cl)cc2C)=N/O)ccn1
Product: Cc1cc(/C(CC(c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 74, step 6, from 3-(4-bromophenyl)-3-(4-chloro-2-methylphenyl)-1-(2-methylpyridin-4-yl)propan-1-one oxime (example 138) and 4-carboxyphenylboronic acid was prepared the title compound as a light brown foam, MS (ESI+): m/z=485.162 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]=[C:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:9][C:8]2=[O:25])=[CH:4][CH:3]=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:9][C:8]2=[O:25])=[CH:26][CH:27]=1
Reactant: O=C1NC(=O)C(=Cc2cc(=O)n(Cc3ccc(Cl)cc3)c3ccccc23)S1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(Cc2cc(=O)n(Cc3ccc(Cl)cc3)c3ccccc23)S1
Yield: 90.2 %

Procedure:
0.96 g of 5-[1-(4-chlorobenzyl)-2-oxo-1,2-dihydroquinolin-4-ylmethylidene]thiazolidine-2,4-dione, 0.735 g of diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate, and 0.96 g of silica gel were added to 30 ml of toluene, followed by heating and refluxing overnight. The solvent was distilled off, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate of 10:1→3:1), and the purified product was recrystallized from a chloroform-ether mixed solvent, giving 0.87 g (91% yield) of 5-[1-(4-chlorobenzyl)-2-oxo-1,2-dihydroquinolin-4-ylmethyl]thiazolidine-2,4-dione as a white powder.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH:3]([C:10](Cl)=[O:11])[CH:2]2[CH3:13].[NH3:14]>>[CH:1]12[CH2:9][CH:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH:3]([C:10]([NH2:14])=[O:11])[CH:2]2[CH3:13]
Reactant: N
Reactant: CC1C(C(=O)Cl)CC2CC1C2(C)C
Product: CC1C(C(N)=O)CC2CC1C2(C)C

Procedure:
2g of (+)-pinane-3-carboxylic acid chloride are mixed with concentrated aqueous ammonia solution; the corresponding carboxylic acid amide precipitates and is filtered off and dried. It melts at 131° C and has an optical rotation of [α]D24 = +22.4° (c = 1, methanol).
Reaction SMILES: [NH:1]([C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])[C@H:2]([C:18]([NH:20][C@H:21]([C:32]([NH:34][C@H:35]([C:51]([NH:53][CH2:54][C:55]([O:57]C)=[O:56])=[O:52])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:33])[C@@H:22]([CH3:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[OH-].[Na+]>CN(C=O)C.CO>[NH:1]([C:59]([O:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:60])[C@H:2]([C:18]([NH:20][C@H:21]([C:32]([NH:34][C@H:35]([C:51]([NH:53][CH2:54][C:55]([OH:57])=[O:56])=[O:52])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])=[O:33])[C@@H:22]([CH3:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: COC(=O)CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)[C@@H](C)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of compound (v) (0.92 g, 0.001 M) in 50% DMF/methanol was treated with 1 N NaOH solution (2.5 ml) and stirred at R.T. for 1 hour. Upon acidification the precipitated product (0.45 g) was recrystallised from methanol in 49% yield. M.P. 171°-173°. T.L.C. 2:1 CHCl3 :MeOH (t.butyl chloroformate/NaI-starch spray) showed one spot at Rf 0.50 [α]D25° =-5.4° (C=1, AcOH). The F.T. 13C NMR was consistent with structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[C:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccc(Cl)cc4)cc23)CC1
Yield: 29.7 %

Procedure:
Beginning with 1.13 gm (5.0 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 0.64 mL (5.0 mMol) 4-chlorobenzoyl chloride, 0.544 gm (29.9%) of the title compound were recovered as a tan solid.