Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[O:5]=[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH2:7][CH2:8][C:9]([OH:11])=[O:10]>OS(O)(=O)=O>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([C:6](=[O:5])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:17][C:16]=1[N+:1]([O-:4])=[O:2]
Reactant: Cc1ccc(C(=O)CCC(=O)O)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccc(C(=O)CCC(=O)O)cc1[N+](=O)[O-]
Temperature: -5 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
HNO3 (65%) (2300 mL) was cooled to about 0° C. Fuming HNO3 (5700 mL) was carefully added maintaining an internal temperature of less than 15° C. The solution was cooled to about −5° C. and H2SO4 (800 mL) was added maintaining an internal temperature of less than 5° C. After cooling to about −8° C., 4-oxo-4-(p-tolyl)butanoic acid (72) (4000 g, 20.8 mol) was added portionwise maintaining the temperature below about 0° C. After completion of addition the mixture was allowed to warm to about 15-17° C. The solution was poured onto crushed ice with stirring. After about 2 h at rt, the solid was collected by filtration washing with water (3×10 L) and then dried to afford 4-(4-methyl-3-nitrophenyl)-4-oxobutanoic acid (73) (3400 g, 69% yield). 1H NMR (300 MHz, DMSO): δ 8.46 (s, 1H), 8.20 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 3.25 (m, 2H), 2.62 (m, 2H), 2.60 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[N:24]1([C:28]([C:30]2[CH:35]=[N:34][C:33](Cl)=[CH:32][N:31]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1>CC(N(C)C)=O.C(OCC)(=O)C>[N:24]1([C:28]([C:30]2[N:31]=[CH:32][C:33]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][O:15][CH2:14]4)[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[N:34][CH:35]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCOC2)c1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@H]2CCOC2)c1
Yield: 66.8 %

Procedure:
A solution of methyl 3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (2.5 g, 10.5 mmol), potassium carbonate (2.9 g, 21.0 mmol) and 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (2.48 g, 12.6 mmol) in DMA (25 mL) was heated at 120° C. for 2 hours. The solution was diluted with ethyl acetate (150 mL), washed with water (3×50 mL), brine (20 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica, eluting with 0-50% ethyl acetate in isohexane, to give the desired compound as a colourless oil (2.8 g). 1H NMR δ (CDCl3): 2.13-2.29 (m, 2H), 2.34-2.41 (m, 2H), 3.88-4.04 (m, 4H), 3.90 (s, 3H), 4.25 (t, 2H), 4.68 (t, 2H), 4.96-5.00 (m, 1H), 6.91 (t, 1H), 7.43 (d, 2H), 8.32 (d, 1H), 8.85 (d, 1H); m/z 386 (M+H)+, 384 (M−H)−
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1[N:29]([CH3:34])[C:30]([SH:33])=[N:31][CH:32]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1[N:29]([CH3:34])[C:30]([S:33][C:2]2[S:6][C:5]([NH:7][C:8]([N:9]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:10]3[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]3)=[O:22])=[N:4][CH:3]=2)=[N:31][CH:32]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cnc(S)n1C
Reactant: CC1CCC(N(C(=O)Nc2ncc(Br)s2)C2CCCC2)CC1
Product: CCOC(=O)c1cnc(Sc2cnc(NC(=O)N(C3CCCC3)C3CCC(C)CC3)s2)n1C

Procedure:
Prepared as described in general procedure (E) using 3-(5-bromo-thiazol-2-yl)-1-cyclopentyl-1-(4-methyl-cyclohexyl)-urea (Example 202) and 2-mercapto-3-methyl-3H-imidazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:2]=1.[OH:13]O>C(O)C.C(OCC)(=O)C.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Cu]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][S@:8]2=[O:13])[CH:2]=1
Reactant: OO
Reactant: c1cncc([C@@H]2CCCCS2)c1
Agent: [Cu]
Agent: CC(=O)/C=C(/C)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=[S@@]1CCCC[C@H]1c1cccnc1

Procedure:
A solution of (S)-2-(3-pyridyl)tetrahydro-2H-thiopyran (0.6 g) and copper (II) acetylacetonate (0.8 g) in ethanol (15 ml) is treated with hydrogen peroxide (2 ml; 27.5%), in 0.5 ml portions during a 20 hour period. Two hours after the final addition the reaction mixture is diluted with ethyl acetate (30 ml) and washed with saturated brine (2×30 ml). The combined brine washes are then extracted with ethyl acetate (3×30 ml), the combined ethyl acetate phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure, to give (1R,2S)-2-(3-pyridyl)tetrahydro-2H-thiopyran 1-oxide (0.5 g), in the form of a white solid, m.p. 131° C. [NMR (CDCl3): 8.7(s,2H), 7.7(d,1H); 7.3(s,1H); 3.6(dd,2H); 2.8(t,1H); 2.3-1.5(m,6H). Elemental analysis: C,61.3; H,6.7; N,6.9; S,16.5.%; calculated: C,61.5; H,6.7; N,7.1; S,16.4%.]
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH2:19][C:20]#[C:21][CH2:22][O:23]C2CCCCO2)[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:30][C:31]1[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=1[F:38])=[O:9])=C.Cl.O1CCOCC1>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH2:19][C:20]#[C:21][CH2:22][OH:23])[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:30][C:31]1[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=1[F:38])=[O:9]
Reactant: C=COCCONC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CC#CCOC1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NOCCO)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CC#CCO
Temperature: 25 °C
Yield: 35.9 %

Procedure:
To a stirred solution of 3-(2-fluoro-4-iodo-phenylamino)-1-[4-(tetrahydro-pyran-2-yloxy)-but-2-ynyl]-1-H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (2-vinyloxy-ethoxy)-amide (47.0 mg, 0.075 mmol) in anhydrous MeOH (3.0 mL) under N2 was added 4 M HCl in dioxane (0.10 mL, 0.40 mmol, 5.5 eq), and the reaction mixture was stirred at room temperature. After 3 h the solvent was removed in vacuo and the residue was redissolved in acetonitrile (2.0 mL) and loaded onto Phenomenex Strata-X cartridge (5 g). The cartridge was washed with water (10 mL) and methanol (15 ml). The desired product was then eluted using 2M ammonia in MeOH. Trituration from DCM-hexane afforded the title compound as a yellow solid (14.1 mg, 36.3%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.66 (broad s, 1H), 8.58 (s, 1H), 8.36 (d, J=5.86 Hz, 1H), 7.70 (d, J=6.8 Hz, 1H), 7.63 (m, 1H), 7.55 (dd, J=11.03, 1.6 Hz, 1H), 7.26-7.17 (m, 1H), 6.23 (t, J=8.8 Hz, 1H), 5.35 (s, 2H), 5.18 (t, J=5.96 Hz, 1H), 4.80-4.74 (m, 1H), 4.02 (d, J=4.25 Hz, 2H), 3.85 (t, J=4.76 Hz, 2H), 3.60-3.48 (m, 2H); LC-MS (method D): [M+H]+=525.1, RT=1.59 min.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:30]=[C:29]3[C:25]([CH2:26][C:27](=[O:31])[NH:28]3)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>N1CCCCC1.C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:30]=[C:29]3[C:25]([C:26](=[CH:11][C:8]4[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=4[CH3:13])[C:27](=[O:31])[NH:28]3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]cc(CCC(=O)O)c2C)cc1
Yield: 58.7 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.5 mg), 120 mg 6-(4-methoxyphenyl)-2-oxindole and 3 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 118 mg (59%) of the title compound as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11]([O:17][C@H:18]([CH3:22])[C:19](Cl)=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(Cl)Cl.N1C=CC=CC=1.Cl>[CH2:11]([O:17][C@H:18]([CH3:22])[C:19]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCO[C@H](C)C(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCO[C@H](C)C(=O)Oc1ccc(C(=O)O)cc1
Yield: 46.4 %

Procedure:
To a solution of p-hydroxybenzoic acid (2.15 g, 15.6 mmol) in methylene chloride (30 ml) and pyridine (10 ml), a solution of (R)-2-n-hexyloxypropanoyl chloride (3.0 g, 15.6 mmol) in methylene chloride (20 ml) was added dropwise and then the mixture was refluxed for 7 hours. After cooling, the resultant mixture was taken up in dilute hydrochloric acid, extracted with ethyl ether; the organic extract was washed twice with dilute hydrochloric acid and with H2O for four times, and dried over anhydrous Na2SO4. The solvent was evaporated and the residue was recrystallized from n-hexane to afford 2.13 g of the title compound as white crystals; mp. 67.0°-72.0° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH3:21])[C@@H:13]3[CH2:18][C:17](=[O:19])[CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:22][C:23]([Si](C)(C)C)([F:25])[F:24].[F-].[Cs+]>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH3:21])[C@@H:13]3[CH2:18][C:17]([OH:19])([C:23]([F:25])([F:24])[F:22])[CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC(=O)C[C@@H]12
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC(O)(C(F)(F)F)C[C@@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-chloro-4-((3S,3aS)-3-methoxy-5-oxo-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile prepared according to example 9 (10 mg, 0.033 mmole) in THF (3 mL) at 0° C. was added trifluoromethyl-trimethyl silane (0.02 mL, 0.0396 mmol) followed by the addition of CsF (0.5 mg, 0.0033 mmol) and the reaction mixture was stirred at room temperature for 3 h. Once the starting material had disappeared (monitored by TLC), the reaction mixture was quenched with 4N HCl and extracted with diethyl ether. Organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by preparative TLC method (2% MeOH in DCM) provided the title compound.
Reaction SMILES: [C:1]1([C@H:7]([CH3:13])[CH2:8][NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:15]([CH2:19][CH3:20])[C:16](O)=[O:17]>>[CH2:19]([C@H:15]1[S:11][C:10]([NH:9][CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:13])=[N:12][C:16]1=[O:17])[CH3:20]
Reactant: C[C@H](CNC(N)=S)c1ccccc1
Reactant: CCC(Br)C(=O)O
Product: CC[C@H]1SC(NC[C@@H](C)c2ccccc2)=NC1=O

Procedure:
Synthesis was performed from N-[(2S)-2-phenylpropyl]thiourea and 2-bromo-butyric acid according to Method D3.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH2:9].[C:11](Cl)(=[O:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>>[CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:9][C:11](=[O:13])[CH3:12]
Reactant: CN(C)[C@@H]1CCCC[C@H]1N
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)N[C@@H]1CCCC[C@H]1N(C)C

Procedure:
This amide was prepared by general procedure A from trans-2-(dimethylamino)cyclohexylamine and acetyl chloride. In the work up the aqueous layer was salted out with solid K2CO3, and extracted well with ether. The resulting oil was crystallized from ether-petroleum ether (30°-60°) to give colorless rods of the sub-titled amide, 79% yield, m.p. 86°-87.5° raised to 88°-89° on recrystallization. ir NH 3280, 3080; N-alkyl 2770; C=O 1660, 1640; amide II 1565. nmr in CDCl3 and 100 NHz was in accord. Mass spectrum M+ 184.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([CH:10]2[C:15](=O)[CH2:14][CH2:13][O:12][CH2:11]2)=O)[CH2:3][CH2:2]1.[CH3:17][C:18]1[N:19]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[CH:25][CH:24]=2)[CH:20]=[CH:21][N:22]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CCO.O>[CH3:17][C:18]1[N:19]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:30]3[N:31]=[C:8]([CH2:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:10]4[CH2:11][O:12][CH2:13][CH2:14][C:15]=4[N:32]=3)=[CH:27][CH:28]=2)[CH:20]=[CH:21][N:22]=1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: O=C1CCOCC1C(=O)CC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCOCC4)n2)COCC3)cc1
Temperature: 50 °C
Yield: 4.2 %

Procedure:
3-(2-(Tetrahydro-2H-pyran-4-yl)acetyl)dihydro-2H-pyran-4(3H)-one (200 mg, 0.88 mmol), 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (190 mg, 0.88 mmol, Example 41c) and potassium carbonate (122 mg, 0.88 mmol) was slurrified in EtOH (4 mL) and heated to 50° C. for 15 h. DCM and water were added. The organic phase was separated, dried with MgSO4 and the solvent was evaporated. The crude product was purified using preparative HPLC yielding N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine (15.0 mg, 4.0%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:30][CH2:29][CH2:28][O:27][CH3:26])=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: COCCN
Product: COCCNC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 2-methoxyethylamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [C:1](O)(=O)[CH3:2].[OH:5][N:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([O:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:8][C:7]1([CH3:35])[CH3:34].OO.S([O-])([O-])=O.[Na+].[Na+]>O.C(O)(=O)C.C(#N)C.C1CCCCC1>[CH:2]1([O:5][N:6]2[C:11]([CH3:12])([CH3:13])[CH2:10][CH:9]([O:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:8][C:7]2([CH3:34])[CH3:35])[CH2:1][CH2:9][CH2:8][CH2:7][CH2:34]1
Reactant: CC(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(O)C(C)(C)C1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: C1CCCCC1
Product: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Yield: 511.4 %

Procedure:
A solution of 0.116 g (0.429 mmol) of ferric chloride hexahydrate and 0.096 g (1.60 mmol) of glacial acetic acid in 2 ml of water is added to a mixture of 5.08 g (11.6 mmol) of 1-oxyl-4-octadecanoyloxy-2,2,6,6-tetramethylpiperidine, 40 ml of cyclohexane, and 60 ml of acetonitrile that has been heated to 60°. A solution of 3.36 g (49.4 mmol) of aqueous 50% hydrogen peroxide is added to the reaction mixture dropwise over 2.5 hours at the reflux temperature of 60-62°. A solution of 0.033 g of ferric chloride hexahydrate and 0.040 g of glacial acetic acid in 1 ml of water is added to the reaction mixture 1.5 hours after the peroxide addition is begun. A solution of 0.031 g of ferric chloride and 0.028 g of glacial acetic acid in 1 ml of water is added to the reaction mixture 4 hours after the peroxide addition is begun. After being heated a total of 5 hours at reflux temperature, the reaction mixture is cooled and excess peroxide is decomposed by the addition of aqueous sodium sulfite solution. The organic layer is concentrated and purified by flash chromatography with 20:1 heptane-ethyl acetate to afford 4.27 g (71% yield) of the title compound, a white solid, mp 42-46. The assay is approximately 90% by NMR integration.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH3:30][N:31]([CH3:36])[CH2:32][CH2:33][NH:34][CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:34]([CH2:33][CH2:32][N:31]([CH3:36])[CH3:30])[CH3:35])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CNCCN(C)C
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)CCN(C)Cc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with N,N,N′-trimethylethylenediamine (32 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[N-(2-(dimethylamino)ethyl)-N-methylaminomethyl]indol-2-yl)isoindolinone.
Reaction SMILES: CS(O)(=O)=O.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH2:16][O:15]1.[SH:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1>C(O)(=O)C>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]([OH:15])([CH2:16][S:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: Sc1nccs1
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Product: OC(CSc1nccs1)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane, methanesulphonate salt, (6 g, 0.0164 m) and 2-mercaptothiazole (6 g, 0.05 m) were heated in glacial acetic acid (200 ml) under refluxed for 4 hours. The solvent was then evaporated and the residue was basified with dilute sodium hydroxide solution and extracted with methylene chloride. The extract was washed once with dilute sodium hydroxide solution, dried (MgSO4) and evaporated to give a pale brown glass (5.4 g) which was chromatographed on silica, eluting with ethyl acetate:ether:methanol:diethylamine 25:75:2:2, to give, after one recrystallization from isopropanol, the title compound 2 g, (32%); m.p. 110°-111° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH:4]([CH3:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25]#[C:26][C:27](O)=[O:28].ClCCl.C(O)C.N>>[CH2:15]([N:3]([CH2:1][CH3:2])[CH:4]([CH3:14])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:27](=[O:28])[C:26]#[C:25][C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])=[CH:11][CH:12]=1)[CH3:16]
Reactant: CCN(CC)C(C)COc1ccc(N)cc1
Reactant: O=C(O)C#Cc1ccc(Cl)cc1Cl
Agent: N
Solvent: ClCCl
Solvent: CCO
Product: CCN(CC)C(C)COc1ccc(NC(=O)C#Cc2ccc(Cl)cc2Cl)cc1

Procedure:
Prepared analogously to Example 3.4.c. from 4-(2-diethylaminopropoxy)phenylamine and (2,4-dichlorophenyl)propynoic acid. Yield: 0.41 g (65.2% of theory); melting point: 70° C.-72° C.; C22H24Cl2N2O2 (M=419.35); calc.: molecular ion peak (M+H)+: 419/421/423; found: molecular ion peak (M+H)+: 419/421/423; Rf value: 0.4 (silica gel, dichloromethane/ethanol/ammonia (5:1:0.01)).
Reaction SMILES: [F:1][C:2]1[C:3]([O:16][CH3:17])=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[C:7]([F:12])[C:6]=2[C:13]([CH3:15])=[CH2:14].O.O.O.O.O.O.O.[Cl-:25].[Ce+3].[Cl-].[Cl-].Cl[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(O)(C)(C)C>[Cl:25][CH2:14][C:13]([C:6]1[C:7]([F:12])=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:16][CH3:17])[C:2]([F:1])=[CH:11]2)=[CH2:15]
Reactant: C=C(C)c1c(F)cnc2cc(F)c(OC)nc12
Reactant: [Cl-]
Agent: O=S([O-])[O-]
Agent: [Ce+3]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: C=C(CCl)c1c(F)cnc2cc(F)c(OC)nc12
Reaction time: 0.5 h

Procedure:
A solution of 3,7-difluoro-8-(1-methylethenyl)-2-(methyloxy)-1,5-naphthyridine (820 mg, 3.5 mmol) in tert-butanol (50 ml) under argon was treated with cerium(III) chloride heptahydrate (1.29 g, 3.5 mmol) followed by a solution of sodium hypochlorite (12% w/v, 2.6 ml, 4.2 mmol). After 30 minutes stirring, saturated aqueous sodium sulphite solution (20 ml) was added. After 15 minutes stirring the mixture was extracted with ether (3×200 ml). The combined organic extracts were dried over magnesium sulphate and evaporated. The residue was chromatographed on silica eluting a gradient of 0-50% ethyl acetate in hexane affording a white solid (320 mg, 34%).
Reaction SMILES: [NH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH2:4][CH2:3][CH2:2]1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][CH2:2][NH:1]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1cccc2c1CCCN2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(Oc2cccc3c2CCCN3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 14.9 %

Procedure:
To a solution of 0.15 g (1.01 mmol) 1,2,3,4-tetrahydro-quinolin-5-ol in 10 ml dichloromethane were added 0.17 g (1.40 mmol) phenylboronic acid, 0.25 g (1.36 mmol) copper(II) acetate, a spatula end of 4 Å molecular sieves and 0.57 ml (4.52 mmol) triethylamine. The reaction mixture was stirred at room temperature for 72 h and then filtered through celite, washing with dichloromethane. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, ethyl acetate/heptane gradient) to afford 34 mg (17%) of the title compound as a pink oil. MS (ISP): 226.3 ([M+H]+).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]=2[C:13]2[O:14][CH:15]=[C:16]([CH:18]=[CH2:19])[N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:12]=2[C:13]2[O:14][CH:15]=[C:16]([CH2:18][CH3:19])[N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Agent: [Pd]
Solvent: CO
Product: CCc1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Reaction time: 2 h
Yield: 24.9 %

Procedure:
To a solution of 2-(3,5-diphenylpyridazin-4-yl)-4-vinyloxazole (25 mg, 0.07 mmol) in methanol (4 mL), 10% Pd/C (20 mg, wt/wt) was added and the reaction mixture was stirred under hydrogen atmosphere for 2 h. The reaction mixture was filtered through a celite bed and washed with methanol. Solvent was evaporated under reduced pressure to obtain the crude product that was purified by column chromatography (100-200 mesh silica gel 25% EtOAc-Hexane) to furnish 2-(3,5-diphenylpyridazin-4-yl)-4-ethyloxazole (compound 22) (5.7 mg, 22%) as a pale yellow gummy liquid.
Reaction SMILES: O1C2=CN=CC=C2C(=O)C1.C(OC([C:16]1[O:25][C:19]2=[C:20]([CH3:24])[N:21]=[CH:22][CH:23]=[C:18]2[C:17]=1[OH:26])=O)C>>[CH3:24][C:20]1[N:21]=[CH:22][CH:23]=[C:18]2[C:17](=[O:26])[CH2:16][O:25][C:19]=12
Reactant: CCOC(=O)c1oc2c(C)nccc2c1O
Agent: O=C1COc2cnccc21
Product: Cc1nccc2c1OCC2=O

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridin-3(2H)-one (A.2.4.3), 3-hydroxy-7-methylfuro[2,3-c]pyridine-2-carboxylic acid ethyl ester replacing 3-hydroxyfuro[2,3-c]pyridine-2-carboxylic acid ethyl ester;