Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]([CH3:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C(=[NH:29])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl>C1(C)C=CC=CC=1.O1CCCC1.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]>[NH2:29][C:2]1[CH:3]=[C:4]([CH:13]([CH3:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1
Reactant: CC(C)c1cc(Br)cc2c1OCC2(C)C
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)c1cc(N)cc2c1OCC2(C)C

Procedure:
Following general procedure D and using 5-bromo-3,3-dimethyl-7-isopropyl-2,3-dihydro-benzofuran (Compound 8, 0.268 g, 1 mmol), benzophenone imine (0.199 g, 1.1 mmol), sodium-tert-butoxide (0.134 g, 1.4 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.020 g, 0.021 mmol) and (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.040 g, 0.064 mmol) in 5 mL of anhydrous toluene, followed by hydrolysis of the intermediary imine with 2M hydrochloric acid in tetrahydrofuran, the title compound was obtained as an oil (0.131 g, 69%). 1H NMR (300 MHz, CDCl3): δ 6.39 (d, 1H, J=2.3 Hz), 6.33 (d, 1H, J=2.3 Hz), 4.15 (s, 2H), 3.32 (br s, 2H), 3.03 (heptet, 1H, J=6.9 Hz), 1.28 (s, 6H), 1.22 (d, 6H, J=6.9 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH:15]=[CH:14][CH:13]=[N:12][C:11]=13)[N:8]=[CH:7][N:6]([C@@H:16]1[C@@H:21]([OH:22])[CH2:20][CH2:19][O:18][CH2:17]1)[C:5]2=[O:23].C([O-])(=O)C.[K+].[B:29]1(B2OC(C)(C)C(C)(C)O2)[O:33]C(C)(C)C(C)(C)[O:30]1.ClCCl.[OH-].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:22][C@H:21]1[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]1[N:6]1[C:5](=[O:23])[C:4]2[C:9](=[C:10]3[CH:15]=[CH:14][CH:13]=[N:12][C:11]3=[C:2]([B:29]([OH:33])[OH:30])[CH:3]=2)[N:8]=[CH:7]1
Reactant: O=c1c2cc(Br)c3ncccc3c2ncn1[C@H]1COCC[C@@H]1O
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1c2cc(B(O)O)c3ncccc3c2ncn1[C@H]1COCC[C@@H]1O
Temperature: 80 °C

Procedure:
To a solution of 6-bromo-3-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]pyrido[2,3-h]quinazolin-4(3H)-one (1.00 g, 2.66 mmol) in 6 mL of DMF under an atmosphere of nitrogen was added potassium acetate (0.783 g, 7.97 mmol), bis(pinacolato)diboron (1.01 g, 3.99 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), 1:1 complex with dichloromethane (0.217 g, 0.266 mmol). The mixture was heated at 80° C. for 2 h, cooled to rt, and treated with 1 N aqueous sodium hydroxide to pH ˜9. The aqueous solution was washed 2× with dichloromethane, then treated with 10% aqueous potassium phosphate to pH ˜7. A brown solid was collected via filtration to provide {3-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-4-oxo-3,4-dihyrdopyrido[2,3-h]quinazolin-6-yl}boronic acid that gave a mass ion (ES+) of 342.0 for [M+H]+.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[OH-].[Na+]>O>[C:1]1([S:7]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccnc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(Oc1cccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46 %

Procedure:
Equimolar portions (0.105 moles) of benzensulfonyl chloride, 3-hydroxy pyridine, (3-pyridinol) and sodium hydroxide were combined in 150 ml of water, heated to ca 50° C. for 1.5 hours, and allowed to stir at ambient temperature for 3 days. The product was extracted with methylene chloride, dried over sodium sulfate, and evaporated to yield an oil that was purified by distillation, bp 135° C. (0.02 torr) to yield 46% of the theoretical weight of 3-pyridinyl benzensulfonate.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:20]=[C:19]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[NH:4][N:3]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1ncnc2[nH]nc(-c3cccc(OC(F)(F)F)c3)c12
Temperature: 80 °C
Reaction time: 12 h
Yield: 41.1 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.00 g, 3.83 mmoles) in DMF (14 ml), ethanol (7 ml) and water (7 ml), 3-trifluoromethoxyphenyl boronic acid (1.025 g, 4.97 mmoles) and sodium carbonate (2.02 g, 19.15 mmoles) were added and the system is degassed for 30 min Tetrakis triphenylphosphine Palladium (0.871 g, 0.754 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as yellow solid (0.465 g, 41% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.71(s, 1H), 8.22(s, 1H), 7.70(m, 2H), .7.59(s, 1H), 7.46(td, J=7.9,1.4Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH:12]=O)[O:7][CH2:6][CH2:5]2.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][N:26]1[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]1)[O:7][CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1c(Br)ccc2c1CCOC2C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(Br)ccc2c1CCOC2CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-bromo-5-methoxy-3,4-dihydro-1H-isochromene-1-carbaldehyde (230 mg, 0.85 mmol) in 10 mL of DCM was added Boc-piperazine (189 mg, 1.02 mmol) and NaBH(OAc)3 (720 mg, 3.4 mmol), and the mixture was stirred at room temperature overnight. The reaction was diluted with DCM, and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give tert-butyl 4-[(6-bromo-5-methoxy-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine-1-carboxylate.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH:9]=1)=[O:4].[CH3:23][O:24][CH:25]([O:29][CH3:30])[CH2:26][NH:27][CH3:28]>C(#N)C>[CH3:23][O:24][CH:25]([O:29][CH3:30])[CH2:26][N:27]([CH3:28])[C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH:9]=1)=[O:4]
Reactant: O=C(Cc1cccc(F)c1F)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reactant: CNCC(OC)OC
Solvent: CC#N
Product: COC(CN(C)C(=O)c1cc(C(=O)Cc2cccc(F)c2F)c[nH]1)OC
Yield: 99.5 %

Procedure:
2,2,2-Trichloro-1-{4-[(2,3-difluoro-phenyl)-acetyl]-1H-pyrrol-2-yl}-ethanone (300 mg, 0.82 mmol) and (2,2-Dimethoxy-ethyl)-methyl-amine (116 μL, 0.900 mmol) in acetonitrile were heated for 5 hr. Evaporation afforded 299 mg (99%) of 4-[(2,3-Difluoro-phenyl)-acetyl]-1H-pyrrole-2-carboxylic acid (2,2-dimethoxy-ethyl)-methyl-amide. 1H NMR (500 MHz, CDCl3) δ: 10.1-9.9 (1H, vbs), 7.02-6.96 (5H, cm), 4.51 (1H, s), 4.05 (2H, s) 3.59 (3H, bs), 3.39-3.36 (6H, s). LC/MS: Rt 3.13 mins.; m/e 367.26 (M+H), 365.34 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([O:10]C)=O.[Cl:12][CH2:13][C:14]#[N:15]>Cl.C1(OC)CCCC1>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:10])[NH:15][C:14]([CH2:13][Cl:12])=[N:1][C:2]=2[CH:6]=1
Reactant: COC(=O)c1sc(Br)cc1N
Reactant: N#CCCl
Agent: Cl
Solvent: COC1CCCC1
Product: O=c1[nH]c(CCl)nc2cc(Br)sc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 3-amino-5-bromothiophene-2-carboxylate (15 g) produced in Example 1, step C, chloroacetonitrile (12 mL) and 4M hydrochloric acid/cyclopentylmethylether solution (100 mL) was stirred at room temperature for 2 hr, and stirred at 70° C. for 1 hr. The reaction system was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the residue. The precipitate was collected by filtration and washed with water. The obtained solid was dried at 80° C. for 8 hr under reduced pressure to give the title compound (18 g) as a pale-brown solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[O:14][CH3:15].[CH3:16][N:17]=[C:18]=[O:19]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:16][NH:17][C:18]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[O:14][CH3:15])=[O:19]
Reactant: CN=C=O
Reactant: COc1cc(OC)c2ccccc2c1O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CNC(=O)Oc1c(OC)cc(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.00 g of 1-hydroxy-2,4-dimethoxynaphthalene, prepared as shown in Preparations 7 and 8, in 50 ml of tetrahydrofuran was added 0.335 g of methyl isocyanate followed by 0.12 g of 4-dimethylaminopyridine. The solution was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate, washed with dilute hydrochloric acid and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue chromatographed on silica gel, eluting with methylene chloride, giving 1-methylcarbamoyloxy-2,4-dimethoxynaphthalene, m.p. 131°-133° C.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][N:22]3[CH:28]=2)=[CH:15][CH:14]=1)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+].O>O1CCCC1.C(#N)C>[OH:1][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][N:22]3[CH:28]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCOc1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: OCCCOc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
1.52 g (corresponding to 2.99 mmol) of 2-[4′-(3″-t-butyldimethylsiloxypropoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine was dissolved in 5.0 mL of tetrahydrofuran, and 2.99 mL of a 1.0 mol/L tetrahydrofuran solution of tetrabutylammoniumfluoride was added thereto. After the reaction mixture was stirred at room temperature for 30 minutes, ammonium chloride solution was added followed by the addition of 10 mL of water and 5.0 mL of acetonitrile to filter precipitates. The filtered precipitates were washed with water and acetonitrile in this order, to obtain 1.03 g (corresponding to 2.61 mmol) of 2-[4′-(3″-hydroxypropoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine (FIG. 2-10, Step 5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2(O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(O)CC(=O)c3ccccc32)c1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: COc1cccc(C2CC(=O)c3ccccc32)c1
Reaction time: 16 h
Yield: 23.2 %

Procedure:
A solution of 3-(3-methoxyphenyl)-3-hydroxyindan-1-one (2.3 g) in 25 ml methylene chloride was stirred at 0°, then treated sequentially with 1.6 ml triethylsilane and 3.3 ml of boron trifluoride etherate. The mixture was warmed to 25° and stirred for 16 hours, then diluted with water and extracted with additional methylene chloride. After drying (MgSO4) and concentration, the residue was chromatographed on silica gel to provide the title compound as a light yellow oil (0.5 g, 23%). NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[N:4]1[CH2:10][C:11]([OH:13])=[O:12].O[N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21]>CN(C=O)C>[O:21]=[C:16]1[CH2:17][CH2:18][C:19](=[O:20])[N:15]1[O:12][C:11](=[O:13])[CH2:10][N:4]1[CH:3]([CH3:2])[CH2:8][CH2:7][CH2:6][CH:5]1[CH3:9]
Reactant: CC1CCCC(C)N1CC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: Cl
Solvent: CN(C)C=O
Product: CC1CCCC(C)N1CC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12.60 g (60 mMol) (2,6-Dimethyl-piperidin-1-yl)-acetic acid hydrochloride (5), in 100 ml DMF, was added to 7.02 g (60 mMol) N-hydroxysuccinimide and 12.58 g (60 mMol) N,N-dicyclohexylcarbodiimide. The reaction mixture was stirred for 16 h at RT. The residue was filtered and the filtrate was evaporated in vacuo to dryness. After dissolving the residue in 300 ml CH2Cl2, the solution was washed with NaHCO3, dried over sodium sulphate and the solvent was evaporated. The compound was then recrystallised from diisopropylether (activated charcoal).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]2[N:22]([CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:21]3[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:20]=3[N:19]=2)=[C:6]([CH:17]=1)[O:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13].[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]2[N:22]([CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:21]3[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:20]=3[N:19]=2)=[C:6]([O:7][CH2:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([C:12]3[NH:38][N:37]=[N:36][N:13]=3)[CH:10]=2)[CH:17]=1
Reactant: N#Cc1cccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCc3cccc(-c4nnn[nH]4)c3)n(CC3CCCCC3)c2cc1F
Temperature: 120 °C
Yield: 14 %

Procedure:
To a stirred solution of 3-[5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenoxymethyl]-benzonitrile (0.15 g, 0.30 mmol) in N,N-dimethylformamide (10 ml) was added sodium azide (27 mg, 0.42 mmol) and ammonium chloride (22 mg, 0.42 mmol) and the reaction mixture was heated for 12 h at 120° C. The solvent was evaporated under reduced pressure, the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography over silica gel (4-5% methanol/dichloromethane) to yield the desired compound as a colorless powder (14%). MS (Turbo Spray): m/z=535.2 (M+H).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[CH:6][C:7]([N+:29]([O-:31])=[O:30])=[C:8]([NH:10][C:11]2[S:12][C:13]([C:26]([NH2:28])=[O:27])=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:15]=2)[CH:9]=1.C(#N)C.Cl>O>[CH:3]([C:4]1[CH:5]=[CH:6][C:7]([N+:29]([O-:31])=[O:30])=[C:8]([NH:10][C:11]2[S:12][C:13]([C:26]([NH2:28])=[O:27])=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)[N:15]=2)[CH:9]=1)=[O:2]
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(Nc2nc(-c3ccc(C(F)(F)F)cc3)c(C(N)=O)s2)c1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1ccc(C(F)(F)F)cc1
Yield: 70.7 %

Procedure:
A mixture of 0.9023 g (1.87 mmole) of 2-(5-dimethoxymethyl-2-nitro-phenylamino)-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide, 34 mL of acetonitrile and 17 mL of 1M hydrochloric acid was heated at 60 degrees for 2 hours. The cooled mixture was diluted with 50 mL of water. The resulting precipitate was collected by filtration, washed with water and dried to give 0.5766 g of 2-(5-formyl-2-nitro-phenylamino)-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.47b) as an orange-red solid.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:22](=[O:24])[CH3:23])=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(CNCc2ccc([N+](=O)[O-])cc2)cc1
Solvent: c1ccncc1
Product: CC(=O)N(Cc1ccc([N+](=O)[O-])cc1)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a solution of bis(4-nitrobenzyl)amine (500 mg, 1.741 mmol) in pyridine (9 mL) was slowly added acetic anhydride (0.18 mL, 1.92 mmol) via syringe. The resulting mixture was stirred at rt for 2 hours, and the reaction was concentrated in vacuo. The residue was dissolved in toluene and evaporated to dryness in vacuo. The residue was dissolved in 19:1 EtOAc:methanol, washed with water and brine, dried (Na2SO4), filtered and concentrated to afford the title compound (551 mg, 96%). MS (APCI) m/z 330.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:17]2[CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[N:14]([C:23](=[O:37])[CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:13][C:12]=2[N:11]=[CH:10]1.[OH-].[Na+]>C1COCC1.CO.Cl.CO.O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:17]2[CH2:16][CH:15]([C:18]([OH:20])=[O:19])[N:14]([C:23](=[O:37])[CH:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:13][C:12]=2[N:11]=[CH:10]1
Reactant: CCOC(=O)C1Cc2c(ncn2Cc2ccccc2O)CN1C(=O)C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1Cc2c(ncn2Cc2ccccc2O)CN1C(=O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of the product from Example 16 (2.35 g) in 25 mL THF-methanol (2:1) is treated with 10 mL 1N NaOH, stirring 90 min at 25° C. After treatment with 10 mL 1N HCl, the mixture is diluted with 60 mL methanol-water (2:1) and concentrated in vacuo until a thick slurry forms. The slurry is diluted with water and the desired carboxylic acid is collected by filtration. MS (FAB) 468 (M+1); mp 187°-190° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:10])[NH:8][CH:9]=1)([O-:3])=[O:2].Cl.[Cl:12]([O-])(=O)=O.[K+]>O>[Cl:12][C:6]1[C:7](=[O:10])[NH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: O=c1ccc([N+](=O)[O-])c[nH]1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]cc([N+](=O)[O-])cc1Cl
Reaction time: 8 h

Procedure:
5-Nitro-2-pyridone (Aldrich Chemical Company) (100 g, 0.71 mol) was added to 1 liter conc. HCl at room temperature, followed by the dropwise addition of a solution of potassium chlorate (87.5 g, 0.71 mol) in 1.2 liter water. A solid material formed during the addition. The mixture was stirred overnight, filtered, and the collected material recrystallized from 50 percent aqueous ethanol. The yield was 77.2 g, 62 percent, m.p. 196°-198° C.
Reaction SMILES: C(OC(NCCC(O)=O)=O)(C)(C)C.[B-](F)(F)(F)F.CCO[C:22]([C:24]([C:34]#[N:35])=NOC(N(C)C)=[N+](C)C)=[O:23].[CH3:36][C:37]1[CH:46]=[C:45]([NH2:47])[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([NH2:48])[CH:43]=2)[N:38]=1.C(N1CCOCC1)C>CN(C=O)C>[NH2:35][CH2:34][CH2:24][C:22]([NH:48][C:42]1[CH:43]=[C:44]2[C:39](=[CH:40][CH:41]=1)[N:38]=[C:37]([CH3:36])[CH:46]=[C:45]2[NH2:47])=[O:23]
Reactant: Cc1cc(N)c2cc(N)ccc2n1
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN1CCOCC1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(N)c2cc(NC(=O)CCN)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 182.5 %

Procedure:
To a solution of 2.18 g (11.55 mmol) of 3-tert-Butoxycarbonylamino-propionic acid in 20 ml of DMF were added 3.78 g (11.55 mmol) TOTU. After 15 min at room temperature 2.0 g (11.55 mmol) of 2-methyl-quinoline-4,6-diamine and 2.66 g (23 mmol) of N-ethylmorpholine were added. After 24 h stirring at room temperature the solution was evaporated and the residue was treated with a saturated aqueous solution of NaHCO3. The aqueous solution was extracted with ethyl acetate. The separated organic layer was dried (Na2SO4) and evaporated. The residue was treated with 20 ml 90% trifluoroacetic acid for 2 h. After evaporation the residue was dissolve in water and extracted with ethyl acetate. The aqueous layer was lyophilized to yield 5.15 g (76%) of the title compound. MS 245.1 (M+)+.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[C:4]([CH3:38])=[C:5]([CH3:37])[C:6]2[O:11][C:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]5[S:31][CH:32]=[CH:33][CH:34]=5)=[NH:29])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)=[O:14])([CH3:12])[CH2:9][CH2:8][C:7]=2[C:35]=1[CH3:36]>CS(C)=O>[ClH:1].[OH:2][C:3]1[C:4]([CH3:38])=[C:5]([CH3:37])[C:6]2[O:11][C@:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]5[S:31][CH:32]=[CH:33][CH:34]=5)=[NH:29])=[CH:25][CH:26]=4)[CH2:17][CH2:16]3)=[O:14])([CH3:12])[CH2:9][CH2:8][C:7]=2[C:35]=1[CH3:36]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N1CCN(c3ccc(NC(=N)c4cccs4)cc3)CC1)O2
Agent: Cl
Solvent: CS(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(C(=O)N1CCN(c3ccc(NC(=N)c4cccs4)cc3)CC1)O2

Procedure:
The NMR and IR analyses are identical to compound 13. [ α ] D 20 = - 43.5 ⁢ ° ⁢   ⁢ ( c = 0.11 ;   ⁢ DMSO )
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=2[CH:5]=[C:4]([CH:13]=[O:14])[CH:3]=1.[O-:15][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[Br:1][C:2]1[C:10]2[O:9][CH2:8][C:7]([CH3:11])([CH3:12])[C:6]=2[CH:5]=[C:4]([C:13]([OH:15])=[O:14])[CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC1(C)COc2c(Br)cc(C=O)cc21
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)COc2c(Br)cc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
A solution of 7-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-5-carbaldehyde (14.61 g, 57.29 mmol) in acetone (80 mL) was added at room temperature to KMnO4 (9.05 g, 57.29 mmol) dissolved in water (200 mL). The reaction mixture was stirred at room temperature overnight filtered over celite then H2SO4 in water was added and the solution extracted with ethyl acetate. The organic layer was further washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 9.9 g of 7-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-5-carboxylic acid (64%). 1H NMR (300 MHz; CDCl3): 1.40 (s, 6H), 4.44 (s, 2H), 7.79 (s, 1H), 8.13 (s, 1H). c. 7-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-5-carbaldehyde.