Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:14][NH:15][CH3:16]>>[CH3:14][N:15]([CH3:16])[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CNC
Product: CN(C)c1ccc([N+](=O)[O-])c(C(=O)O)c1

Procedure:
Concretely, 5-chloro-2-nitrobenzoic acid is dissolved in a dimethylamine aqueous solution and heated to produce 5-dimethylamino-2-nitrobenzoic acid. Hydrochloric acid is added to the reaction solution to precipitate out the product as a solid material. The solid material is separated to obtain 5-dimethylamno-2-nitrobenzoic acid almost quantitatively.
Reaction SMILES: C[C:2]1[C:9](F)=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][NH2:15]>CN(C=O)C>[CH3:14][NH:15][C:9]1[CH:2]=[C:3]([CH:6]=[CH:7][C:8]=1[N+:11]([O-:13])=[O:12])[C:4]#[N:5]
Reactant: CN
Reactant: Cc1c(C#N)ccc([N+](=O)[O-])c1F
Solvent: CN(C)C=O
Product: CNc1cc(C#N)ccc1[N+](=O)[O-]

Procedure:
3-Methylamino-4-nitro-benzonitrile (1.58 mg) was prepared by following General Procedure A starting from methyl 3-fluoro-4-nitrobenzonitrile (1.66 g) and methylamine (2 M in THF, 10.0 mL) in DMF. The crude product was used in the next step without further purification.
Reaction SMILES: O1CCC[CH2:2]1.[CH3:6][O:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]([CH3:18])[C:9]=1[CH:19]([C:21]1[C:26]([Br:27])=[CH:25][N:24]=[CH:23][C:22]=1Br)[OH:20].C([Li])CCC.CI>O>[CH3:6][O:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]([CH3:18])[C:9]=1[CH:19]([C:21]1[C:22]([CH3:2])=[CH:23][N:24]=[CH:25][C:26]=1[Br:27])[OH:20]
Reactant: C1CCOC1
Reactant: COc1cc(C)c(C(O)c2c(Br)cncc2Br)c(OC)c1OC
Agent: [Li]CCCC
Solvent: O
Solvent: CI
Product: COc1cc(C)c(C(O)c2c(C)cncc2Br)c(OC)c1OC
Reaction time: 0.08 h
Yield: 25 %

Procedure:
A tetrahydrofuran (15 ml) solution of 2.0 g (4.6 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(3,5-dibromo-4-pyridyl)methanol obtained in step (a) was cooled to −78° C., 6.0 ml (9.4 mmol) of n-butyllithium (1.56 M hexane solution) was dropwise added thereto, followed by stirring for 5 minutes, and 0.5 ml (8.0 mmol) of methyl iodide was added thereto, followed by stirring for 2.5 hours. 20 ml of water was added, and tetrahydrofuran was distilled off under reduced pressure. The aqueous layer was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 0.44 g (yield 25%) of (2,3,4-trimethoxy-6-methylphenyl)(3-bromo-5-methyl-4-pyridyl)methanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16]([CH2:17][OH:18])=[CH:15][S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].CC(O)=O.C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16]([CH2:17][OH:18])=[C:15]([Br:30])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2Cc3c(CO)csc3C2C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)N1CC2Cc3c(sc(Br)c3CO)C2C1
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of the product from Example 17, step c) (199 mg, 0.79 mmol) in CHCl3 (3 ml) and AcOH (3 ml) was added NBS (156 mg, 0.88 mmol). The reaction mixture was stirred for 30 minutes, quenched with saturated NaHCO3 (10 ml), and extracted with EtOAc (20 ml). The EtOAc layer was dried (MgSO4), filtered, and solvent evaporated in vacuo to give the crude product that was purified by silica-gel preparative TLC (hexanes:EtOAc-3:1) providing the subtitle compound (99.6 mg, 36%). 1H NMR (300 MHz, CDCl3, ppm) 1.22 (t, J=7 Hz, 3H); 2.42 (br s, 1H); 2.63-2.78 (m, 1H); 2.95-3.18 (m, 2H); 3.30-3.48 (br m, 1H); 3.50-3.72 (br m, 2H); 3.75-3.88 (br m, 2H); 4.08 (q, J=7 Hz, 2H); 4.52 (s, 2H).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[O:10][C:9](=[O:17])[CH:8]=[CH:7]2)[CH:2]=[CH2:3].[C:18](OC(=O)C)(=[O:20])[CH3:19].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:18]([O:14][C:13]1[C:12]([O:15][CH3:16])=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:17])[O:10]2)=[CH:5][C:4]=1[CH2:1][CH:2]=[CH2:3])(=[O:20])[CH3:19]
Reactant: C=CCc1cc2ccc(=O)oc2c(OC)c1O
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=CCc1cc2ccc(=O)oc2c(OC)c1OC(C)=O
Reaction time: 2 h

Procedure:
A solution of 2.32 g. (0.010 mole) of 6-allyl-7-hydroxy-8-methoxycoumarin in 8 ml. of chloroform was treated with 4.5 ml. of acetic anhydride/pyridine, 1:2. The reactants were stirred at 25° for 2.0 hours and then partitioned between 1 N HCl/methylene chloride. The aqueous phase was further extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, and evaporated to afford pure 7-acetoxy-6-allyl-8-methoxycoumarin as a white solid, mp 101°-102°. Recrystallization from ethanol afforded an analytical sample, mp 102°14 103°.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:11][NH2:12].O1CCCC1>O1CCCC1.O>[CH3:11][NH:12][S:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(Br)s1
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromothiophene-2-sulfonyl chloride (602 mg) in tetrahydrofuran (5 mL) was added dropwise a solution of 2.0M methylamine-tetrahydrofuran (3.5 mL) on an ice bath. After stirring for 15 minutes on an ice bath, the solution was diluted with water and extracted with ethyl acetate. After washing with an aqueous solution of saturated sodium bicarbonate and saturated sodium chloride water, the solution was dried with anhydrous sodium sulfate. After filtration through silica gel, the solvent was removed by evaporation to provide the title compound (608 mg) as a colorless oily matter.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([N:25](C)[C:26](=O)OC(C)(C)C)[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:42])[CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:15]3[CH:43]=[CH:44][CH:45]=[CH:46][C:14]1=3)=[C:7]([O:47][CH3:48])[CH:6]=[CH:5]2.[ClH:49]>CO.CCOCC>[ClH:49].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([NH:25][CH3:26])[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36](=[O:42])[CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:15]3[CH:43]=[CH:44][CH:45]=[CH:46][C:14]1=3)=[C:7]([O:47][CH3:48])[CH:6]=[CH:5]2
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccccc21
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3cc(Br)ccc23)c2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a rt solution of tert-butyl(S)-1-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (80 mg, 107 μmol) in MeOH (107 μl) was added 2 M HCl in Et2O (429 μl). The reaction was stirred at rt for 2 h then concentrated, taken up in H2O, and lyophilized to provide (S)-N-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (65.7 mg, 90%) as a white solid. MS m/z 645/647 (MH)+.
Reaction SMILES: C(OC[C:6]1[O:7][C:8]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:9]=2[CH:10]=1)(=O)C.C(=O)([O-])[O-:18].[K+].[K+].C(OCC)(=O)C>CO>[F:16][C:11]1[C:9]2[CH:10]=[C:6]([OH:18])[O:7][C:8]=2[C:14]([F:15])=[CH:13][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OCc1cc2c(F)ccc(F)c2o1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1cc2c(F)ccc(F)c2o1
Reaction time: 2 h
Yield: 84.9 %

Procedure:
The 2-acetoxymethyl-4,7-difluorobenzofuran (252 mg) was dissolved in methanol (5 ml). After adding potassium carbonate (455 mg) at room temperature, the resulting mixture was stirred at the same temperature for 2 hr. Then ethyl acetate was added to the liquid reaction mixture and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: 5% ethyl acetate/n-hexane) to give 4,7-difluoro-2-hydroxybenzofuran (161 mg) as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)[CH2:12][CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1>>[CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[N:6]=[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH3:13])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1N
Reactant: CCC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCC(=Nc1ccccc1C(C)C)c1ccccc1
Temperature: 200 °C

Procedure:
2-Isopropylaniline (11.6 mL, 82 mmol, Aldrich) was mixed with propiophenone (10 mL, 74.5 mmol, Aldrich) and p-TsOH (1.4 g, 7.3 mmol, Aldrich). The resulting mixture was heated for 2 h at 200° C. under a slow stream of Ar to remove H2O that formed. After cooling to RT the reaction mixture was poured into hexanes (100 mL), filtered, the precipitate washed with additional hexanes (2×100 mL) followed by the evaporation of the filtrate. The residue was filtered through a 9×4.1 cm plug of silica gel in hexanes/ether 10/1 (300 mL collected). After evaporation of the solvent the residue was distilled in vacuo. The initial fraction contained unreacted starting materials (45–50 C/0.4 mm), in the next fraction the product was collected as an orange oil, bp 125–135 C/0.4 mm, 8.0 g, (42.7%). 1H NMR (CDCl3) 8.03–7.95 (m, 2H); 7.53–7.46 (m, 3H); 7.34 (dd, 1H; J=1.4; 7.6 Hz); 7.21 (dt, 1H; J=1.4; 7.6 Hz); 7.1 (dt, 1H; J=1.4; 7.6 Hz); 6.65 (dd, 1H; J=1.4; 7.6 Hz); 3.00 (septet, 1 H; J=6.9 Hz); 2.67 (q, 2H; J=7.6 Hz); 1.22 (d, 6H; J=6.8 Hz); 1.11 (t, 3 H; J=7.6 Hz).
Reaction SMILES: [F:1][C:2]1[C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][CH:5]=[C:4]([F:16])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([O:25]C)=[O:24])[CH:20]=[CH:19][CH:18]=1.[CH2:27]([Zn]CC)[CH3:28]>C1(C)C=CC=CC=1.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].C(Cl)Cl>[CH2:27]([C:7]1[C:2]([F:1])=[C:3]([C:17]2[N:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[CH:19][CH:18]=2)[C:4]([F:16])=[CH:5][CH:6]=1)[CH3:28]
Reactant: COC(=O)c1cccc(-c2c(F)ccc(OS(=O)(=O)C(F)(F)F)c2F)n1
Reactant: CC[Zn]CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCc1ccc(F)c(-c2cccc(C(=O)O)n2)c1F
Temperature: 70 °C

Procedure:
To a solution of methyl 6-(2,6-difluoro-3-(trifluoromethylsulfonyloxy)-phenyl)picolinate (1.0 equiv.) in toluene (0.15 M) was added Pd(dppf)Cl2-DCM (0.1 equiv.) followed by diethyl zinc (3.0 equiv.). The solution turned from orange to bright yellow. The reaction was heated to 70° C. for 2 hours at which time, LC/MS analysis indicated a mixture of 1:3:1 ratio of hydrolyzed product, desired product and unknown by-product. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with 1N NaOH (2×). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to provide a brown oil. The oil was redissolved in THF and treated with 1N NaOH for one hour. The reaction was then diluted with ethyl acetate and washed with 1N NaOH (2×). The basic washings were combined, acidified with concentrated HCl and extracted with ethyl acetate (3×). The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide 6-(3-ethyl-2,6-difluorophenyl)picolinic acid as a light brown oil in >99% yield. LC/MS=264.1 (M+H), Rt=0.88 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:18])[C:10]([C:13]([CH3:17])([CH3:16])[CH:14]=O)=[N:11][N:12]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:18])[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:11][N:12]=1
Reactant: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)C=O
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)CNc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-[5-(2-Chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]-2-methylpropanal (200 mg) was dissolved in 1,2-dichloroethane (4 ml) and then aniline (73 μl) and sodium triacetoxyborohydride (225 mg) were added thereto, followed by stirring at room temperature for 3 days. The reaction solution was diluted with a saturated aqueous sodium bicarbonate solution (30 ml), followed by extraction with chloroform (10 ml×3). The organic layer was dried and then concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (methanol:chloroform=2:98). The resulting solid washed with diethyl ether to obtain 98 mg of N-{2-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]-2-methylpropyl}aniline (white solid).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[C:28]([CH:38]([CH3:40])[CH3:39])[NH:27][N:26]=1)(=[O:3])[CH3:2].[N+](C1C=C(S(O[CH2:54][C@@H:55]2[O:57][CH2:56]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:54][C@@H:55]3[O:57][CH2:56]3)=[CH:35][CH:36]=2)=[C:28]([CH:38]([CH3:40])[CH3:39])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OC[C@H]3CO3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.1 %

Procedure:
A mixture of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-hydroxyphenyl)methyl]-5-isopropyl-1H-pyrazole (0.55 g), (R)-1-(3-nitrobenzenesulfonyloxy)-2,3-epoxypropane (0.38 g) and cesium carbonate (0.57 g) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(R)-2,3-epoxypropoxy]phenyl}methyl)-5-isopropyl-1H-pyrazole (0.4 g). This material (43 mg) was dissolved in ethanol (1.5 mL). To the solution was added 2-amino-2-methyl-1,3-propanediol (51 mg), and the mixture was stirred at 75° C. for 14 hours. To the reaction mixture was added 1 mol/L aqueous sodium hydroxide solution (0.28 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μm, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient, water/methanol 90/10-10/90) to give the title compound (12 mg).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)=[CH:18]\[CH2:19][O:20][C:21]2[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:23]([CH3:33])[CH:22]=2)=[CH:13][CH:12]=1>O1CCCC1.C(N(CC)CC)C.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:33][C:23]1[CH:22]=[C:21]([O:20][CH2:19]/[CH:18]=[C:17](\[C:14]2[CH:15]=[CH:16][C:11]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[CH:12][CH:13]=2)/[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[CH:32]=[CH:31][C:24]=1[O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: C#CCN1CCOCC1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2cccc(C(F)(F)F)c2)cc1C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2cccc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-Propargylmorpholine (171 mg, 1.37 mmol) was added to a solution of methyl (E)-[4-[3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.68 mmol; prepared as described in example 34) in a mixture of tetrahydrofuran (12 mL) and triethylamine (12 mL). The mixture was degassed and copper(I) iodide (20 mg, 0.108 mmol) and tetrakis(triphenylphosphine)-palladium (62 mg, 0.054 mmol) were added. The reaction mixture was degassed once more and then stirred at ambient temperature for 2 days under argon. The mixture was evaporated in vacuo; the residue was dissolved in ethyl acetate (50 mL) and the solution was washed with water (2×15 mL) and brine (10 mL). The organic solution was dried with anhydrous magnesium sulfate and its evaporation gave oil that was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 1:1) yielding methyl (E)-[2-methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyl-oxy]phenoxy]acetate as oil.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=O.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:20]([O:19][C:17]([N:11]1[CH2:16][CH2:15][N:14]([CH2:1][C:3]2[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=2)[CH2:13][CH2:12]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(C(=O)O)s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)O)s2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 194.1 %

Procedure:
To a solution of 5-formylthiophene-2-carboxylic acid (0.505 g, 3.23 mmol) in MeOH (35 mL) and acetic acid (0.30 mL) was added tert-butyl piperazine-1-carboxylate (1.20 g, 6.47 mmol) and sodium cyanoborohydride (0.406 g, 6.47 mmol). The reaction mixture was allowed to stir at rt for 15 h and was then concentrated to give 5-{[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}thiophene-2-carboxylic acid (2.05 g, 6.27 mmol) as a white solid. LCMS: (FA) ES+ 327.3, ES-325.4.
Reaction SMILES: F[C:2]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([C:10]([F:13])([F:12])[F:11])[C:3]=1[NH2:4].SC1SC2C(F)=CC=C(C(F)(F)F)C=2N=1.[Cl:29][C:30]1[S:31]C2C=CC(Cl)=CC=2N=1>>[Cl:29][C:30]1[S:31][C:2]2[C:8]([F:9])=[CH:7][CH:6]=[C:5]([C:10]([F:13])([F:12])[F:11])[C:3]=2[N:4]=1
Reactant: Nc1c(C(F)(F)F)ccc(F)c1F
Reactant: Clc1ccc2sc(Cl)nc2c1
Agent: Fc1ccc(C(F)(F)F)c2nc(S)sc12
Product: Fc1ccc(C(F)(F)F)c2nc(Cl)sc12
Temperature: 90 °C

Procedure:
The title compound was prepared from 2,3-difluoro-6-trifluoromethylaniline via 2-mercapto-7-fluoro-4-trifluoromethyl-1,3-benzothiazole as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 90° C. for 4 h.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].I.C(O)(=O)C>C(OCC)(=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Agent: I
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
A mixture of 432 mg of 1-bromo-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (1 mmol), 63 mg of red phosphorous (2 mmol), 0.4 ml of aqueous 57 wt % HI (3 mmol), and 1 ml of glacial acetic acid was refluxed with stirring for 30 min. Then the reaction mixture was diluted with 25 ml of ethyl acetate, filtered by suction through a pad of celite, washed with a solution of 0.2 g of NaHSO3 in 5 ml of water, and washed two times with 5 ml of concentrated aqueous sodium bicarbonate solution. The organic phase was dried over MgSO4 and-evaporated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with hexanes:ethyl acetate (85:15). 123 mg of the title compound were obtained; 1H NMR (CDCl3): δ=11.85 (s, 1H), 8.60 (s, 1H), 8.23 (d, 1H), 7.38 to 7.63 (m, 7H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: [NH2:1][C:2]([CH3:23])([CH3:22])[CH2:3][C:4]1[N:5]([CH2:18][CH2:19][O:20][CH3:21])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=[O:29]>>[NH2:17][C:8]1[C:7]2=[N:6][N:5]([CH2:18][CH2:19][O:20][CH3:21])[C:4]([CH2:3][C:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:33]([F:34])=[C:25]([F:24])[CH:26]=3)([CH3:23])[CH3:22])=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Product: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)c1ccc(F)c(F)c1

Procedure:
Using the general method of Example 599, 1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (0.52 g, 1.66 mmol, prepared as described in Example 590) was reacted with 3,4-difluorobenzoyl chloride. The crude product was purified as described in Example 599 to provide 382 mg of N-{2-[4-amino-2-(methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}-3,4-difluorobenzamide as a white solid, mp 199-200° C. MS (ESI) m/z 454 (M+H)+; Anal. Calcd for C24H25F2N5O2: C, 63.57; H, 5.56; N, 15.44. Found: C, 63.37; H, 5.50; N, 15.58.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Cl[CH2:17][CH:18]([OH:27])[CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.[OH-].[Na+]>C(O)C.O>[C:10]1(/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:17][CH:18]([OH:27])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:7][CH:6]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OC(CCl)CCc1cccnc1
Reactant: Oc1ccc(/C=C/c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC(CCc1cccnc1)COc1ccc(/C=C/c2ccccc2)cc1
Yield: 40.2 %

Procedure:
Prepared according to the method described in Example 24b) from trans-4-hydroxystilbene (2.6 g), (±)-α-(chloromethyl)-3-pyridinepropanol (2.5 g) and sodium hydroxide (0.54 g) in ethanol (50 ml) and water (10 ml) at reflux for 2 hours to give the title compound as a solid (1.84 g)