Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:16]([O:20][C:21](=[O:33])[CH2:22][N:23]([C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27](Cl)[N:26]=1)[CH3:24])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>>[C:16]([O:20][C:21](=[O:33])[CH2:22][N:23]([C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:26]=1)[CH3:24])([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(N(C)CC(=O)OC(C)(C)C)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Nc2nc(C)cc(N(C)CC(=O)OC(C)(C)C)n2)ccc1-n1cnc(C)c1
Yield: 79 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and [(2-chloro-6-methyl-pyrimidin-4-yl)-methyl-amino]acetic acid tert-butyl ester, using potassium carbonate as a base. The title compound was isolated as a slightly yellow foam in a yield of 79%. MS ISP (m/e): 439.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.65 (s broad, 1H), 7.60 (d, 1H), 7.12 (d, 1H), 7.05-6.95 (m, 2H), 6.85 (s, 1H), 5.94 (s, 1H), 3.87 (s, 3H), 3.12 (s broad, 3H), 2.30 (s, 3H), 2.29 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[S:7]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8]1.Br[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[S:7]1[CH:11]=[CH:10][C:9]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=2)=[CH:8]1
Reactant: OB(O)c1ccsc1
Reactant: CC(=O)Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)Nc1ccc(-c2ccsc2)cc1
Yield: 52.9 %

Procedure:
A mixture of toluene (7.5 mL) and water (3 mL) was degassed with argon for 10 min, to which sodium carbonate (297 mg, 2.8 mmol) was added and the mixture was further degassed with argon for 5 min. Thiophene-3-boronic acid (215 mg, 1.68 mmol) and N-(4-bromo-phenyl)-acetamide (300 mg, 2.27 mmol) were added and the mixture was degassed with argon for another 10 min. To the above resulting mixture was added tetrakispalladium triphenylphosphine (161 mg, 0.14 mmol) and the mixture was degassed with argon for another 10 min. The resulting reaction mixture was heated to reflux for 3 hrs. After completion, the reaction mixture was diluted with ethyl acetate and washed with water followed by brine solution. The ethyl acetate layer collected was dried over sodium sulphate and concentrated under reduced pressure. Purification by column chromatography, (using silica gel 60-120 and 35% ethyl acetate in hexane as eluent) afforded 193 mg (63.44% Yield) of N-(4-thiophen-3-yl-phenyl)-acetamide.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[C:18]([OH:26])[CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].[CH3:28][NH:29][CH3:30].C=O.[CH3:33]C(C)=O>C(O)(=O)C>[CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16](=[CH:15][C:14]=1[CH2:13]3)[C:17]([CH2:28][N:29]([CH3:33])[CH3:30])=[C:18]([OH:26])[CH:19]=[CH:20]2)=[O:11].[CH3:3][C:8]([OH:9])=[O:7]
Reactant: CNC
Reactant: CC(C)=O
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(O)ccc3nc2-1
Agent: C=O
Solvent: CC(=O)O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(CN(C)C)c(O)ccc3nc2-1
Temperature: 45.29999923706055 °C
Reaction time: 0.08 h

Procedure:
0.3 Kg of 10-hydroxy camptothecin (Formula IV) prepared according to Example-1 was suspended in 6 L of acetic acid and stirred for 5 minutes. The obtained solution was charged into a reactor and stirred for 20 minutes. 0.51 L of a 40% aqueous solution of dimethyl amine and 0.078 L of a 37% of aqueous solution of formaldehyde were charged into the reactor, the temperature raised to 45.3° C. and the reaction mixture stirred for 2 hours at 45.3° C. The reaction solution was allowed to cool to 34.8° C. and then cooled to 27.5° C. 42 L of acetone was charged into above reaction solution and stirred for 1 hour at 27.5° C. for complete precipitation. The formed solid was filtered and the reactor rinsed with 1.5 L of acetone. The wet solid was washed with the rinsing and then washed with 0.3 L of 1-propanol. The resultant solid was suction dried for 20 minutes and then dried for 5 hours at 52° C. under a vacuum of 690 mm Hg to afford 330 g of title compound having a purity by HPLC of about 98.9%.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:7].[C:9]([C:12]1[CH:17]=[N:16][N:15]2[CH:18]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:20]=[C:14]2[C:13]=1Cl)(=[O:11])[NH2:10].ClC1C2N(C=C(Cl)C=2)N=CC=1C(N)=O>>[C:9]([C:12]1[CH:17]=[N:16][N:15]2[CH:18]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:20]=[C:14]2[C:13]=1[NH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][C:2]1([CH3:8])[CH3:1])(=[O:11])[NH2:10]
Reactant: CCOC(=O)c1cc2c(Cl)c(C(N)=O)cnn2c1
Reactant: CC1(C)CCC[C@H]1N
Agent: NC(=O)c1cnn2cc(Cl)cc2c1Cl
Product: CCOC(=O)c1cc2c(N[C@@H]3CCCC3(C)C)c(C(N)=O)cnn2c1

Procedure:
Prepared by reacting (R)-2,2-dimethylcyclopentylamine with ethyl 3-carbamoyl-4-chloropyrrolo[1,2-b]pyridazine-6-carboxylate (Preparation 4) according to the procedure described in Step 5 of Intermediate 4. HPLC (condition B): retention time=3.67 min. LCMS (condition E): m/z 345+ve. 1H NMR (400 MHz, MeOD) δ ppm 10.86 (1 H, br. s.), 8.20 (1 H, s), 8.01 (1 H, d, J=1.76 Hz), 7.38 (1 H, d, J=1.54 Hz), 4.27-4.43 (2 H, m), 4.13-4.29 (1 H, m), 2.29-2.46 (1 H, m), 1.58-1.92 (5 H, m), 1.38 (3 H, t, J=7.15 Hz), 1.13 (3 H, s), 1.10 (3 H, s).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2C([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:17][O:16][P:15]([O:19]CC)(=[O:18])[CH2:14][CH2:13]2)=C(Cl)[N:3]=1.[OH-:23].[Na+:24].[CH2:25]([OH:27])[CH3:26]>O>[NH:1]1[C:25](=[O:27])[C:26]2[N:6]=[CH:7][N:8]([CH2:11][CH:12]([CH2:17][OH:16])[CH2:13][CH2:14][P:15]([O-:19])(=[O:23])[O-:18])[C:9]=2[N:10]=[C:2]1[NH2:3].[Na+:24].[Na+:24]
Reactant: CCOP1(=O)CCC(Cn2cnc3c(Cl)nc(N)nc32)CO1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: Nc1nc2c(ncn2CC(CO)CCP(=O)([O-])[O-])c(=O)[nH]1

Procedure:
A solution of 2-amino-6-chloro-9-[(2-ethoxy-2-oxo-1,2-oxaphosphorinan-5-yl)methyl]purine (VSC 655; 102 mg, 0,295 mmol) in ethanol (2 ml), water (2 ml), and 2M aqueous sodium hydroxide (1.0 ml, 2 mmol) was kept at 80° C. for 3 days, neutralized by addition of weakly acidic Amberlite cation exchange resin, filtered, and evaporated to dryness to give disodium 3-(guanin-9-ylmethyl)-4-hydroxybutanephosphonate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([O-:3])=[O:2].C(N(CC)CC)C.Cl.Cl[CH2:25][C:26]1[C:27]([NH2:33])=[N:28][C:29]([CH3:32])=[N:30][CH:31]=1>CN(C)C=O>[CH3:32][C:29]1[N:28]=[C:27]([NH2:33])[C:26]([CH2:25][N:13]2[CH2:12][CH2:11][N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:15][CH2:14]2)=[CH:31][N:30]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CN2CCN(c3ccccc3[N+](=O)[O-])CC2)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
A solution of 1.25 g (0.0060 mol) of 1-(2-nitro-phenyl)-piperazine and 2.1 ml (0.015 mol) of triethylamine in 20 ml of dimethylformamide was treated with 0.97 g (0.0050 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride and the mixture was stirred at room temperature under argon for 3 hours. The mixture was completely freed from the solvents and the residue was triturated in 20 ml of water. The resulting crystals were filtered off under suction, dried and chromatographed over silica gel with dichloromethane/methanol 19:1 as the eluent. 1.25 g (76%) of 2-methyl-5- [4-(2-nitro-phenyl )-piperazin-1-ylmethyl]-pyrimidin-4-ylamine were obtained as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[CH2:9]=O.[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH3:9])[CH2:13][CH2:2][C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: C=O
Reactant: CNC
Reactant: CC(=O)c1cccs1
Product: CN(C)CCC(=O)c1cccs1

Procedure:
In this example, 2-acetylthiophene is used as the starting material for reacting with formaldehyde and dimethylamine to form a Mannich product namely 3-dimethylamino-1-(2-thienyl)propan-1-one. A hydride reduction is performed on this propanone to form corresponding 3-dimethylamino-1-(2-thienyl)propan-1-ol. The resulting propanol is then reacted with fluoronaphthalene to form N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine. Subsequently, racemic Duloxetine® is obtained by demethylation of this propylamine. In this process, the yield of demethylation is very low, about 41%. In addition, Duloxetine® produced via this route is racemic. Resolution is therefore needed to obtain chiral Duloxetine which renders this process less competitive.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][NH2:22])[CH3:19].C([O-])([O-])=O.[K+].[K+]>O>[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][NH:22][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2)[CH3:19]
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: CCCCC(CC)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCC(CC)CNc1nc(C)[nH]c2cc(-c3ccccc3)nc1-2
Yield: 62.5 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (70.0 mg, 0.29 mmol), 2-ethylhexylamine (Aldrich Chemical Company) (0.24 mL, 1.44 mmol) and K2CO3 (0.40 g, 2.87 mmol) in H2O (2 mL) to give 61 mg (63%) of the title compound as a white solid. An analytical sample was obtained by recrystallization from i-PrOH. Mp: 288-289° C. (dec.). 1H NMR (CDCl3; 500 MHz): δ 0.72-0.78 (m, 6), 1.15-1.34 (m, 9), 2.62 (s, 3), 3.56 (dd, 2, J=5.3, 7.6), 6.71 (s, 2), 7.17-7.24 (m, 3), 7.59 (d, 2, J=7.6), 12.78 (br s, 1). MS m/z: 337 (M+1), 335 (M−1). HRMS: Calcd for M+H: 337.2392. Found: 337.2397.
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]([NH2:15])=[NH:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.O.[NH2:17]N.[C:19]([NH:22][CH:23]([CH3:31])[C:24](=O)[C:25](OCC)=[O:26])(=[O:21])[CH3:20]>>[O:26]=[C:25]1[C:24]([CH:23]([NH:22][C:19](=[O:21])[CH3:20])[CH3:31])=[N:17][N:15]=[C:13]([CH2:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]=[CH:3][CH:4]=[CH:5]3)[NH:14]1
Reactant: N=C(N)Cc1ccc2ncccc2c1
Reactant: CCOC(=O)C(=O)C(C)NC(C)=O
Reactant: NN
Agent: Cl
Solvent: O
Product: CC(=O)NC(C)c1nnc(Cc2ccc3ncccc3c2)[nH]c1=O

Procedure:
Analogously to Example 10A, 3.5 g (15.8 mmol) 2-(6-quinolinyl)ethanamidine hydrochloride are reacted with 950 mg (19.0 mmol) of hydrazine hydrate and 4.43 g (23.7 mmol) of ethyl 3-(acetylamino)-2-oxobutanoate to give N-{1-[5-oxo-3-(6-quinolinylmethyl)-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}acetamide.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[C:16]1([S:22]([N:25]2[CH:29]=[CH:28][CH:27]=[CH:26]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:30][C:31]1[N:36]=[C:35]([CH:37]=[O:38])[CH:34]=[CH:33][CH:32]=1>C1COCC1.CCCCCC.O>[C:16]1([S:22]([N:25]2[CH:26]=[CH:27][CH:28]=[C:29]2[CH:37]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:30])[N:36]=2)[OH:38])(=[O:24])=[O:23])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccc(C=O)n1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C(O)c2cccn2S(=O)(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
Under nitrogen atmosphere, a solution of 2,2,6,6-tetramethyl-piperidine (5.00 mL) in THF (120 mL) was cooled to −78° C., and thereto was added dropwise a 1.6N solution of BuLi in hexane (18.5 mL), and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled again to −78° C., and thereto was added a solution of N-benzenesulfonylpyrrole (5.58 g) in THF (25 mL). The mixture was stirred for 30 minutes, and thereto was added a solution of 6-methyl-pyridine-2-aldehyde (3.94 g) in THF (20 mL), and the mixture was stirred at −78° C. for 2 hours. Water was added to the mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated brine and dried over MgSO4. The solvent was evaporated under reduced pressure, and the precipitated solid was suspended in a mixed solvent of hexane/ethyl acetate=5/1, and collected by filtration to give [1-(phenylsulfonyl)-1H-pyrrol-2-yl](6-methylpyridin-2-yl)methanol (6.78 g, 77%).
Reaction SMILES: B([O-])O[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C=CCCCCCC.B1C2CCCC1CCC2.[OH-].[Na+].Br[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C:37](=[O:42])[CH2:36][CH2:35]2>C1COCC1>[CH2:3]([C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C:37](=[O:42])[CH2:36][CH2:35]2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCOB[O-]
Reactant: O=C1CCc2cc(Br)ccc2C1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C=CCCCCCC
Product: CCCCCCCCc1ccc2c(c1)CCC(=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
An octyl boronate intermediate is first generated by adding 1-octene (1.38 g, 14.1 mmol) to a solution of 9-BBN in THF (28.3 mL of a 0.5 M solution, 14.1 mmol). The reaction is stirred at room temperature overnight, then an aqueous solution of sodium hydroxide (5.0 mL of a 3.0 M solution) is added, followed by the addition of 6-bromo-2-tetralone (2.40 g, 10.0 mmol) and Pd[P(Ph)3]4 (0.310 g, 0.270 mmol). The reaction is brought to reflux and maintained for 12 hours under an inert atmosphere. The reaction is then cooled, filtered, concentrated in vacuo and the residue purified using silica gel chromatography with hexanes/ethyl acetate (75:25) as solvent to provide 6-octyl-2-tetralone (2.35 g, 8.5 mmol, 85%) as a clear liquid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]=[C:11]=[S:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[CH3:14][NH:15][O:16][CH2:17][C:18]([OH:20])=[O:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([N:15]([CH3:14])[O:16][CH2:17][C:18]([OH:20])=[O:19])=[S:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: S=C=Nc1ccc2c(c1)CCC2
Reactant: CNOCC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(OCC(=O)O)C(=S)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.8 %

Procedure:
A mixture of 5-indanyl-isothiocyanate (18.5 g), N-methyl aminooxy acetic acid hydrochloride (16.2 g), triethylamine (25 g) and chloroform (150 mL) was heated at reflux for one half hour, stirred at ambient temperature for one hour, then evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with 2N HCl (2×400 mL) then with water (400 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness affording (31.3 g) of [[[[(5-indanyl)amino]thioxomethyl]methylamino]oxy]acetic acid as an oil. 1H-NMR (DMSO-d6; 300 MHz) δ13.1 (br s, 1H), 10.5 (s, 1H), 7.38 (s, 1H), 7.18 (m, 2H), 4.62 (s, 2H), 3.50 (s, 3H), 2.82 (m, 4H), and 2.03 ppm (m, 2H). The acid (26.1 g) was dissolved in benzene (200 mL). Phosphorus pentachloride (25 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (400 mL) and washed with sodium bicarbonate saturated solution (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (10% ethyl acetate in hexane). Crystallization from ether afforded the title compound (4.3 g) as a solid, m.p. 135-137° C. Mass spectrum (El, M.+) m/z 262. 1H-NMR (CDCl3; 400 MHz) δ7.31 (d, 1H), 7.04 (s, 1H), 6.96 (d, 1H), 4.84 (ABq, 2H), 3.75 (s, 3H), 2.96 (t, 4H), and 2.11 ppm (m, 2H).
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([C:14]1[CH:15]=[C:16]([CH2:20][C:21]#[N:22])[CH:17]=[CH:18][CH:19]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:23](OCCC(C)C)=[O:24]>C(O)C.C(OCC)(=O)C>[C:6]([C:14]1[CH:15]=[C:16]([C:20](=[N:23][OH:24])[C:21]#[N:22])[CH:17]=[CH:18][CH:19]=1)(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#CCc1cccc(C(=O)c2ccccc2)c1
Reactant: CC(C)CCON=O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CC(=NO)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
To a solution of sodium ethoxide prepared from sodium (1.70 g) and ethanol (40 ml) was added dropwise a solution of 2-(3-benzoylphenyl)acetonitrile (13.6 g) in ethanol (30 ml) at 0° C., and then isoamyl nitrite (12.4 ml) was added dropwise. After stirring at room temperature for 15 hours, the reaction mixture was diluted with ethyl acetate and washed successively with 1N hydrochloric acid and an aqueous saturated solution of sodium chloride. The ethyl acetate layer was dried (MgSO4) and concentrated to obtain 2-(3-benzoylphenyl)-2-(hydroxyimino)acetonitrile (15.2 g, yield 99%) as crystals. Recrystallization from ethyl acetate-hexane gave an isomer of 2-(3-benzoylphenyl)-2-(hydroxyimino)acetonitrile as colorless crystals. m.p. 175-176° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].OB(O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1>COCCOC.CO.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>[N+:21]([C:17]1[CH:16]=[C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:20]=[CH:19][CH:18]=1)([O-:23])=[O:22]
Reactant: Brc1ccccn1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
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: [Na+]
Solvent: CO
Solvent: COCCOC
Product: O=[N+]([O-])c1cccc(-c2ccccn2)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 2-bromopyridine (1.91 ml) and tetrakis(triphenylphosphine)palladium(0) (0.46 g) in 1,2-dimethoxyethane (40 ml) was added 2M aqueous solution of sodium bicarbonate (20 ml) and a solution of dihydroxy(3-nitrophenyl)borane (3.67 g) in methanol (10 ml). The mixture was stirred at 80° C. for 2.5 hours and cooled. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate (3:1)) to give 2-(3-nitrophenyl)pyridine (1.35 g).
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[N:34]1[CH:41]=[C:40]([F:42])[C:38](=[O:39])[NH:37][C:35]1=[O:36])(=O)C1C=CC=CC=1>CO.C[O-].[Na+]>[C@@H:11]1([N:34]2[CH:41]=[C:40]([F:42])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: O=C(OC[C@@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c(=O)n([C@@H]2O[C@@H](CO)[C@H](O)[C@H]2O)cc1F
Yield: 92.1 %

Procedure:
To a solution of compound 3 (11.7 g, 20.37 mmol) in MeOH (300 ml), NaOMe (4.2 ml of a methanolic 25% w/v solution) was added and the solution was stirred until the reaction was complete. The solvent was then evaporated and the residue was dissolved in H2O (200 ml), washed with ether and neutralized with Dowex 50 ion exchange resin. After filtration of the resin, the aqueous solution was evaporated to give compound 4 (4.92 g, 92% yield) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH2:24]([N:26]([CH2:31][CH3:32])[C:27](=[O:30])[CH2:28]Br)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:24]([N:26]([CH2:31][CH3:32])[C:27](=[O:30])[CH2:28][O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N:10]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:16]3[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9]2)[CH:18]=1)[CH3:25]
Reactant: CCN(CC)C(=O)CBr
Reactant: Oc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)COc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 40.9 %

Procedure:
In 75 ml of dimethylformamide were suspended 5.0 g of 3-(4-fluorophenyl)-1-(3-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine, 3.5 g of N,N-diethylbromoacetamide and 2.5 g of potassium carbonate. The mixture was stirred at 60° C. for 5 hours. After the solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate-water. The organic layer was concentrated. Isopropyl ether was added to the residue for crystallization. The obtained crude crystals were recrystallized from ethyl acetate to give 2.8 g of N,N-diethyl-3-[3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1yl]phenoxyacetamide, m.p. 102°-105° C.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1([F:17])[CH2:9][CH2:8][C:7]([CH2:15][F:16])([C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5]1>C1COCC1.CO>[F:3][C:4]1([F:17])[CH2:5][CH2:6][C:7]([CH2:15][F:16])([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]1
Reactant: CCOC(=O)C1(CF)CCC(F)(F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(CF)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1 N NaOH (0.994 mL, 0.994 mmol) was added to a solution of ethyl 4,4-difluoro-1-(fluoromethyl)cyclohexanecarboxylate (73.6 mg, 0.331 mmol) in THF (1 mL) and MeOH (1 ml) and the mixture was stirred at rt for 3-4 h. The reaction mixture was acidified and extracted with EtOAc, washed with brine and dried (MgSO4). Evaporation of the solvent afforded Cap-7 as a beige solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.38 (d, J=47.1 Hz, 2H), 2.30-2.16 (m, 2H), 2.11-1.98 (m, 2H), 1.96-1.76 (m, 2H), 1.65-1.51 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH:34][NH2:35].C[OH:37]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:25])([F:24])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17](/[CH:18]=[N:35]/[NH:34][C:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=4)=[O:37])=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Reactant: CO
Reactant: NNCc1ccccn1
Agent: Cl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1/C=N/NC(=O)c1ccccn1
Yield: 45 %

Procedure:
A solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde (i.e. the product of Step 1, 500 mg), concentrated hydrochloric acid (5 drops) and 2-picolyl hydrazine (188 mg) in methanol (20 mL) were heated at reflux for 5 h. The mixture was concentrated and the residue was triturated with water. Filtration yielded the title compound (289 mg, 45%).