Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C2C(=C(N)C=1)[N:9]=C(C)C=C2.C[C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[C:18]([N+:26]([O-:28])=[O:27])[CH:17]=1>N1C=CC=CC=1>[N+:26]([C:18]1[CH:17]=[CH:16][CH:21]=[CH:20][C:19]=1[S:22]([NH2:9])(=[O:24])=[O:23])([O-:28])=[O:27]
Reactant: COc1cc(N)c2nc(C)ccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 153.3 %

Procedure:
To a solution of 6-methoxy-2-methylquinolin-8-amine 2a (0.19 g, 1.0 mmol) in pyridine (5 ml) was added 4-methyl-2-nitrobenzenesulfonyl chloride (0.24 g, 1.0 mmol). The mixture was stirred at room temperature overnight and precipitated with H2O. The crude product was filtered and recrystallized from EtOH to afford nitrobenzenesulfonamide (0.31 g, 79%) as red crystal. 1H NMR (300 MHz, CDCl3) δ 10.1 (br, 1H); 8.04 (d, 1H), 7.86 (d, 1H), 7.62 (m, 2H), 7.39 (d, 1H), 7.24 (d, 1H), 6.73 (s, 1H), 3.88 (s, 3H), 2.66 (s, 3H), 2.41 (s, 3H); ESI-MS (M++1): 388.0. To a suspension of above nitro compound (0.20 g, 0.56 mmol) in EtOH (5 ml) was added SnCl2 (0.32 g, 1.7 mmol) slowly. The mixture was refluxed for 2 h. After removal of EtOH, the residue was treated with 1M NaOH. The aqueous solution was extracted with CH2Cl2. The combined organic phases were washed by brine, dried over Na2SO4, and concentrated to yield 9a (0.18 g, 92%) as white solid. 1H NMR (300 MHz, CDCl3) δ 9.42 (br, 1H); 7.83 (d, 1H), 7.65 (d, 1H), 7.30 (s, 1H), 7.23 (d, 1H), 6.64 (s, 1H), 6.48 (d, 1H), 6.42 (s, 1H), 3.80 (s, 3H), 2.61 (s, 3H), 2.17 (s, 3H); ESI-MS (M++1): 358.1.
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1C(OC)=O.[OH-].[Na+].C(O)(=O)C.C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>C(O)C.O>[CH3:7][C:6]1[C:2]([NH:1][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:3][S:4][CH:5]=1
Reactant: COC(=O)c1scc(C)c1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=CNc1cscc1C)C(=O)OCC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of methyl 3-amino-4-methylthiophene-2-carboxylate (commercially available from Avocado, catalog number 10115, 5.00 g, 29.2 mmol) in 95% ethanol (25 mL) was added 1.0 N NaOH (35 mL). The mixture was heated to reflux and stirred for 2.5 hrs. The resulting solution was cooled to room temperature before the addition of glacial acetic acid (2.05 mL, 35.8 mmol). After stirring for 5 minutes at room temperature, diethyl ethoxymethylenemalonate (DEEM, 6.5 mL, 32.2 mmol) was added. The mixture was stirred vigorously until it nearly solidified (ca. 5 min), and then it was left standing at room temp for 3 hours. 95% ethanol (60 mL) was added, and the mixture was warmed on a steam bath until solution was achieved. Water (50 mL) was added with continued heating on the steam bath, resulting in a slightly cloudy solution. The flask was removed from the steam bath and allowed to cool to room temp and then placed in a 0° C. refrigerator, at which point crystallization of the product as fine white filaments was rapid. After standing at 0° C. for. 2 hours, the mixture was filtered. The collected solid was washed with 50% ethanol/water and dried, affording a white solid (5.79 g). The filtrate was diluted with water to a total volume of 500 mL, left overnight at 0° C., and filtered to afford a second crop (0.96 g) that was of equal purity to the first crop by HPLC analysis.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:28]>C(Cl)Cl.C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:28])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3.00 g (8.59 mmol) 4-benzyloxy-1-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 15b) in 20 mL of DCM and 20 mL THF is added 0.81 mL (8.59 mmol) phosphorus tribromide at 0° C. The cooling bath is removed and the mixture is stirred 1 h at RT in an ultrasound bath.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])NN)[CH3:2].[C:12](=[N:25][NH:26][C:27]([NH2:29])=[O:28])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[K+].C(Br)C=C>C1COCC1.CCOCC>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][C:7](=[O:10])[CH2:27][NH:26][NH:25][CH:12]=[CH2:13])[CH3:2].[C:12](=[N:25][NH:26][C:27]([NH2:29])=[O:28])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CNC(=O)NN
Agent: CC(C)(C)[O-]
Agent: NC(=O)NN=C(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CNNCC(=O)NCC(=O)OCC
Reaction time: 1 h

Procedure:
To a solution of semicarbazone 5i, (50 mg, 0.15 mmol) in THF (0.5 mL), potassium t-butoxide (25 mg, 0.18 mmol) was added at 0° C. under argon. The reaction mixture was stirred for 1 h, treated drop-wise with allyl bromide (20 μL, 0.18 mmol), stirred for 3 h at room temperature (22° C.) under argon, diluted in Et2O (5 mL) and extracted with NaHCO3 (2×2 mL) and brine (2×2 mL). The organic phase was dried over MgSO4, concentrated in-vacuo and purified by flash chromatography using 2:1 Hexane:EtOAc [Rf (6i): 0.45] to yield a an oil (35 mg, 60%). 1H NMR (CDCl3) δ: 1.23 (t, J=7 Hz, 3H), 3.86 (dd, J=1.6 Hz, 3.8 Hz, 2H), 4.05 (d, J=5.7 Hz, 2H), 4.16 (q, J=7 Hz, 2H), 4.78 (dd, J=1 Hz, 10 Hz, 1H), 4.92 (dd, J=1 Hz, 10 Hz, 1H) 5.33-5.43 (m, 1H), 6.89 (t, J=5.5 Hz, 1H), 7.18-7.42 (m, 10H); 13C NMR (CDCl3) δ: 13.8, 42.2, 47.9, 60.8, 116.3, 127.8, 128.2, 128.3, 128.7, 129.3, 129.6, 132.4, 135.6, 138.4, 157.7, 158.4, 170.2; LCMS (ESI) Calcd. for C21H23N3O3, M+: 365.4. Found (M+H)+366.1.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]1>CN(C=O)C.CS(C)=O.CO>[OH:32][CH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:26][CH2:27]1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: OCC1CCNCC1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCC(CO)CC3)n2n1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 81 mg, 0.235 mmol) and piperidin-4-ylmethanol (35 mg, 0.294 mmol) in DMF (1 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (25-35% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (62.1 mg, 62%). Melting point (164.0-169.5° C.). 1H NMR (DMSO-d6) δ: 10.86 (s, 1H), 7.99 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.27 (s, 1H), 6.17 (s, 1H), 4.50 (d, J=12.1 Hz, 2H), 3.33 (d, J=6.3 Hz, 2H), 2.99-3.11 (m, 2H), 2.38 (s, 3H), 1.79-1.87 (m, 2H), 1.67-1.78 (m, 1H), 1.45 (s, 6H), 1.28-1.42 (m, 2H); ESI-MS: m/z 424.3 (M+H)+.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH2:16]>CC(C)=O>[CH:1]1[C:2](=[O:16])[CH:3]=[CH:4][C:5]2=[N:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]=12
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: O
Solvent: CC(C)=O
Product: O=c1ccc2nc3ccccc3ccc-2c1
Temperature: 4 °C
Yield: 34 %

Procedure:
To a solution of Na2HPO4 (2.5 g, 9.32 mmol) in water (95 mL) was added (KSO3)2NO (1.8 g, 12.7 mmol). This solution was added to a solution of the (Z)-5H-dibenzo[b,f]azepine (0.5 g, 2.59 mmol) in acetone (50 mL). This reaction mixture was stirred at 4° C. over night. The solid was filtered and the filtrate was evaporated. The residue was dissolved in ether and water. The 2 layers were split. The organic layer and the solid were mixed and evaporated. The crude product was purified by flash chromatography to afford title compound 374 (170 mg, 34%). MS (m/z): 207 (M+H). Step 2: (Z)-5H-dibenzo[b,f]azepin-2-ol (375)
Reaction SMILES: I[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F-:12].[K+].Cl[C:15]([F:21])([F:20])C(OC)=O.O>CN(C)C=O.C(OCC)(=O)C>[F:20][C:15]([F:21])([F:12])[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)C(F)(F)Cl
Reactant: Ic1cnc2ccccc2c1
Reactant: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)c1cnc2ccccc2c1
Reaction time: 6 h
Yield: 36.9 %

Procedure:
3-Iodoquinoline (13.65 g, 53.5 mmol), cuprous iodide (21.12, 111 mmol), potassium fluoride (7.11 g, 122 mmol), and methyl 2-chloro-2,2-difluoroacetate (23 ml, 216 mmol) in dimethylforamide (200 ml) was placed into a preheated oil bath at 120° C. After stirring for 6 h, the solution was diluted water and extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was flash chromatographed with 99:1, 49:1, 24:1, 23:2, 9:1, and 4:1 hexane:ethyl acetate as the eluant to afford 3.89 g (37% yield) of 3-(trifluoromethyl)quinoline. Method [7] retention time 4.67 min by HPLC (M+198).
Reaction SMILES: CN([CH2:4][CH2:5]N(C)C)C.[Li][CH2:10][CH2:11][CH2:12][CH3:13].[CH:14]([CH:16]=[CH2:17])=[O:15]>>[C:16]1([CH:14]([OH:15])[CH:4]=[CH2:5])[C:10]2[C:11](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:12][CH2:13][CH:17]=1
Reactant: [Li]CCCC
Reactant: C=CC=O
Reactant: CN(C)CCN(C)C
Product: C=CC(O)C1=CCCc2ccccc21
Temperature: -50 °C
Reaction time: 0.67 h
Yield: 10 %

Procedure:
Into a dry round bottom flask containing the appropriate hydrazone (1.995 g, 6.35 mmol), 20 mL of TMEDA were added and, nitrogen was circulated through the reaction system. After the solution was cooled at −50° C., 10.2 mL of BuLi (2.5 M/hex, 25.5 mmol) were added and, the reaction mixture was stirred first at −50° C. for 40 minutes and then at room temperature for 35 minutes. After bubbling stopped, the flask was cooled at 0° C. and, 2.0 mL of acrolein (1.63 g, 29.1 mmol) were added. The reaction was stirred at 0° C. for 5 h, at which point, 30 mL of ice water were added. The product was extracted once from the aqueous phase with EtOAc and, the combined organic phase was washed 3 times with H2O and with brine. The organic phase was dried under Na2SO4 and, the solvent was removed under vacuum. After the product was purified by flash chromatography (10% EtOAc/90% hex), 0.1165 g (0.626 mmol) was obtained in a 10% yield.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([NH:22][C@@H:23]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:24]=[CH2:25])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].ClCCl>C(Cl)(Cl)Cl>[C:12]([NH:22][C@@H:23]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:24]1[O:6][CH2:25]1)([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C[C@H](CC(C)C)NC(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CO1
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a solution of 600 mg of 3-chloroperoxybenzoic acid in 5 ml of dry chloroform was added a solution of 850 mg of (3S)-3-carbobenzoxyamino-5-methyl-1-hexene in 5 ml of dry chloroform under ice-cooling, and the mixture was stirred for 16 hours. Dichloromethane was added to the reaction mixture, and the mixture was successively washed with an aqueous sodium thiosulfate solution, a 5% aqueous sodium bicarbonate solution and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: benzene/hexane=1/1 by volume) to obtain 401 mg of (3S)-3-carbobenzoxyamino-5-methyl-1,2-epoxyhexane as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[F:13][C:14]([F:19])([F:18])[C:15](Cl)=[O:16].[CH3:20][O:21][C:22]1[CH:23]=[C:24](O)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29]>>[F:13][C:14]([F:19])([F:18])[C:15]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][C:24]1[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=1)=[O:6])=[O:16]
Reactant: O=C(Cl)C(F)(F)F
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: COc1ccc(C(=O)O)cc1N
Product: COc1ccc(C(=O)Oc2cc(OC)c(OC)c(OC)c2)cc1NC(=O)C(F)(F)F

Procedure:
Compound 353 is synthesized following a similar method as in Example 1 and using 3-amino-4-methoxybenzoic acid, trifluoroacetyl chloride and 3,4,5-trimethoxyphenol as materials. Total yield of the two steps: 46%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][CH2:11][CH2:12][OH:13])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[Cl:8].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>[Fe](Cl)(Cl)Cl.O1CCOCC1>[Cl:8][C:7]1[N:6]=[C:5]([CH3:9])[N:4]=[C:3]2[C:2]=1[N:1]=[C:17]([C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[Cl:14])[N:10]2[CH2:11][CH2:12][OH:13]
Reactant: Cc1nc(Cl)c(N)c(NCCO)n1
Reactant: O=Cc1ccccc1Cl
Agent: Cl[Fe](Cl)Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(CCO)c2n1
Temperature: 102.5 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
Charge a 500 mL three-necked round bottom flask with 2-[(5-amino-6-chloro-2-methyl-pyrimidin-4-yl)amino]ethanol (13.0 g, 0.064 mol) and 1,4-dioxane (300 mL). Add 2-chlorobenzaldehyde (13.5 g, 0.096 mol) followed by iron (III) chloride, 5 wt % on silica gel (37.5 g) in one portion. Heat the mixture to 100-105° C. for 48 h. Cool to 20-35° C., filter and rinse the cake with 1,4-dioxane (40 mL). Combine the filtrates and concentrate under vacuum. Dissolve the residue with dichloromethane (260 mL, 20 mL/g) and cool to 0-5° C. Add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (14.5 g, 0.064 mol) at 0° C., warm up the mixture to 10-25° C., and stir for 2 h. Filter and rinse the cake with ethanol (100 mL) and combine the filtrates. Concentrate down the filtrates under vacuum to give a dark residue. Re-dissolve the residue with dichloromethane (300 mL), wash this solution with 1 N aqueous sodium hydroxide to pH 10-11 followed by water (2×60 mL). Concentrate the organic layer to give crude material. Purify the crude over 400 g silica gel, eluting with dichloromethane/methanol (50:1) to afford a yellow solid (6.5 g). 1H NMR (dmso-d6): δ 7.73-7.56 (m, 4H); 4.83 (t, J=6 Hz, 1H); 4.12 (t, J=6 Hz, 2H); 3.61 (q, J=6 Hz, 2H); 2.73 (s, 3H).
Reaction SMILES: [C:1]([O:16][CH2:17][CH:18]1[O:20][CH2:19]1)(=[O:15])[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)=[O:7])=[CH:4][CH:3]=1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>COCCOC>[OH:12][CH:10]([CH2:11][N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])[CH2:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([C:1]([O:16][CH2:17][CH:18]([OH:20])[CH2:19][N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])=[O:15])=[CH:14][CH:13]=1
Reactant: O=C(OCC1CO1)c1ccc(C(=O)OCC2CO2)cc1
Reactant: CCNCC
Solvent: COCCOC
Product: CCN(CC)CC(O)COC(=O)c1ccc(C(=O)OCC(O)CN(CC)CC)cc1
Temperature: 60 °C

Procedure:
Diglycidyl terephthalate (145 parts, 1.0 epoxy equivalent) was dissolved in 1,2-dimethoxyethane (145 parts). Diethyl amine (73 parts, 1 mol.) was added at room temperature. The mixture was heated at 60° C. for 20 hours and part of the solvent (75 parts) was stripped off in vacuo. The product, a light-brown viscous solution, had a solids content of 4.45 meq./g theory: 4.59). 2-hydroxy-3-diethylaminiopropyl groups per molecule: 2; molecular weight: 436 (calculated).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)[CH:23]=[CH:22][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[C:12](=[CH:17][N:18](C)C)[CH2:11]2)[C:6]1=[O:21].O.[NH2:33]N>CO>[Cl:1][C:2]1[CH:25]=[C:24]([C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)[CH:23]=[CH:22][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13]3[C:12](=[CH:17][NH:18][N:33]=3)[CH2:11]2)[C:6]1=[O:21]
Reactant: CN(C)C=C1CC(N2CCC(Cc3ccc(-c4cnn(C)c4)cc3Cl)C2=O)CCC1=O
Reactant: NN
Solvent: O
Solvent: CO
Product: Cn1cc(-c2ccc(CC3CCN(C4CCc5n[nH]cc5C4)C3=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Dissolve 3-[2-Chloro-4-(1-methyl-1H-pyrazol-4-yl)-benzyl]-1-(3-dimethylaminomethylene-4-oxo-cyclohexyl)-pyrrolidin-2-one (Preparation 30) (0.327 g, 0.745 mmol) in methanol (3.0 mL), and hydrazine hydrate (0.038 mL) stir the resulting orange solution for 17 hours at room temperature. Filter the mixture, rinse with cold methanol and vacuum dry to 0.138 g of a solid. MS (m/z): 410 (M+1).
Reaction SMILES: CC[O:3][C:4]1[CH:5]=[CH:6][C:7](N=NC2C=CC(N)=CC=2N)=[CH:8]C=1.Cl.Cl[C:22]1C=CC=C(C(OO)=O)C=1.[C:32](=[O:35])([O-])[OH:33].[Na+]>C(Cl)Cl>[CH3:22][C:6]1[C@H:7]2[CH2:8][O:35][C@H:32]([O:33]2)[C:4](=[O:3])[CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1ccc(N=Nc2ccc(N)cc2N)cc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC1=CC(=O)[C@@H]2OC[C@H]1O2
Reaction time: 0.33 h

Procedure:
The serenium derivative obtained by the above reaction was dissolved in 20 ml of dry methylene chloride under an inert atmosphere of nitrogen gas, and 60 mg of m-chloroperbenzoic acid was added thereto at -78° C. The mixture was stirred for 20 minutes and then a saturated sodium hydrogencarbonate aqueous solution was added. The mixture was extracted twice with methylene chloride. The organic layers were put together and washed twice with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by silica gel thin layer chromatography (methylene chloride) to obtain 1.7 mg of desired 1,6-anhydro-3,4-dideoxy-4-methyl-β-D-glycero-hex-3-enopyranos-2-ulose (Intermediate No. 43) as a colorless transparent liquid. The NMR analytical data of this product are as follows.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[NH2:10][NH2:11]>>[NH:10]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1)[NH2:11]
Reactant: NN
Reactant: COc1cccc(Cl)n1
Product: COc1cccc(NN)n1
Temperature: 23 °C
Yield: 57 %

Procedure:
A mixture of 2-chloro-6-methoxypyridine (compound 12; 2.87 g, 20 mmol) and anhydrous hydrazine (11 mL, excess) was heated under argon on a steam bath overnight. The mixture was allowed to cool to 23° C. and then was extracted with Et2O (10×10 mL). The combined ether extracts were rotary evaporated to afford 1.58 g (57%) of 2-hydrazino-6-methoxypyridine 13 as a yellow liquid that was ˜95% pure by NMR: 1H NMR (CDCl3) δ 7.38 (pseudo-t, 1), 6.20 (d, J =8.0 Hz, 1), 6.09 (d, J=8.0 Hz, 1), 5.71 (bs, 1, exchanges upon addition of D2O, NH), 3.84 (s, 3, OCH3), 3.1 (bs, 2, exchanges upon addition of D2O, NH2). A solution of this hydrazine (1.58 g, 11 mmol) in 10 mL of absolute ethanol was combined with a solution of 1 (1.8 g, 10 mmol) in 20 mL of absolute ethanol, and the reaction mixture produced a precipitate within several minutes. The mixture was allowed to stand at 23° C. overnight. The solid was collected by suction filtration, washed with a small amount of ethanol, and was dried in vacuo, giving 1.65 g of the methoxy precursor 14. An additional 510 mg of this precipitated from the filtrate after it had been concentrated on a rotary evaporator to a small volume. Combined yield: 2.15 g (76%): mp 161-162° C. (ethanol). 1H NMR ((CD3)2SO) δ 10.45 (s, 1, exchanges upon addition of D2O, OH), 8.25 (s, 1, H4), 8.04 (d, J=8.2 Hz, 1), 7.88 (pseudo-t, 1), 7.54 (d,J=8.2 Hz, 1), 7.36 (s, 1), 7.26 (d, J=8.25 Hz, 1), 6.68 (d, J=7.9 Hz, 1), 6.64 (pseudo-t 1), 3.92 (s, 3, OCH3), 3.90 (s, 3, OCH3). Low-resolution DCI mass spectrum, m/z 284 (100%, MH+). Exposure of this compound to molten C5H5N.HCl for 10 min effected removal of the hydroxy pyridine protecting group only, by 1H NMR. Exposure to BBr3 in CH2Cl2 solution at 23° C. overnight effected the removal of the phenolic protecting group only, giving 15: mp 198-199° C. (ethanol). 1H NMR ((CD3)2SO) δ 8.17 (s, 1, H4), 7.98 (d, 1), 7.88 (pseudo-t, 1), 7.54 (d, 1), 7.12 (m, 3), 6.67 (d, 1), 3.92 (s, 3, OCH3). Low-resolution DCI mass spectrum, m/z 270 (100%, MH+). X-ray quality crystals of 15 were grown from absolute ethanol and a crystal structure deterrnination was made; the crystal structure of the compound is shown in FIG. 1. Robinson et al. (1999), “A Boron-Containing Estrogen Mimic,” J. Act Crystallogr. C55:1701-1704.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][CH:9]([CH3:15])[CH2:10][CH2:11][C:12](Cl)=[O:13].O>C(#N)C>[Br:8][CH:9]([CH3:15])[CH2:10][CH2:11][C:12]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)=[O:13]
Reactant: CC(Br)CCC(=O)Cl
Reactant: CC1CCNCC1
Solvent: CC#N
Solvent: O
Product: CC(Br)CCC(=O)N1CCC(C)CC1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
1.09 g of 4-methylpiperidine was dissolved in 10 ml of acetonitrile and added dropwise with 1.09 g of 4-bromovaleroyl chloride. The reaction mixture was stirred for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with wafer and dried over sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain 1.07 g of the title compound (yield: 82%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]2)[CH:2]=1.[CH3:13][C:14]([CH3:16])=O.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OC(C)C)(=O)C>[CH:14]([NH:12][C:10]1[CH:9]=[N:8][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:11]=1)([CH3:16])[CH3:13]
Reactant: Nc1cnn(-c2cccnc2)c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)C
Product: CC(C)Nc1cnn(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
1-pyridin-3-yl-1H-pyrazol-4-ylamine (0.6 g, 3.7 mmol) was dissolved in isopropyl acetate (8.5 ml). To the mixture, acetone (0.261 g, 4.5 mmol), trifluoroacetic acid (0.855 g, 7.5 mmol) and sodium triacetoxyborohydride (0.945 g, 4.5 mmol) were added. The reaction was stirred under nitrogen at room temperature for 4.5 hours and then quenched with 10% sodium hydroxide solution until the pH reached ˜9. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate and concentrated to dryness. The crude material was purified by silica gel chromatography (gradient elution of 5% methanol/dichloromethane) to give the title compound as an off white solid (0.35 g, 46%): mp 105-107° C.; 1H NMR (300 MHz, CDCl3) δ 8.82 (d, J=2.2 Hz, 1H), 8.63 (dd, J=4.8, 1.5 Hz, 1H), 8.13 (d, J=1.8 Hz, 1H), 8.03 (d, J=2.7 Hz, 1H), 7.94-7.77 (m, 1H), 7.38 (dt, J=15.2, 7.6 Hz, 1H), 6.99 (t, 1H), 3.72 (m, 1H), 1.30 (t, J=10.0 Hz, 6H). ESIMS 214 m/z (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[CH:29]=[N:28][NH:27][C:24]2=[N:25][CH:26]=1)=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[CH:29]=[N:28][N:27]([CH2:11][C:9]3[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]4[C:8]=3[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]4)[C:24]2=[N:25][CH:26]=1)=[O:20]
Reactant: COC(=O)c1cnc2[nH]ncc2c1
Reactant: CC(C)Cn1ncc2cc(Cl)cc(CO)c21
Product: COC(=O)c1cnc2c(cnn2Cc2cc(Cl)cc3cnn(CC(C)C)c23)c1
Yield: 53 %

Procedure:
Compound 33 was prepared following general method 3A, using compound 17 as a starting material and 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid methyl ester as the heterocycle. Yield: 53%.