Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH3:32])[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)(Cl)[Cl:41]>C(Cl)Cl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH3:32])[C:27]([Cl:41])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=C(C(=O)Cl)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred solution of anhydrous methylene chloride (200 ml) containing 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino acetic acid (syn-isomer) (11.35 g; 0.0256 mole) and triethylamine (3.61 ml; 0.0256 mole), was cooled at 0° C. and phosphorus pentachloride (5.6 g; 0.027 mole) was added portionwise. After 15 minutes of stirring at 0° C. and 1 hour at room temperature, the mixture was evaporated under reduced pressure, taken up with anhydrous benzene, evaporated again in order to remove any trace of phosphorus oxychloride. This treatment was repeated twice (2×50 ml). The residue was suspended in 50 ml of anhydrous acetone; triethylamine hydrochloride was then removed by filtration. The acetone solution of 2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetyl chloride thus obtained was dropped into a vigorously stirred ice-cooled solution of 7-amino-3-[(8-carboxy-6-tetrazolo[1,5-b]pyridazinyl)-thiomethyl]-3-cephem-4-carboxylic acid (10 g; 0.0232 mole) NaHCO3 (15 g) in a mixture of water and acetone (500 ml; 250 ml). The mixture was stirred for 30 minutes at 0°-5° C. and then for 90 minutes at room temperature, the undissolved matter was filtered off, the acetone was eliminated by evaporation under vacuum. The aqueous phase was brought to pH 2 with 8% HCl and extracted with ethyl acetate (3×400 ml), washed with aqueous sodium chloride, dried (Na2SO4) and evaporated to dryness. The residue was stirred with diethyl ether; after 20 minutes of stirring the white solid was filtered, washed with ether and dried thus giving 3-[(8-carboxy-6-tetrazolo[1,5-b]pyridazinyl)-thiomethyl]-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid. The above mentioned compound was added portionwise to a stirred hot (55° C.) solution of 50% formic acid (140 ml). Stirring and heating at the same temperature was maintained for 30 minutes and then the solid was filtered from the cooled mixture. The filtrate was evaporated to dryness under vacuum, leaving a residue. After complete removal of water and formic acid, followed by trituration with water, a solid was obtained. The crude product was crystallized from 50% ethanol to give 9.1 g (60%) of the title compound, which decomposed at 255° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[Cl:27][C:28]1[CH:29]=[C:30]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[CH:31]=[CH:32][CH:33]=1>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=1)[C:34]([NH:36][C:37]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[C:17]([F:23])[CH:18]=1)=[S:38])=[O:35]
Reactant: O=C(N=C=S)c1cccc(Cl)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Cl)c4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 90%).
Reaction SMILES: [S:1](=[O:26])(=[O:25])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[Cl:24])[O:6]1)[NH2:2].CCN(C(C)C)C(C)C.[C:36](Cl)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[C:36]([NH:2][S:1](=[O:26])(=[O:25])[O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:13])([CH3:14])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[Cl:24])[O:6]1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(Cl)ncnc21
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(=O)(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)O[C@H]2n1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a solution of [(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl sulfamate (13.4 g, 33.1 mmol) in DCM (330 mL) at r.t. was added DIPEA (11.5 mL, 66.2 mmol) followed by Ph3CCl (9.23 g, 33.1 mmol). The reaction was stirred at r.t. for 4 hours. The mixture was diluted with DCM, the layers were separated, and the organic layer was washed with 1N HCl followed by brine. The combined organic phases were dried (Na2SO4) and concentrated to yield the title compound as a white solid (17.6 g, 82%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:24]([O:25]C)=[CH:23][C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([F:34])[CH:20]=1)[C:14](=[O:35])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:24]([OH:25])=[CH:23][C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([F:34])[CH:20]=1)[C:14](=[O:35])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Agent: BrB(Br)Br
Product: O=c1ccc2cc(SCc3ccccc3)ccc2n1-c1cc(F)c(-c2cccc(F)c2)cc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 6-(benzylthio)-1-(2,3′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)quinolin-2(1H)-one (1.700 g, 3.50 mmol) was added boron tribromide (1.0 M in DCM) (17.51 ml, 17.51 mmol) at rt to give a dark solution and stirred for 1 h. The whole was poured on to ice-water mixture. The product was extracted with DCM (3×30 mL). The organic layer was separated, combined, dried over MgSO4, filtered, and concentrated to afford beige solid. The solid was triturated with a mixture of EtOAc/Et2O. The solid was filtered with an aid of Et2O. 1.32 g was obtained. A second batch was obtained from the filtrate. The filtrate was concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 50% EtOAc in heptane, to provide 6-(benzylthio)-1-(2,3′-difluoro-5-hydroxy-[1,1′-biphenyl]-4-yl)quinolin-2(1 H)-one (1.42 g, 80% yield) as light brown solid. m/z (ESI): [M+H]+=472.0. 1 H NMR (400 MHz, DMSO-d6) □ppm 4.24 (s, 2 H) 6.63 (d, J=8.80 Hz, 1 H) 6.69 (d, J=9.59 Hz, 1 H) 7.15 (d, J=7.34 Hz, 1 H) 7.18-7.37 (m, 7 H) 7.38-7.48 (m, 3 H) 7.57 (dd, J=8.02, 6.06 Hz, 1 H) 7.79 (d, J=2.15 Hz, 1 H) 7.95 (d, J=9.49 Hz, 1H) 9.97 (s, 1 H).
Reaction SMILES: CO[C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH3:12])[N:4]=1.[NH3:13]>O>[NH2:13][C:3]1[N:4]=[C:5]([O:11][CH3:12])[N:6]=[C:7]([O:9][CH3:10])[N:8]=1
Reactant: COc1nc(OC)nc(OC)n1
Reactant: N
Solvent: O
Product: COc1nc(N)nc(OC)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 10.1 g (0.059 mole) of 2,4,6-trimethoxy-1,3,5-triazine and water (100 mL) was stirred at 25° C. while 110 mL of 28% aqueous ammonia was added. The mixture was held at 48-51° C. for two hours before it was cooled to 25° C. and the insoluble white crystals were removed. The product was washed with water and dried to give 7.84 g (86%), mp 218-221° C. 1H NMR (DMSO-d): 3.81 (s, 6H); 7.38 (s, 2H). 13C NMR (DMSO-d6): 53.9, 169.0, 171.9.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]#[N:16].[Al+3].[Cl-].[Cl-].[Cl-]>ClC(Cl)C.O>[Br:1][C:2]1[C:3]([NH:9][C:15]([C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)=[NH:16])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1
Reactant: N#Cc1cccs1
Reactant: Nc1ncc(Br)nc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: N=C(Nc1ncc(Br)nc1Br)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A stirred solution of 3,5-dibromo-pyrazin-2-ylamine (500 mg, 1.98 mmol), thiophene-2-carbonitrile (260 uL, 2.04 mmol) and AlCl3 (232 mg, 1.74 mmol) in dichloroethane (5 ml) was heated at 115° C. overnight. The mixture was allowed to cool to room temperature and diluted with water (5 mL). After 30 minutes, the resulting precipitate was collected and purified by column chromatography (SiO2, THF) to afford 488 mg (68%) of N-(3,5-dibromo-pyrazin-2-yl)-thiophene-2-carboxamidine as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.22 (t, J=3.9 Hz, 1H), 7.83 (dd, J=4.8 Hz, 1H), 7.99 (d, J=4.1 Hz, 1H), 8.49 (s, 1H), 8.88 (br. s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.F[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([O:9][C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: OCc1cccc(Oc2ccc(C(F)(F)F)cc2)c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 60.8 %

Procedure:
3-Hydroxymethyl-phenol (1.0 g, 8.1 mmol), 4-fluorobenzotrifluoride (1.32 g, 8.1 mmol) and cesium carbonate (3.28 g, 10.1 mmol) were suspended in dimethylsulfoxide (15 mL) and heated to 110° C. After stirring for 16 h, the reaction was partitioned between water (150 mL) and ethyl acetate (150 mL). The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-40%, EtOAc:heptane) to afford the title compound (1.32 g) as a thick oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:20])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[O:5]1.I[CH2:22][CH3:23]>C1COCC1>[CH2:22]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([B:6]3[O:5][C:4]([CH3:20])([CH3:3])[C:8]([CH3:9])([CH3:10])[O:7]3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)[CH3:23]
Reactant: CCI
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Temperature: 0 °C

Procedure:
To a 0° C. suspension of NaH (43 mg, 1.81 mmol) in THF (4 mL) was added a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (400 mg, 1.65 mmol, Aldrich) in THF (4 mL). The reaction mixture was maintained at 0° C. for 15 min, iodoethane (0.200 mL, 2.47 mmol) was added and the reaction was heated at 50° C. for 30 min. The mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated. Chromatography over silica eluting with 1-8% EtOAc/hexanes afforded the title compound as a white solid. LC-MS: calculated for C16H22BNO2 271.16, observed m/e 273.2 (M+H)+ (Rt 2.09 min).
Reaction SMILES: Cl.C([N:9]1[CH2:15][CH:14]2[N:16]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:11]([CH2:12][CH2:13]2)[CH2:10]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:21][C:18]([F:19])([F:20])[C:17]([N:16]1[CH:11]2[CH2:12][CH2:13][CH:14]1[CH2:15][NH:9][CH2:10]2)=[O:22]
Reactant: [H][H]
Reactant: O=C(N1C2CCC1CN(Cc1ccccc1)C2)C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(N1C2CCC1CNC2)C(F)(F)F

Procedure:
A solution of the 3-benzyl-8-trifluoroacetyl-3,8-diazabicyclo-(3.2.1)octane hydrochloride in 50 mL of methanol was hydrogenated at atmospheric pressure in the presence of 10% Pd/C (0.5 g) until the theoretical quantity of hydrogen was absorbed. The mixture was filtered and the filtrate was evaporated to dryness to yield 1.08 g of titled compound as a white solid. MP 224° C. (dec).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].[CH2:13](I)[CH:14]([CH3:16])[CH3:15].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(C)CI
Reactant: CCOC(=O)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(CC(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1H-Pyrazole-4-carboxylic acid ethyl ester (5.0 g) was dissolved in DMF (50 mL), 60% sodium hydride (1.57 g) was added, and the mixture was stirred at 0° C. for 30 min. Then, isobutyl iodide (4.7 mL) was added, and the mixture was stirred for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=8:2) to give 1-(2-methylpropyl)-1H-pyrazole-4-carboxylic acid ethyl ester (6.0 g) as an oil. The obtained compound was subjected to reactions in the same manner as in Reference Examples 17 to 18 to give the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([N:10]=[C:11]=[O:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.Cl.[NH2:14][OH:15]>C(N(CC)CC)C>[OH:15][NH:14][C:11]([NH:10][CH:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:9][CH2:8][CH2:7]1)=[O:12]
Reactant: O=C=NC1CCCc2sccc21
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(NO)NC1CCCc2sccc21

Procedure:
The above compound is prepared in the manner described in Example 6, by allowing 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate to react with hydroxylamine hydrochloride in the presence of triethylamine. The product melts at 158.5° C. to 160.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[CH:8]=[CH:9][C:10]([NH:17][C:18](=[O:20])[CH3:19])=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[H-].[Na+].CI.[CH:25](Cl)(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[CH:8]=[CH:9][C:10]([N:17]([CH3:25])[C:18](=[O:20])[CH3:19])=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: CC(=O)Nc1ccc2sc3ccc(Br)cc3c(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(=O)N(C)c1ccc2sc3ccc(Br)cc3c(=O)c2c1
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a stirred solution of 1.1 g (3.2 mmol) acetamide 23 in 20 mL of THF was added 0.17 g (4.2 mmol) of NaH (60%) under N2. The mixture was stirred for 15 min followed by the dropwise addition of 0.70 g (4.9 mmol) of methyl iodide. The reaction mixture was stirred at room temperature for 48 h and then concentrated in vacuo to obtain a solid residue. To the residue was added CHCl3, followed by filtration and concentration of the filtrate in vacuo to obtain 1.1 g (97% yield) of methyl amide (25) as a yellow solid, mp 240-241° C. 1H-NMR (400 MHz, CDCl3): 1.93 (3H, s), 3.34 (3H, s), 7.46-7.54 (2H, m), 7.66 (1H, d, J=8.7 Hz), 7.76 (1H, d, J=8.7 Hz), 8.45 (1H, s), 8.75 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]([CH3:15])[C:13](=[O:16])[N:12]([CH3:17])[C:11](=[N:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Na+].[CH3:30]I.O>CN(C)C=O>[CH3:15][N:14]1[C:9]([C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([O:1][CH3:30])[CH:3]=2)=[CH:10][C:11](=[N:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])[N:12]([CH3:17])[C:13]1=[O:16]
Reactant: CI
Reactant: Cc1cc(C)c(N=c2cc(-c3ccc(O)c(O)c3)n(C)c(=O)n2C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4-dihydro-6-(3,4-dihydroxyphenyl)-1,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2(1H)pyrimidinone (2.0 g) in N,N-dimethylformamide (20 ml) were added sodium hydride (60% in Nujol, 0.22 g) and methyl iodide (0.37 ml), and the mixture was stirred at ambient temperature for 2 hours. Then the reaction mixture was poured into water (200 ml), and extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel eluting with chloroform to give 3,4-dihydro-1,3-dimethyl-6-(4-hydroxy-3-methoxyphenyl)-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.66 g).
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][C@H:4]([NH2:7])[CH2:3]1.C[Al](C)C.[CH3:12][C:13]1[N:14]=[C:15]([CH2:21][CH2:22][C:23]2[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:25][O:26][C:27]=2[CH3:28])[S:16][C:17]=1[C:18](O)=[O:19]>C1(C)C=CC=CC=1>[O:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:18]([C:17]2[S:16][C:15]([CH2:21][CH2:22][C:23]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:25][O:26][C:27]=3[CH3:28])=[N:14][C:13]=2[CH3:12])=[O:19])[CH2:3]1
Reactant: N[C@H]1CCOC1
Reactant: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)O
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)N[C@H]1CCOC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
To a stirred suspension of (S)-tetrahydrofuran-3-amine HCl (127 mg, 1.0 mmol) in toluene (2 mL) under argon at room temperature was added trimethylaluminium (1 mL of a 2M solution in toluene, 2.0 mmol). After 2 h, a solution of 4-methyl-2-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (130 mg, 0.39 mmol) in toluene (4 mL) was added and the reaction mixture warmed to 90° C. After 2 h, the reaction mixture was cooled, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with Seignette's salt solution then dried, filtered, and concentrated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) gave the title compound (71 mg, 45%) as a colourless oil. MS: m/e=398.1 [M+H]+.
Reaction SMILES: [CH3:1]/[CH:2]=[C:3]1\[C@H:4]2[CH:11]=[C:10]([CH3:12])[CH2:9][C@@:8]\1([NH2:13])[C:7]1[CH:14]=[CH:15][C:16]([NH:18][C:6]=1[CH2:5]2)=[O:17].C=O.[CH2:21]1COCC1>C(O)(C)C>[CH3:21][NH:13][C@@:8]12[C:7]3[CH:14]=[CH:15][C:16](=[O:17])[NH:18][C:6]=3[CH2:5][C@@H:4](/[C:3]/1=[CH:2]\[CH3:1])[CH:11]=[C:10]([CH3:12])[CH2:9]2
Reactant: C1CCOC1
Reactant: C/C=C1\[C@H]2C=C(C)C[C@@]1(N)c1ccc(=O)[nH]c1C2
Agent: C=O
Solvent: CC(C)O
Product: C/C=C1\[C@H]2C=C(C)C[C@]1(NC)c1ccc(=O)[nH]c1C2
Reaction time: 4 h

Procedure:
Huperzine A 10 mg, and 37% aqueous solution of formaldehyde were refluxed for 1 hour in 2 mL of isopropanol; the solvent was stripped in vacuo; THF (dry, 5 mL) and NaBH(OOCCH3)3 0.15 g were added, the reaction mixture was allowed to stir for 4 hours; and then filtered to remove solid substances. The filtrate was purified after concentrating on prep TLC (chloroform:methanol=9:1) to yield 6 mg of pure title compound. MS: 257 (M+1).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C(O[CH:20](OCC)[N:21]([CH3:23])[CH3:22])C>>[CH3:20][N:21]([CH3:23])[CH:22]=[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:8][CH:7]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Product: CCOC(=O)C(=CN(C)C)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared in a manner similar to Example Preparation 10 using ethyl 2-(4-(trifluoromethyl)phenyl)acetate and 1,1-diethoxy-N,N-dimethylmethanamine to give the title compound. 1H NMR (400 MHz, chloroform-d) δ ppm 1.21 (t, J=7.1 Hz, 3H) 2.71 (s, 6H) 4.14 (q, J=7.2 Hz, 2H) 7.31 (d, J=7.8 Hz, 2H) 7.53 (d, J=7.8 Hz, 2H) 7.61 (s, 1H).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[C:8](Cl)(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+]>CCOCC.O>[C:8]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CC(C)(N)C(=O)O
Reactant: CCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCCC(=O)NC(C)(C)C(=O)O
Yield: 48.7 %

Procedure:
2-Aminoisobutyric acid (2.0 g, 19.4 mmol) and n-hexanoyl chloride (3.0 g, 22.4 mmol) were reacted in the presence of NaOH (1.6 g, 40 mmol) in a mixture of ether and water using the method described in Example 5, Part A. The title compound (1.90 g, 49%) was obtained after crystallization from benzene, m.p. 141°-143° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>CN1CCCC1=O>[N:10]1([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccnc(Cl)c1
Solvent: CN1CCCC1=O
Product: N#Cc1ccnc(-n2ccnc2)c1
Temperature: 150 °C
Yield: 24.4 %

Procedure:
A mixture of 2-chloro-4-cyanopyridine (4.0 g, 28.9 mmol), imidazole (7.9 g, 115 mmol) and N-methyl-2-pyrrolidinone (50 ml) was heated at 150° C. for 58 hours. The solvent was removed by distillation and the residue was partitioned between chloroform and water. The organic layer was separated and the aqueous layer was extracted with chloroform (2×100 ml). The organic layers were combined and the solvent was removed in vacuo. The residue was triturated with ether and a solid was collected by filtration. The solid residue was purified by column chromatography eluting with hexanes/acetone (1/1) to afford 1.2 g (24%) of 2-(1-imidazolyl)-4-cyanopyridine as a tan solid, m.p. 146°-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:21]1[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=1)=[O:6]
Reactant: NCC(c1ccncc1)N1CCOCC1
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Product: Cc1ccc(Cl)c(C(=O)NCC(c2ccncc2)N2CCOCC2)c1

Procedure:
From 2-chloro-5-methylbenzoic acid and (2-morpholin-4-yl-2-pyridin-4-ylethyl)amine. LCMS (MH+): m/z=360.0, tR (minutes, Method A)=0.77
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[C:12]1([C:18]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C>CO>[C:12]1([C:18]2[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:1][C:2]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[NH2:8])[N:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cccc2nc(-c3ccccc3)c(-c3ccccc3)nc12

Procedure:
1.53 g (10 mmol) of 2,3-diaminonitrobenzene and 2.00 g (9.6 mmol) of benzil were placed in four-necked flask, to which 30 g of a solvent of acetic acid and methanol at a mixing ratio of 1:1 was added for dissolution. Subsequently, the mixture was reacted at a reaction temperature of 70° C. for 2 hours. After the reaction, the solvent was removed and the resulting product was extracted with a silica gel column (ethyl acetate:hexane=1:1).