Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[CH2:5]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12])[CH:6]=[CH2:7].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:5]([O:8][CH2:9][CH:10]1[CH2:11][O:12][C:2]([CH3:4])([CH3:1])[O:13]1)[CH:6]=[CH2:7]
Reactant: C=CCOCC(O)CO
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C=CCOCC1COC(C)(C)O1

Procedure:
The 4-allyloxymethyl-2,2-dimethyl-1,3-dioxolane was prepared by mixing acetone, 225 parts, 3-allyloxy-1,2-propanediol, 195 parts and toluene, 480 parts in a flask fitted with a magnetic stirring bar and a water trap mounted with a reflux condenser. Concentrated sulfuric acid, 4 parts, was added to the flask and the mixture was heated to reflux. The first 170 parts of distillate were removed via the water trap, after which reflux was conducted and water was collected in the water trap. After 13 hours the reaction mixture was cooled, neutralized with aqueous sodium bicarbonate, distilled to remove water and toluene and then distilled under vacuum to give 161 parts of 4-allyloxymethyl-2,2-dimethyl-1,3-dioxolane having a boiling point of 57° to 58° at 4.5 Torr.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([O:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH:24]=[CH:25][C:19]=3[CH:18]=2)=[CH:13][CH:12]=1.O>C1COCC1>[Br:8][C:18]1[C:19]2[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:22][C:20]=2[S:21][C:17]=1[C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=1
Reactant: CCN(CC)C(=O)Oc1ccc2cc(-c3ccc(OC)cc3)sc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)Oc1ccc2c(Br)c(-c3ccc(OC)cc3)sc2c1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
Add NBS (7.37 g, 40.99 mmoles) to the solution of diethyl-carbamic acid 2-(4-methoxy-phenyl)-benzo[b]thiophen-6-yl ester in THF at ambient temperature. Stir the mixture for 20 minutes. Distill the resulting solution to 47 mL. Add Methanol (15 mL) to the distilled solution and cool the solution to 50° C. Add seed crystals of Example 2 (340 mg, 0.8 mmoles) to the cooled solution and stir the mixture for 15 minutes. Slowly add water (35 mL). Allow the mixture to cool to ambient temperature, and hold at ambient temperature for one hour. Collect the product by vacuum filtration, wash with aqueous THF (30 mL, 2 water: 1 THF) and dry in a vacuum oven to yield diethyl-carbamic acid 3-bromo-2-(4-methoxy-phenyl)-benzo[b]thiophen-6-yl ester. Yield 15.75 g (36.26 mmol, 93% of theory).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.[N:23]1C=CC=C[CH:24]=1.Cl>C(Cl)(Cl)Cl>[C:24]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1)#[N:23]
Reactant: CCOC(=O)Cc1ccc2occ(-c3ccc(Br)cc3)c2c1
Reactant: c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccc2occ(-c3ccc(C#N)cc3)c2c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A mixture of 99 g. (0.29 mole) of the known (Belgian Pat. No. 846,502, Example 22) compound ethyl 3-(4-bromophenyl)benzofuran-5-acetate in 40 g. of cuprous cyanide in 30 ml. of pyridine is heated at 160°-175 C. with stirring under a nitrogen atmosphere for 20 hours. To this solution is added 200 g. of ferric chloride, 100 ml. of concentrated hydrochloric acid, and 200 ml. of ice water with rapid stirring. Next, 300 ml. of chloroform is added, and the mixture is stirred for one hour, then filtered, and the insoluble material is extracted several times with chloroform. The combined chloroform extracts are dried and evaporated to provide a residue. The residue is recrystallized from a N,N-dimethyl formamide-water mixture to provide ethyl 3-(4-cyanophenyl)benzofuran-5-acetate.
Reaction SMILES: N1C2OCC(N)C=2C=CN=1.CO[N:13]=[C:14]1[C:22]2[C:17](=[CH:18][N:19]=[C:20]([CH3:23])[CH:21]=2)[O:16][CH2:15]1>>[CH3:23][C:20]1[CH:21]=[C:22]2[CH:14]([NH2:13])[CH2:15][O:16][C:17]2=[CH:18][N:19]=1
Reactant: CON=C1COc2cnc(C)cc21
Agent: NC1COc2nnccc21
Product: Cc1cc2c(cn1)OCC2N

Procedure:
This compound was prepared using a method analogous to that of 5,6-dihydrofuro[2,3-c]pyridazin-5-amine (A.2.3.4), 5-methylfuro[2,3-c]pyridin-3(2H)-one O-methyl oxime replacing furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime;
Reaction SMILES: CS(O)(=O)=O.[CH2:6]([N:13]([CH2:23][C:24]([OH:26])=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O>[CH2:6]([N:13]1[CH2:23][C:24](=[O:26])[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc(CN(CC(=O)O)Cc2ccccc2)c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1)CN(Cc1ccccc1)CC2=O
Temperature: 100 °C
Yield: 74.8 %

Procedure:
To a round-bottomed flask containing methanesulfonic acid (75 mL) was added [benzyl-(3-methoxy-benzyl)-amino]-acetic acid (11.0 g, 38.5 mmol) with stirring. The mixture was heated to 100° C. for five hours whereupon LCMS showed completion of the reaction. The mixture was cooled to ambient temperature, water (300 mL) was added and the mixture was cooled in an ice-water bath and adjusted to pH 9 (10N NaOH), keeping the internal temperature below 30° C. The precipitate was collected by vacuum filtration, washed with water to neutrality, and dried to constant weight in vacuo to afford 2-benzyl-7-methoxy-2,3-dihydro-1H-isoquinolin-4-one (7.7 g, 75%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J=8 Hz, 1H), 7.34 (m, 5H), 6.95 (d, J=8 Hz, 1H), 6.90 (s, 1H), 3.82 (s, 3H), 3.76 (s, 2H), 3.71 (s, 2H), 3.27 (s, 2H); (m/e) 268 (M+1); mp 135° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)Cc1ccc(N)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)OCC)c(F)c1

Procedure:
A solution of 8.2 g. of 2-fluoro-4-aminophenylacetic acid, 150 ml. of absolute ethanol, and 3 ml. of boron trifluoride etherate is heated to reflux for 15 hours. The solution is concentrated by distillation and then evaporated to dryness in vacuo. The residue is dissolved in ethyl ether, washed with aqueous sodium bicarbonate dried and evaporated to yield ethyl 2-fluoro-4-aminophenylacetate. A mixture of 5.0 g. of this amine, 9.4 g. of 1-bromohexadecane, 4.2 g. of anhydrous potassium carbonate and 40 ml. of hexamethylphosphoramide is heated at 80° C. for 7 hours. The mixture is then cooled, diluted with water, and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from a mixture of chloroform and hexane, yielding ethyl 2-fluoro-4-(hexadecylamino)phenylacetate.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19](=[N:25]O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[CH3:11][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[CH2:7][C:8]1[O:10][N:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: Cc1cccc(CC(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc(Cc2cccc(C)c2)n1
Yield: 23.2 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-m-tolylacetic acid (0.568 g; 3.78 mmol) and oxalyl chloride (0.352 mL; 4.16 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (6 mL), and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.216 g (23%) of ethyl 5-(3-methylbenzyl)-1,2,4-oxadiazole-3-carboxylate as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([NH2:9])[N:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[N:5]=1)([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:31]([O:33][C:34]([CH3:36])=[CH2:35])=[O:32]>>[CH:1]([C:4]1[CH:8]=[C:7]([NH:9][C:31](=[O:32])[O:33][C:34]([CH3:36])=[CH2:35])[N:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[N:5]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)OC(=O)Cl
Reactant: CC(C)c1cc(N)n(-c2ccc3ncccc3c2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: C=C(C)OC(=O)Nc1cc(C(C)C)nn1-c1ccc2ncccc2c1
Yield: 63.2 %

Procedure:
Using the procedure of Example B26, 3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-amine from Example B9 (1.00 g, 4.0 mmol), lithium bis(trimethylsilyl)amide (1.0 M in THF, 7.9 mL, 7.9 mmol) and isopropenyl chloroformate (0.48 mL, 4.4 mmol) were combined to provide prop-1-en-2-yl 3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-ylcarbamate (0.85 g, 65% yield). MS (ESI) m/z: 337.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([C:8]([O-:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:8](=[O:10])[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])([CH3:1])[CH3:11])[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CCOC(=O)C(C)(C)C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
To a solution of the obtained mono-ethyl dimethylmalonate (1 g) in N,N-dimethylformamide (20 mL) were added 1-(benzyloxycarbonyl)piperazine (1.38 g), 1-hydroxybenzotriazole (0.93 g), triethylamine (1.31 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine, 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=4/1-2/1) to give 1-benzyloxycarbonyl-4-[2-ethoxycarbonyl-2-(methyl)propionyl]piperazine (1.77 g). This material was dissolved in ethanol (5 mL). To the solution was added 2 mol/L aqueous sodium hydroxide solution (2.93 mL), and the mixture was stirred at 55° C. overnight. The reaction mixture was poured into water, and the resulting mixture was washed with diethyl ether. The aqueous layer was acidified by addition of 2 mol/L hydrochloric acid, and the mixture was extracted with diethyl ether. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.28 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CN(C=O)C>[CH3:25][O:24][C:22](=[O:23])[CH2:21][N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: COC(=O)CBr
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 74.1 %

Procedure:
To a solution of 5-benzyloxyindole (1.67 g, 7.489 mmol) in DMF (50 mL) was added sodium hydride (60% dispersion in mineral oil, 389 mg, 9.735 mmol). The resulting suspension was stirred at rt for 1 h at which time methyl bromoacetate (1.26 g, 8.238 mmol) was added. The resulting solution was stirred at rt for 4.5 h. The reaction was quenched with sat. aqueous ammonium chloride solution (25 mL), and diluted with EtOAc (50 mL). The organic layer was washed three times with water. The aqueous layer was extracted with EtOAc again and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated via rotary evaporation. The resulting brown oil was purified on silica gel (hexanes/EtOAc 1:1) to give the title compound as a brownish oil (1.64 g, 74%). LC/MS m/z 296 (M+H)+, RT 3.21 min; 1H NMR (400 MHz, CDCl3) δ 7.35-7.37 (m, 2H), 7.23-7.30 (m, 3H), 7.02-7.08 (m, 2H), 6.95 (d, 1H), 6.87 (dd, 1H), 6.37 (dd, 1H), 5.01 (s, 2H), 4.72 (s, 2H), 3.64 (s, 3H).
Reaction SMILES: C(O)C.C([O:8][C:9](=O)[CH2:10][CH2:11][N:12]([C:17]1[C:22]([NH2:23])=[CH:21][N:20]=[C:19]([Cl:24])[N:18]=1)[CH2:13][CH2:14][CH2:15][CH3:16])(C)(C)C>C(O)(=O)C>[CH2:13]([N:12]1[CH2:11][CH2:10][C:9](=[O:8])[NH:23][C:22]2[CH:21]=[N:20][C:19]([Cl:24])=[N:18][C:17]1=2)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1N
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCN1CCC(=O)Nc2cnc(Cl)nc21
Yield: 89.4 %

Procedure:
A mixture of 50 mL of ethanol, 1 mL of acetic acid and 1.3 g of the 3-[(5-amino-2-chloro-pyrimidin-4-yl)-butyl-amino]-propionic acid tert-butyl ester (V-44), prepared in the previous step, was heated at reflux overnight, and then concentrated under reduced pressure. The residue was taken up in dichloromethane and washed successively with 10% sodium bicarbonate solution, water and then dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated under reduced pressure. Trituration of the residue with ether, provided 0.90 g of 9-butyl-2-chloro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-44).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>C(OCC)(=O)C>[ClH:22].[NH:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(C=Cc3ccccc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: C1=CC2(CCNCC2)c2ccccc21

Procedure:
1'-(t-Butyloxycarbonyl)spiro(indene-1,4'-piperidine) (16 g, 56 mmole) in ethyl acetate (250 ml) was stirred in an ice bath and saturated with HCl(g) for 30 minutes. The mixture was evaporated to dryness. Ethyl acetate was added and removed in vacuo three times, and the residue was triturated with diethyl ether and filtered to provide spiro(1H-indene-1,4'-piperidine) hydrochloride. The free base was obtained by slurrying the hydrochloride in aqueous sodium bicarbonate solution and extracting with CH2Cl2. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to provide spiro(1H-indene-1,4'piperidine.
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O>CC(C)=O>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][CH2:8][I:1])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [I-]
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCC(c1ccccc1)c1ccccc1
Yield: 84.8 %

Procedure:
To a solution of sodium iodide (2.80 g, 18.9 mmol) in acetone (20 mL) was added a solution of 3,3-diphenylpropyl methanesulfonate (5.00 g, 17.2 mmol) in acetone (10 mL) at 0° C. and the mixture was refluxed for 3 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was diluted with water (30 mL) and extracted with 2 portions of ethyl acetate. The pooled extract was washed with saturated aqueous sodium chloride solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was crystallized from methanol to provide 4.70 g of the title compound. Yield 85%.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C1COCC1>[CH:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cyclohexylamine (8.5 mL, 0.1 mole) was added drop wise to a solution of benzoylchloride (1.17 mL, 10 mmol) in 35 mL of dry THF at 0° C. The reaction was then stirred at room temperature for 3 hours. After that time water was added and the mixture was poured onto crushed ice. A white solid precipitated. It was collected by filtration and rinsed thoroughly with water. The solid was then dried under vacuum (1.63 g, 80%). NMR 1H (ppm, CDCl3): 7.72 (d, J3=6.78 Hz, 2H), 7.48-7.36 (m, 3H), 6.02 (br. d., J3=6.58 Hz, 1H), 4.00-3.89 (m, 1H), 2.03-1.99 (m, 2H), 1.79-1.71 (m, 3H), 1.44-1.37 (m, 2H), 1.25-1.15 (m, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44](O)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]>C(Cl)Cl>[CH3:1][N:2]([C:44](=[O:45])[C:43]1[CH:47]=[C:39]([CH2:38][C:32]2[C:33](=[O:37])[C:34]([O:35][CH3:36])=[C:29]([O:28][CH3:27])[C:30](=[O:53])[C:31]=2[CH3:52])[CH:40]=[CH:41][C:42]=1[O:48][C:49](=[O:51])[CH3:50])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: CNc1ccc(OC)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)N(C)c3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.8 %

Procedure:
N-Methyl-4-methoxyaniline (0.220 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (0.142 g, 0.288 mmol, 54%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:5][CH2:4]1.C[O-].[Na+].CO.[CH2:29]([C:31]1[C:32]([O:39][CH3:40])=[CH:33][C:34]([CH:37]=O)=[N:35][CH:36]=1)[CH3:30].C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:29]([C:31]1[C:32]([O:39][CH3:40])=[CH:33][C:34]([CH2:37][NH:2][CH:3]2[CH2:4][CH2:5][N:6]([CH2:9][CH2:10][N:11]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[CH:14]=[CH:13][C:12]3=[O:23])[CH2:7][CH2:8]2)=[N:35][CH:36]=1)[CH3:30]
Reactant: CCc1cnc(C=O)cc1OC
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCc1cnc(CNC2CCN(CCn3c(=O)ccc4ncc(OC)cc43)CC2)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.6 %

Procedure:
To a suspension of 0.10 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride in 2 mL of methanol, 0.14 g of a 28% sodium methoxide/methanol solution, 40 mg of 5-ethyl-4-methoxypyridine-2-carbaldehyde and 14 μL of acetic acid were added. Then, 30 mg of sodium cyanoborohydride was added thereto, and the mixture was stirred at room temperature for 5 hours. To the reaction mixture, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using gradient elution with chloroform:methanol=9:1 to 86:14 to obtain 51 mg of 1-(2-(4-(((5-ethyl-4-methoxypyridin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one as a yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([C:16]4[N:26]=[C:19]5[C:20]([CH3:25])=[N:21][CH:22]=[C:23]([CH3:24])[N:18]5[N:17]=4)[CH:13]=[CH:12][N:11]3[CH:27]=2)[CH:5]=[CH:6][CH:7]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[Br-]>[NH4+].[Cl-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:24][C:23]1[N:18]2[N:17]=[C:16]([C:14]3[CH:13]=[CH:12][N:11]4[CH:27]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([N:28]6[CH2:32][CH2:31][CH2:30][CH2:29]6)[CH:3]=5)[N:9]=[C:10]4[CH:15]=3)[N:26]=[C:19]2[C:20]([CH3:25])=[N:21][CH:22]=1
Reactant: C1CCNC1
Reactant: Cc1ncc(C)n2nc(-c3ccn4cc(-c5cccc(Br)c5)nc4c3)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1ncc(C)n2nc(-c3ccn4cc(-c5cccc(N6CCCC6)c5)nc4c3)nc12
Temperature: 100 °C
Yield: 54.5 %

Procedure:
To a microwave vial was added 2-(2-(3-bromophenyl)imidazo[1,2-a]pyridin-7-yl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (37 mg, 0.088 mmol), pyrrolidine (18.83 mg, 0.265 mmol), SODIUM TERT-BUTOXIDE (29.7 mg, 0.309 mmol), BINAP (5.49 mg, 8.82 mmol), and Toluene (1 mL). The solution was purged with nitrogen for 5 min and then PALLADIUM(II) ACETATE (0.991 mg, 4.41 mmol) was added. The reaction vial was sealed and heated to 100° C. for 16 hours. The reaction turned black and was then checked by LC/MS. The reaction was complete as indicated by no starting bromide being present. The reaction was cooled to rt diluted with saturated NH4Cl and extracted with EtOAc 4×. The organic fractions were combined, dried over Na2SO4 and evaporated in vacuo. The crude oil was purified by silica gel chromatography eluting with 5% Acetone/95% Hexanes to 60% Acetone/40% Hexanes. The pure fractions were combined and evaporated in vacuo affording 5,8-dimethyl-2-(2-(3-(pyrrolidin-1-yl)phenyl)imidazo[1,2-a]pyridin-7-yl)-[1,2,4]triazolo[1,5-a]pyrazine (21.9 mg, 0.048 mmol, 53.9% yield) as a tan solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.71 (s, 1H), 8.23 (dd, J=7.0, 1.5 Hz, 1H), 7.96-7.92 (m, 1H), 7.89 (d, J=1.0 Hz, 1H), 7.78 (dd, J=7.0, 1.5 Hz, 1H), 7.35-7.28 (m, 2H), 7.26-7.18 (m, 1H), 6.66-6.54 (m, 1H), 3.48-3.33 (m, 4H), 2.97 (s, 3H), 2.80 (s, 3H), 2.06 (m, 4H), LC/Mass spec. (Method 1) RT=2.32 min. Mass=410.2 (MH)+.