Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].Br[CH2:15][CH2:16][O:17][CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:15][CH2:16][O:17][CH3:18])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: COCCBr
Reactant: COC(=O)c1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1ccc(C#N)cc1C(=O)OC
Temperature: 60 °C

Procedure:
Methyl 5-cyano-2-hydroxybenzoate (Astatech, 3.0 g, 16.9 mmol), 1-bromo-2-methoxyethane (2.6 g, 18.6 mmol), and K2CO3 (2.3 g, 16.9 mmol) were mixed in 25 mL of DMF and heated at 60° C. for 48 hours. The reaction was diluted with 100 mL of EtOAc washed with water, brine, dried with MgSO4 and the solvent removed to provide the title compound. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 3.46 (s, 3H) 3.79-3.84 (m, 2H) 3.90 (s, 3H) 4.23-4.28 (m, 2H) 7.07 (d, J=8.82 Hz, 1H) 7.72 (dd, J=8.65, 2.20 Hz, 1H) 8.11 (d, J=2.37 Hz, 1H). MS (DCI/NH3) m/z 236.0 (M+H)+.
Reaction SMILES: [OH2:1].NN.[OH:4][CH2:5][CH2:6][O:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[CH3:19]O>>[OH:4][CH2:5][CH:6]([O:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17])[CH2:19][OH:1]
Reactant: CO
Reactant: O
Reactant: O=C1c2ccccc2C(=O)N1OCCO
Agent: NN
Product: O=C1c2ccccc2C(=O)N1OC(CO)CO

Procedure:
Hydrazine monohydrate (3.96 mg, 0.124 mmol) was added to a solution of 2-(2-hydroxyethoxy)isoindoline-1,3-dione (produced with a similar procedure for intermediate B) (25.6 mg, 0.124 mmol) in 5 mL of MeOH. The solution was heated at reflux for 2 h and then cooled to rt. White precipitate was filtered off and 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (41.2) (15 mg, 0.049 mmol) was added. The pH value of the solution was adjusted to 5-6 with 1N HCl solution. The reaction solution was then stirred at it for 2 h. Solvent was evaporated and the crude was purified by HPLC (acidic with 0.05% TFA) to give 8 mg (44.5%) of the title compound as a white TFA salt. 1H-NMR (400 MHz, MeOH-d4) δ ppm 9.09 (s, 1H), 8.93 (d, 1H), 8.27 (s, 1H), 8.16 (m, 3H), 7.98 (d, 1H), 7.93 (m, 1H), 4.92 (s, 2H), 4.38 (t, 2H), 3.86 (t, 2H), 2.34 (s, 3H). LC-MS (method B): [MH]+=363.1, tR=2.31 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[N:7]([O])[C:6]([CH3:10])([CH3:9])[CH2:5][CH:4]([OH:11])[CH2:3]1.[CH:13]1([C:16](O)=[O:17])[CH2:15][CH2:14]1.C1CCC(N=C=NC2CCCCC2)CC1.C(OCC)(=[O:36])C>CN(C1C=CN=CC=1)C.ClCCl.CCCCCC>[OH:36][N:7]1[C:2]([CH3:12])([CH3:1])[CH2:3][CH:4]([O:11][C:16]([CH:13]2[CH2:15][CH2:14]2)=[O:17])[CH2:5][C:6]1([CH3:10])[CH3:9]
Reactant: O=C(O)C1CC1
Reactant: CC1(C)CC(O)CC(C)(C)N1[O]
Reactant: CCOC(C)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC1(C)CC(OC(=O)C2CC2)CC(C)(C)N1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of Tempol (1.72 g, 0.01 mmole), cyclopropanecarboxylic acid (0.946 g, 0.011 mmole), and DMAP (0.12, 0.001 mmole) in dichloromethane (25 ml) was added DCC (2.27 g, 0.11 mmole) and the mixture was stirred overnight at room temperature. The mixture was filtered over celite and the solution was evaporated under reduced pressure. The product was isolated by silica gel column chromatography using first hexane and then 10% ethyl acetate in hexane. Yield: 2.26 g (94.1). IR and NMR were consistent with the assigned structure.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8](=[O:10])[CH3:9])=[C:5]([CH3:7])[N:6]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C(O)C>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:2]2[S:3][C:4]([C:8](=[O:10])[CH3:9])=[C:5]([CH3:7])[N:6]=2)[CH:12]=1
Reactant: CC(=O)c1sc(Br)nc1C
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CC(=O)c1sc(-c2cccnc2)nc1C
Temperature: 25 °C

Procedure:
2-Bromo-4-methyl-5-acetylthiazole (12.0 g, 54.5 mmol) was dissolved in a mixture of dimethoxyethane (180 ml), water (76 ml) and ethanol (52 ml). To this solution was then added 3-pyridineboronic acid (20.1 g, 163.5 mmol), tetrakis(PPh3)palladium(0) (6.3 g, 5.4 mmol), and sodium carbonate (17.3 g, 163.5 mmol), and the reaction mixture was heated to 160° C. in a microwave oven for a period of 1 hour. The reaction was allowed to cool to ambient temperature, the solvents were removed by evaporation, the residue taken up in ethyl acetate, and the mixture filtered through silica gel and celite. The ethyl acetate was washed with water, dried over magnesium sulfate, and the solvent removed by evaporation. The crude product was purified by chromatograph and the product was obtained as a fawn colored solid. 1H NMR (CDCl3): 2.6 ppm (3H, s); 2.8 ppm (3H, s); 7.4 ppm (1H, m); 8.25 ppm (1H, m); 8.7 ppm (1H, m); 9.2 ppm (1H, m).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[CH3:15][C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([O:37][C@@H:38]([C@H:40]3[CH2:44][NH:43][C:42](=[O:45])[CH2:41]3)[CH3:39])[C:20]=12.C(N(CC)CC)C>ClCCl>[C:1]([N:34]1[CH2:33][CH2:32][N:31]([C:28]2[CH:29]=[CH:30][C:25]([C:23]3[N:22]=[C:21]([O:37][C@@H:38]([C@H:40]4[CH2:44][NH:43][C:42](=[O:45])[CH2:41]4)[CH3:39])[C:20]4[N:19]([N:18]=[CH:17][C:16]=4[CH3:15])[CH:24]=3)=[CH:26][CH:27]=2)[CH2:36][CH2:35]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cnn2cc(-c3ccc(N4CCNCC4)cc3)nc(O[C@H](C)[C@H]3CNC(=O)C3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(-c3cn4ncc(C)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc2)CC1
Reaction time: 2 h
Yield: 79.3 %

Procedure:
Acetic anhydride (3.1 μL, 0.03 mmol) was added to a solution of (R)-4-((R)-1-(3-methyl-6-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 2,2,2-trifluoroacetate 5.56 (14.6 mg, 0.03 mmol) and triethylamine (0.03 mL, 0.21 mmol) in dichloromethane (1.5 mL) at room temperature. After two hours, reaction mixture was directly loaded onto silica gel and purified (0-10% methanol/dichloromethane) to yield (R)-4-((R)-1-((6-(4-(4-acetylpiperazin-1-yl)phenyl)-3-methylpyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.57 (11 mg).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[CH:10][O:9][CH:8]=2)=[CH:3][CH:2]=1.BrC1C=CC(C2C=CC([C:31]#[N:32])=CC=2)=CC=1>CO>[O:9]1[CH:10]=[CH:11][C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:12]3[CH:17]=[CH:16][C:15]([C:31]#[N:32])=[CH:14][CH:13]=3)=[CH:2][CH:3]=2)=[CH:8]1
Reactant: N#Cc1ccc(-c2ccc(Br)cc2)cc1
Reactant: c1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Solvent: CO
Product: N#Cc1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Yield: 53 %

Procedure:
As described in Example 1(a) for the preparation of 3-biphenyl-4-yl-furan, crude 4′-bromo-biphenyl-4-carbonitrile (200 mg, 0.775 mmol) and 3-fuiranboronic acid (see Thompson, W. J.; Gaudino, G. J. Org. Chem. 1984, 49, 5237-5243; 105 mg, 0.937 mmol) in MeOH (2 mL) were coupled to give a yellow solid, which was purified via preparative TLC. Elution with EtOAc:benzene (1:99) provided 100 mg (53%) of 4′-furan-3-yl-biphenyl-4-carbonitrile as a grey powder, mp 199-203° C.
Reaction SMILES: OCCC1C=CC([NH2:8])=CC=1C(F)(F)F.N1C(C)=CC=CC=1C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH2:27]([O:26][C:24](=[O:25])[NH2:8])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc(CCO)c(C(F)(F)F)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 141.9 %

Procedure:
4-(2-Hydroxyethyl)-3-(trifluoromethyl)aniline (408 mg, 2.0 mmol) was dissolved in DCM (10 mL), and 2,6-lutidine (426 mg, 4.0 mmol) and then benzyl chloroformate (678 mg, 4.0 mmol) were dropwise added thereto. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction solution was quenched with a saturated sodium bicarbonate solution, and the organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=3:1) to give 4-(2-hydroxyethyl)-3-(trifluoromethyl)phenyl]carbamic acid benzyl ester (429 mg, 64%) as a light-yellow oil.
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].[C:7]([CH:9]([C:36](OCC)=[O:37])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]([S:26]([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=1)#[N:8]>C(O)C.C(O)(=O)C.C(OCC)(=O)C>[NH2:5][C:4]1[NH:6][C:36](=[O:37])[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:15]2[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)=[C:7]([NH2:8])[N:3]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)c1ccc(N(CCCCC(C#N)C(=O)OCC)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N(CCCCc2c(N)nc(N)[nH]c2=O)c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.377 g (0.0164 mol) of sodium in 8 mL of absolute ethanol under nitrogen was added 1.04 g (0.0109 mol) of guanidine hydrochloride and 1 mL of rinse absolute ethanol. The mixture was stirred for 30 min, and to it was added a solution of 2.73 g (0.00546 mol) of ethyl 4-[(5-cyano-6-ethoxy-6-oxohexyl)tosylamino]benzoate.0.15 ethyl acetate in 6 mL of absolute ethanol and then 7 mL of rinse absolute ethanol. The mixture was refluxed for 4 h and was allowed to cool to room temperature and stand under nitrogen overnight. The reaction mixture was filtered by suction, and the filtrate was neutralized with 0.984 g (0.0164 mol) of glacial acetic acid. The solution was concentrated under vacuum at 30° C. to a solid that was washed well with 50 mL of water, collected by suction filtration, washed again with 25, 25, and 10 mL of water, and dried under vacuum at 60° C.; yield, 2.76 g. Fourier transform NMR (Me2SOd6) and chemical ionization mass spectroscopy indicated a mixture of product and uncyclized intermediates. A 2.41 g sample of solid was added to a solution of 3.16 g (0.137 mol) of sodium in 138 mL of absolute ethanol under nitrogen. The mixture was heated to reflux, and the resulting solution was refluxed for 3 h 15 min. The slightly cloudy solution was allowed to cool to room temperature, and the resulting mixture was allowed to stand under nitrogen overnight. The mixture was heated briefly back to reflux, and the resulting slightly cloudy, hot solution was neutralized with 8.30 g (0.138 mol) of glacial acetic acid. The thick mixture was concentrated under vacuum at 35° C. to a white solid to which was added 50 mL of water. Then to the stirred mixture was added approximately 5-8 mL of concentrated hydrochloric acid. The mixture with a pH of 5.5 was filtered by suction, and collected solid was washed with 15 and 20 mL of water and dried under vacuum overnight at room temperature in a desiccator; yield, 1.98 g (84%): NMR (Me2SOd6) δ 1.2-1.4 (m, 4H), 2.06 (t, 2H), 2.37 (s, 3H), 3.54 (t, 2H), 5.58 (br s, 2H), 5.89 (br s, 2H), 7.14 (d, 2H), 7.3-7.5 (AA'BB', 4H), 7.86 (d, 2H), 9.75 (br), 0.13 mol of acetic acid.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[CH2:29]([O:31][CH2:32][CH2:33][C:34](=[N:36]O)[NH2:35])[CH3:30]>>[CH2:29]([O:31][CH2:32][CH2:33][C:34]1[N:36]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:35]=1)[CH3:30]
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: CCOCCC(N)=NO
Product: CCOCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.434 mmol) of the compound from Example 25A and 307 mg (approx. 1.864 mmol) of 3-ethoxy-N′-hydroxypropanimidamide were reacted Yield: 403 mg (55% of theory)
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH2:18])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:28]12([C:38](Cl)=[O:39])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:38]([C:28]34[CH2:37][CH:32]5[CH2:31][CH:30]([CH2:36][CH:34]([CH2:33]5)[CH2:35]3)[CH2:29]4)=[O:39])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ncnc2c1CCN(Cc1ccccc1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ncnc2c1CCN(Cc1ccccc1)C2)C12CC3CC(CC(C3)C1)C2
Temperature: 160 °C
Yield: 41.8 %

Procedure:
In a 20 ml microwave vessel was added 7-benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-ylamine (1.5 g, 6.3 mmole) in 7.0 ml of chloroform, diisopropylethylarnine (2.2 ml, 12.6 mmole) and 1-adamantane carbonylchloride (2.51 g, 12.6 mmole). The reaction was heated at 160° C. for 7.0 minutes in a microwave. After completion the solvent was evaporated and the residue was dissolved in EtOAc and washed with sat. NaHCO3, washed with brine and dried over sodium sulphate. The solvents were removed under reduced pressure and the residue was chromatographed using chloroform (100%) to give the desired product as a white solid (1.06 g).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[CH2:10]([N:17]([CH2:21][Si](C)(C)C)[CH2:18]OC)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:17]1[CH2:18][CH2:7][C:3]([C:2]([F:9])([F:8])[F:1])([C:4]([OH:6])=[O:5])[CH2:21]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1(C(F)(F)F)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 2.48 g sample of 2-(trifluoromethyl)acrylic acid was dissolved in 40 mL of dry methylene chloride, and a solution of 4.75 g of N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine in 20 mL of dry methylene chloride was added dropwise under N2 at 0° C. To this mixture was added 2 mL of trifluoroacetic acid, and the mixture was stirred for 2 hours at room temperature. The product was removed by filtration, washed and dried to give the title product.
Reaction SMILES: C(OC([N:8]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:44])[N:14]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:35])[N:20]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(ON(C(=O)CCCCNOCC1C=CC=CC=1)CCCCC#N)C1C=CC=CC=1>C(Cl)Cl>[CH2:28]([O:27][N:20]([C:19](=[O:35])[CH2:18][CH2:17][CH2:16][CH2:15][N:14]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:13](=[O:44])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N(CCCCC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Agent: N#CCCCCN(OCc1ccccc1)C(=O)CCCCNOCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCCCN(OCc1ccccc1)C(=O)CCCCNOCc1ccccc1
Yield: 57.1 %

Procedure:
Compound (7) (2.85 g, 3.99 mmol) in CH2Cl2 was treated with excess TFA following the procedure used for (5). Silica gel column chromatography, eluting with 3:2 EtOAc/hexane gave 1.4 g (57%) of (8) as an oil: NMR δ 1.43-1.83 (m, 12 H), 2.20-2.50 (m, 6 H), 2.90 (t, 2 H, J=6), 3.60 (t, 4 H, J=6), 4.63 (s, 2 H), 4.75 (s, 4 H), 7.28 (s, 5 H) , 7.33 (s, 10 H). Anal. (C36H46N4O5) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][C:28]([OH:30])=[O:29])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.O.[OH-].[Li+:35].CO>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][C:28]([O-:30])=[O:29])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.[Li+:35]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC(=O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC(=O)[O-])cc1
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
2-[2-[4-[(5-Methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetic acid (0.20 g) was added to a mixture of lithium hydroxide monohydrate (19 mg), methanol (5 mL) and tetrahydrofuran (5 mL) at room temperature, and the mixture was stirred for 30 min. The reaction mixture was concentrated, and the residue was crystallized from methanol and diethyl ether to give crystals (0.18 g, yield 90%) of lithium 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetate. Recrystallization from methanol-diethyl ether gave colorless prism crystals. melting point: 207-209° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CCN(CC)CC.[NH2:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23](=[O:35])[N:24]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:25]3=[N:26]2)=[CH:21][CH:20]=1>O=S(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:18][C:19]2[CH:28]=[C:27]3[C:22]([C:23](=[O:35])[N:24]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:25]4=[N:26]3)=[CH:21][CH:20]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc2c(=O)n3c(nc2c1)CCCCCC3
Reactant: O=C(O)c1ccc(F)cc1
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(=O)n3c(nc2c1)CCCCCC3)c1ccc(F)cc1
Reaction time: 1 h
Yield: 6.1 %

Procedure:
A solution of 4-fluorobenzoic acid (100 mg, 0.71 mmol) in SOCl2 (2 mL) was stirred at reflux for 1 h. Excess SOCl2 was removed and the residue was dissolved in THF (10 mL). The solution was added to a mixture of Et3N (1 mL) and 3-amino-8,9,10,11-tetrahydro-6H-azocino[2,1-b]quinazolin-13(7H)-one (22 mg, 0.09 mmol). After stirring for 1 h, the mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the desired product (2 mg). MS (ESI): 366 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=8.70 Hz, 1H), 7.96-7.91 (m, 4H), 7.75-7.71 (dd, J=8.72 Hz, 2.12 Hz, 1H), 7.24-7.19 (t, J=8.60 Hz, 2H), 4.34 (broad, 2H), 3.06-3.02 (m, 2H), 1.99-1.87 (m, 4H), 1.68-1.66 (m, 2H), 1.47-1.46 (d, J=4.32 Hz, 2H). mGluR5 PAM EC50: +.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][CH2:17][CH2:18][CH2:19][N:20]1[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:21]1=[O:35]>>[ClH:16].[CH2:28]([N:22]1[C:23](=[O:27])[C:24]([CH3:26])=[CH:25][N:20]([CH2:19][CH2:18][CH2:17][N:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:14][CH3:15])[CH2:13][CH2:12]2)[C:21]1=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1cn(CCCCl)c(=O)n(Cc2ccccc2)c1=O
Reactant: COc1cc(F)ccc1N1CCNCC1
Product: COc1cc(F)ccc1N1CCN(CCCn2cc(C)c(=O)n(Cc3ccccc3)c2=O)CC1
Product: Cl

Procedure:
substituting 1-(4-fluoro-2-methoxyphenyl)piperazine and 1-(3-chloropropyl)-3-benzyl-5-methyl-2,4(1H,3H)-pyrimidinedione gave 3-benzyl-1-{3-[4-(4-fluoro-2-methoxyphenyl)piperazin-1-yl]propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 210°-212° C.; Anal.: Calcd. for C26H31FN4O3.(HCl)2 : C, 57.88; H, 6.16; N, 10.38%; Found: C, 57.50; H, 6.18; N, 10.62%;
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:29])=[C:9]([C:25]([O:27][CH3:28])=[O:26])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH2:30]([O:32][C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH3:31]>C(Cl)(Cl)Cl>[Cl:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:25]([O:27][CH3:28])=[O:26])=[C:8]([CH3:29])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:36]([NH:35][C:33]([O:32][CH2:30][CH3:31])=[O:34])=[S:37])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)N=C=S
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC(=S)NCCOCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 2-(2-aminoethoxymethyl)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (4.43 g) in dry chloroform (50 ml) was added, dropwise, a solution of ethoxycarbonylisothiocyanate (1.31 g) in dry chloroform (25 ml). The reaction was stirred for 18 hours at room temperature before evaporating the solvent and triturating the residue with ether to afford a solid which was recrystallised from diisopropyl ether to give the title compound, yield 2.6 g, m.p. 144°.
Reaction SMILES: [CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl.O.[CH2:26](O)[CH3:27]>>[CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]([O:23][CH2:26][CH3:27])=[O:22])=[CH:16][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1cc2cc(C(=O)O)ccc2[nH]1
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCCCCCCCCCCc1cc2cc(C(=O)OCC)ccc2[nH]1

Procedure:
A solution of 2-(n-undecyl)indole-5-carboxylic acid (15.0 g) in ethanol (50 ml) containing a solution of hydrogen chloride gas in ethanol (100 ml of strength 34% w/v) was refluxed for 3 hours. The solution was poured onto a mixture of crushed ice and water and the precipitated solid was collected. Recrystallisation from ethanol (100 ml) with charcoal treatment gave ethyl 2-(undecyl)indole-5-carboxylate (7.5 g), in the form of white crystals, m.p. 76°-77° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:15])[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=[O:5])[CH3:2].[B-](F)(F)(F)[F:17].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:15])[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:10]=1[F:17])=[O:5])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(F)c(C(C)(C)C)nn1C
Temperature: 80 °C
Reaction time: 12 h

Procedure:
5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (210 mg, 1.00 mmol) was added dropwise to a stirred solution of SELECTFLUOR® (531 mg, 1.50 mmol) in anhydrous acetonitrile (4 mL) under an Ar atmosphere. The resulting mixture was then stirred at 80° C. for 12 h, then cooled to room temperature, diluted with EtOAc (2 mL), and filtered. The solvent was removed under reduced pressure and the resulting residue was chromatographed on a 24-g SiO2 pre-packed column eluting with 0:1-1:4 EtOAc/hexanes to yield 5-tert-Butyl-4-fluoro-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester. 1H-NMRH-NMR (400 MHz, CDCl3) δ: 4.37 (q, J=7.2 Hz, 2H), 4.03 (d, J=1.0 Hz, 3H), 1.39 (t, J=7.1 Hz, 3H), 1.34 (s, 9H).