Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3](O)C.[SH:6][C:7]1[N:8]=[N:9][C:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:12]=1.CI>O>[CH3:3][S:6][C:7]1[N:8]=[N:9][C:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[N:12]=1
Reactant: CCO
Reactant: COc1ccc(-c2nnc(S)nc2-c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: COc1ccc(-c2nnc(SC)nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Eight grams (0.20 mole) of sodium hydroxide were dissolved in 600 ml. of ethanol by warming. The basic solution was cooled to room temperature and 67.0 grams (0.20 mole) of 3-mercapto-5,6-bis(4-methoxyphenyl)-1,2,4-triazine were added. Methyl iodide, 67 g. (0.47 mole), was added to the reaction mixture and the mixture immediately became a slurry. Three hundred milliliters of ethanol were added to the slurry and stirring was continued for about 3 hours. One hundred milliliters of water were added to the reaction mixture and the solid product was collected by filtration. The yield of 3-methylmercapto-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, mp about 152°-155°C., was 67.3 g.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH3:13])([CH3:12])[S:9][C:8]=2[CH:14]=1)([OH:3])=O.C(Cl)(=O)[C:16]([Cl:18])=O.Cl>CCOCC>[Cl:18][CH2:16][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH3:13])([CH3:12])[S:9][C:8]=2[CH:14]=1)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)Oc2ccc(C(=O)O)cc2S1
Agent: Cl
Solvent: CCOCC
Product: CC1(C)Oc2ccc(C(=O)CCl)cc2S1
Reaction time: 2 h
Yield: 52 %

Procedure:
A mixture consisting of 10 g of 5-carboxy-2,2-dimethyl-1,3-benzoxathiole (IV), 10 g of oxalyl chloride and 20 ml of ether was boiled gently for 2 hours. The solution was cooled and evaporated and the residue (V) was added to an ether solution of diazomethane prepared from 25 g of N-nitroso-N-methyl urea. After stirring the mixture for 18 hours at room temperature the solution (VI) was acidified with methanolic hydrogen chloride and then evaporated to leave a solid residue which was recrystallized from ether/hexane to yield 6 g of 5-chloroacetyl-2,2-dimethyl-1,3-benzoxathiole (VII), m.p. 84°-86° C.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:24])[CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[OH-].[Na+]>CO>[CH2:17]([O:16][C:14]([NH:13][CH2:12][CH2:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2])=[O:24])=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CCCCCNC(=O)CCNC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCNC(=O)CCNC(=O)OCc1ccccc1

Procedure:
The compound 36 was prepared using General Procedure A with ester 35 (3.20 g, 9.13 mmol) and an aqueous NaOH solution (1.46 g, 36.53 mmol in 40 mL of H2O) in MeOH (40 mL). Recrystallization from MeOH produced the desired acid 36 in 95% (2.92 g) yield as a white solid. 1H NMR (CDCl3): δ 7.32 (m, 5H, ArH), 6.10 (s, 1H, NH), 5.67 (s, 1H, NH), 5.04 (s, 2H, OCH2Ar), 3.45 (dt, J=6.4, 12.0 Hz, 2H, CH2NHCO), 3.21 (dt, J=6.4, 12.8 Hz, 2H, CH2NHCO), 2.40 (dt, J=6.0, 6.4 Hz, 2H, CH2CO), 2.32 (t, J=7.2 Hz, 2H, CH2CO), 1.61 (m, 2H, CH2), 1.48 (m, 2H, CH2), 1.33 (m, 2H, CH2); ESI-MS m/z 371[M+Cl]−, 359[M+Na]+, 337[M+H]+, 335[M−H]−.
Reaction SMILES: [Cl-].[Na+].[Na+].[Na+].[Cl-].[Cl-].[I:7][C:8]1[N:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[O:11][C:12]=1[C:13]([OH:15])=O.[O-:23][N+:24]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[C:26]([C@H:34]([NH2:36])[CH3:35])[CH:25]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[I:7][C:8]1[N:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[O:11][C:12]=1[C:13]([NH:36][C@@H:34]([C:26]1[CH:25]=[N+:24]([O-:23])[C:29]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:27]=1)[CH3:35])=[O:15]
Reactant: Cc1ccc(-c2nc(I)c(C(=O)O)o2)cc1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)[n+]([O-])c1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1ccc(-c2nc(I)c(C(=O)N[C@H](C)c3ccc(C(F)(F)F)[n+]([O-])c3)o2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a solution of tri sodium chloride salt of iodo-2-(4-methylphenyl)-1,3-oxazole-5-carboxylic acid (55.2 mg, 0.11 mmol) in DMF (1.1 mL) were added (1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethanamine (27.9 mg, 0.12 mmol), EDC (36.7 mg, 0.19 mmol), HOAT (7.45 mg, 55.0 μmol) and triethylamine (61 μL, 0.44 mmol). The mixture was stirred at 50° C. After 30 min, the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) to give the title compound (41 mg). MS 517.8 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[C:28]([OH:32])(=[O:31])[CH:29]=[CH2:30]>[Cl-].C[N+](C)(C)C>[C:28]([O:32][CH2:3][CH:2]([OH:4])[CH2:1][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:31])[CH:29]=[CH2:30]
Reactant: c1ccc(OCC2CO2)cc1
Reactant: C=CC(=O)O
Agent: C[N+](C)(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Product: C=CC(=O)OCC(O)COc1ccccc1

Procedure:
To 3000 g of phenyl glycidyl ether (epoxide content 6.16 equiv./kg) containing 9 g of tetramethylammonium chloride and 6 g of 2,6-di-t-butyl-p-cresol, stirred at 100°, was added 1332 g of acrylic acid over one hour. The mixture was stirred at 100° for a further 4 hours, by which time the epoxide content was 0.91 equiv./kg and the viscosity was 60 cP at 25°, to yield 3-phenoxy-2-hydroxypropyl acrylate.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:2]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:13])[CH:3]=[C:2]2[Cl:1])[C:11]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1cc(Cl)c2cccc(OCc3ccccc3)c2n1
Temperature: 70 °C
Yield: 77.8 %

Procedure:
To 4-chloro-2-methylquinolin-8-ol (10.20 g, 52.7 mmol), potassium carbonate (10.9 g, 79.0 mmol) in 2-butanone (100 mL) was added benzyl bromide (6.89 mL, 58.0 mmol) vial syringe with stirring. The suspension was heated at 70° C. for 4 h, stirred at ambient temperature overnight and poured into ice water (200 mL). The precipitate was filtered, washed with a little EtOAc/water and dried to give 8-(benzyloxy)-4-chloro-2-methylquinoline (5.82 g). The filtrate was extracted with EtOAc, dried, filtered and evaporated. Solid from Hex/EtOAc (10/1) was filtered and dried to give additional 8-(benzyloxy)-4-chloro-2-methylquinoline, 13.72 g (92% total crude yield).
Reaction SMILES: C([NH:4][C:5]1[C:10]2[C:11](=[O:20])[CH:12]([NH:16][C:17](=[O:19])[CH3:18])[CH2:13][CH2:14][CH2:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=O)C.C(NC1CCC2C(=C(NC(=O)C)C=CC=2)C1=O)(=O)C>>[C:17]([NH:16][CH:12]1[C:11](=[O:20])[C:10]2[C:5]([NH2:4])=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:15][CH2:14][CH2:13]1)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CCC2
Agent: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CC2
Product: CC(=O)NC1CCCc2cccc(N)c2C1=O

Procedure:
The reaction was carried out in the same manner as in Example 1-(4), except that 115 mg of the compound prepared in (3) above was used instead of 2,8-diacetylamino-1-tetralone of Example 1-(4). The product was post-treated to produce 90 mg of the title compound.
Reaction SMILES: [ClH:1].Cl.FC1C=CC(C2C=NC(N3CCNCC3)=NC=2)=CC=1.C(OC([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)=[CH:37][N:36]=2)[CH2:31][CH2:30]1)=O)(C)(C)C>>[ClH:1].[ClH:1].[F:47][C:44]1[CH:43]=[CH:42][C:41]([C:38]2[CH:39]=[CH:40][C:35]([N:32]3[CH2:31][CH2:30][NH:29][CH2:34][CH2:33]3)=[N:36][CH:37]=2)=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1
Agent: Cl
Agent: Fc1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Product: Fc1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Yield: 89 %

Procedure:
Prepared according to the method for the preparation of 5-(4-fluorophenyl)-2-piperazin-1-ylpyrimidine dihydrochloride, from 4-[5-(4-fluorophenyl)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (0.146 g), to provide the title compound as a white solid (0.120 g, 89%).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:5]=1[C:6]([O:8]C)=[O:7])[CH:2]=[CH2:3].[OH-].[K+]>C(O)C>[CH2:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:5]=1[C:6]([OH:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCc1cccc(N)c1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCc1cccc(N)c1C(=O)O

Procedure:
To a solution of Step 2 intermediate (3.0 g, 15.7 mmol) in ethanol (10 ml) was added 2.0 M potassium hydroxide (4.0 ml) and the mixture was refluxed for 3 h. The mixture was concentrated under reduced pressure and diluted with water. The basic aqueous solution containing the product was washed with diethyl ether (2×25 ml). The aqueous solution was acidified to pH 4.0 with 1N HCl. The solid separated out was filtered and washed with water and dried to give 550 mg of the product as an off-white solid; 1H NMR (δ ppm, CDCl3, 300 MHz): 7.01 (t, J=9.0, 1H); 6.57 (d, J=9.0, 1H); 6.36 (d, J=9.0, 1H); 5.94-5.79 (m, 1H); 5.02-4.90 (m, 2H); 3.46 (d, J=6.0, 2H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[NH:16][N:15]=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH:43]([C:49](=O)[CH2:50][CH2:51][CH3:52])[C:44](OCC)=[O:45])=[C:38]([O:54][CH3:55])[CH:37]=1)#[N:29].C(OCC)(=O)C>CCN(C1C=CC=CC=1)CC.O>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([N:11]3[C:44](=[O:45])[C:43]([CH2:42][C:39]4[CH:40]=[CH:41][C:36]([C:31]5[C:30]([C:28]#[N:29])=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:37][C:38]=4[O:54][CH3:55])=[C:49]([CH2:50][CH2:51][CH3:52])[N:16]4[N:15]=[CH:14][CH:13]=[C:12]34)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1OC)C(=O)OCC
Reactant: c1cc(NC2CCC3(CC2)OCCO3)[nH]n1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2OC)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Yield: 86 %

Procedure:
A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (0.53 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.071 mL) and ethyl 2-[(2′-cyano-3-methoxybiphenyl-4-yl)methyl]-3-oxohexanoate (1.81 g) in diethylaniline (3 mL) was stirred at 180° C. for 2 hr. The mixture was allowed to cool, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.1 g, 83%).
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.[CH3:21][N:22]([CH2:24][C:25]1[O:29][C:28]([CH2:30][S:31][CH2:32][CH2:33]N)=[CH:27][CH:26]=1)[CH3:23]>C(O)C>[CH3:23][N:22]([CH2:24][C:25]1[O:29][C:28]([CH2:30][S:31][CH2:32][CH2:33][NH:4][C:5]2[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[CH:7][N:6]=2)=[CH:27][CH:26]=1)[CH3:21]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: COc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: CCO
Product: COc1ccc(Cc2cnc(NCCSCc3ccc(CN(C)C)o3)[nH]c2=O)cn1

Procedure:
An equimolar mixture of 2-nitroamino-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone and 2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamine are refluxed in ethanol for 18 hours and evaporated to dryness. The residue is triturated with water and recrystallised to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[C:27]([OH:28])=[C:26]([O:29][CH3:30])[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33].N(S([O-])(=O)=O)(S([O-])(=O)=[O:37])[O].[K+].[K+].O.P(O)(O)([O-])=O.[K+]>CN(C)C=O.CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[C:27](=[O:28])[C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24](=[O:37])[C:23]=1[CH3:33]
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Reactant: COc1cc(C)c(CCCCCCCCCCCCCCCCCCCCO)c(O)c1OC
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCCCCCCCCO)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1080 h
Yield: 54.9 %

Procedure:
To a solution of 6-(20-hydroxyeicosyl)-2,3-dimethoxy-5-methylphenol (2.3 g) in dimethylformamide (1.5 l) are added potassium nitrosodisulfonate (30 g), water (1.5 l), methanol (300 ml) and monopotassium phosphate (1.3 g) and the mixture is stirred at room temperature for 45 days. The reaction mixture is extracted with dichloromethane and recrystallized from ether. The above procedure gives 6-(20-hydroxyeicosyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (1.3 g) as yellow needles. Melting point: 85° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[SH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C(N(CC)CC)C.O>O1CCCC1>[CH3:19][O:18][C:16]([CH2:15][S:14][C:2]1[S:3][C:4]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8])=[O:17]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Br)s1
Reactant: COC(=O)CS
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CSc1sc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-bromo-5-methoxycarbonyl-3-nitrothiophene (110.7 g) and methyl mercaptoacetate (37.2 ml) in tetrahydrofuran (1 l) was added triethylamine (63.8 ml). After stirring for 4 hours at room temperature, the reaction mixture was poured into water. The resulting precipitate was collected by filtration and washed with water to give 2-methoxycarbonylmethylthio-5-methoxycarbonyl-3-nitrothiophene (118.15 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClCCl.[OH-].[Na+].[F:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:16]=1[CH2:17]Br>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[NH2:1][C:2]1[C:7]([O:8][CH2:17][C:16]2[C:15]([F:14])=[CH:22][C:21]([F:23])=[CH:20][C:19]=2[F:24])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1cc(F)c(CBr)c(F)c1
Reactant: Nc1ncccc1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Nc1ncccc1OCc1c(F)cc(F)cc1F
Reaction time: 0.08 h

Procedure:
A mixture of 2-amino-3-hydroxy pyridine (2.44 g, 0.022 mol), dichloromethane (20 ml) and 40% aqueous sodium hydroxide solution (20 ml) was stirred for five minutes, then 2,4,6-trifluorobenzyl bromide (5.00 g, 0.022 mol) and Adogen 464 (3 ml) were added and stirring continued for 16 hours. The mixture was diluted with water and extracted with dichloromethane. Drying and evaporation of the organic extracts, and trituration with ether gave the desired product. Yield 2.76 g (49%), m.p. 122°-124 ° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[CH3:30][O:31][C:32]1[N:33]=[CH:34][C:35]([O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[CH:36][CH:37]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(Oc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cn1

Procedure:
The title compound was prepared from [4-(3-hydroxy-phenyl)-8-trifluoromethylquinolin-3-yl]-phenyl methanone and 2-Methoxy-5-pyridineboronic acid, following the procedure of Example 519: MS m/z 501.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][CH2:12][O:13][C:14]=2[N:15]=1)[CH2:2][CH3:3].[ClH:23].C(OCC)(=O)C>>[ClH:23].[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][O:13][C:14]=2[N:15]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCOc1ccc2c(n1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
A mixture of the compound obtained in step 1 (0.36 g) and 4N hydrogen chloride/ethyl acetate (3 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration, and recrystallized from ethanol-diisopropyl ether to give the title compound (0.25 g, 87%) as a white powder.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1[CH:9]=[N:10][N:11]([CH:13]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14]2)[CH:12]=1>C1COCC1.CCOC(C)=O>[CH3:18][N:15]1[CH2:16][CH2:17][CH:13]([N:11]2[CH:12]=[C:8]([NH2:7])[CH:9]=[N:10]2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC(n2cc(N)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
A reaction flask containing a suspension of LAH (499 mg, 13.2 mmol) in THF (22 mL) was evacuated and back-filled with nitrogen three times. A solution of tert-butyl 3-(4-amino-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (830 mg, 3.3 mmol) in THF (11 mL) was added dropwise, via an addition funnel and the reaction mixture was stirred at rt under nitrogen overnight. The reaction was quenched sequentially with water (1 mL), 1N NaOH (1 mL), and water (3 mL) to afford a suspension. The precipitate was filtered off and washed with ethyl acetate. The combined filtrates were diluted with a small amount of water and transferred to a separatory funnel. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The organics were combined and concentrated to give crude material (137 mg). To recover product in the aqueous layer, the aqueous extraces were lyophilized to give a solid residue. This was suspended in EtOAc and filtered. The filtrate was evaporated to give additional crude material (287 mg). The combined crude was purified via Biotage flash chromatography (25S column, eluting with 7 N NH3/MeOH in DCM (1%-4%)) to give the title compound (279 mg, 51% yield). m/z (APCI+) for C8H14N4 167.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.89-2.00 (m, 1H) 2.20-2.31 (m, 1H) 2.26 (s, 3H) 2.42 (td, J=8.40, 6.19 Hz, 1H) 2.60 (dd, J=9.60, 4.80 Hz, 1H) 2.64-2.77 (m, 2H) 3.79 (br. s., 2H) 4.67 (m, J=9.44, 7.23, 4.67, 4.67 Hz, 1H) 6.87 (s, 1H) 7.07 (s, 1H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)([CH3:8])[CH3:7].CN([CH:24]=[O:25])C>CCOC(C)=O>[CH:6]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH:24]=[O:25])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)([CH3:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: CC(C)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)c1[nH]c2cc([N+](=O)[O-])ccc2c1C=O
Reaction time: 0.33 h

Procedure:
POCl3 (0.12 ml, 1.4 mmol) was added dropwise to anhydrous DMF (1.5 ml) at 0° C. under argon. After stirred for 20 min, a solution of 2-isopropyl-6-nitro-1H-indole (Compound 120, 115 mg, 0.56 mmol) in anhydrous DMF (1.5 ml) was added slowly to the above reaction and stirred for 1 h at 0° C. and 2 h at room temperature. The reaction was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=2)[C:15]([OH:17])=[O:16])[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=2)[C:9]([OH:11])=[O:10])[C:15]([OH:17])=[O:16])=[CH:24][CH:23]=1
Reactant: COc1ccc(C[C@@H](CC[C@H](Cc2ccc(OC)cc2)C(=O)O)C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C[C@@H](CC[C@H](Cc2ccc(O)cc2)C(=O)O)C(=O)O)cc1
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 30.8 %

Procedure:
To a round bottom flask was added (2R,5R)-2,5-bis(4-methoxybenzyl)hexanedioic acid (124 mg, 0.321 mmol) and pyridine hydrochloride (371 mg, 3.21 mmol). The reaction was stirred at 160° C. for 20 min. After cooling to rt, the reaction was diluted with water and extracted with EtOAc (2×15 mL). The combined EtOAc extracts were concentrated in vacuum. The resulting residue was purified using RP prep-HPLC (Method B) to give (2R,5R)-2-(4-hydroxybenzyl)-5-(4-methoxybenzyl)hexanedioic acid (37 mg, 0.099 mmol, 31% yield) as white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]=[C:16]1[O:20][C:18](=[O:19])[CH2:17]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:18](=[O:19])[CH2:17][C:16]([CH3:15])=[O:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1CC(=O)O1
Reactant: OC1CCCN(Cc2ccccc2)C1
Product: CC(=O)CC(=O)OC1CCCN(Cc2ccccc2)C1
Yield: 62.7 %

Procedure:
Then, 11.8 g of the 1-benzyl-3-hydroxypiperidine and 5.6 g of diketene were reacted similarly as in Reference Example 1, and the reaction product was purified by silica gel column chromatography (eluent:chloroform:methanol=9:1 v/v), to obtain 10.65 g of acetoacetic acid-N-benzyl-3-piperidinyl ester (yield: 62.5%). This was used in the reaction of Example 4 without distillation.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([O:8][CH2:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=O)=O)=[CH:4][CH:3]=1.C([NH2:20])(=O)C.B(F)(F)F.CCOCC>>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[O:8][CH:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[N:20]=2)=[CH:4][CH:3]=1
Reactant: O=C(OCC(=O)C1CC1)c1ccc(Br)cc1
Reactant: CC(N)=O
Agent: FB(F)F
Solvent: CCOCC
Product: Brc1ccc(-c2nc(C3CC3)co2)cc1
Yield: 16.4 %

Procedure:
To a mixture of 2-cyclopropyl-2-oxoethyl 4-bromobenzoate (4.51 g, 15.93 mmol) and acetamide (4.71 g, 79.74 mmol) was added BF3/Et2O (1 ml). The mixture was heated at 140C for 8 h. Upon cooling, the mixture was partitioned between water and Et2O. The aqueous phase was extracted with Et2O (1×125 ml). The combined organic phases were washed with Water and brine, dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (CH2Cl2/hexanes, 30:70 to 50:50) to yield the title compound as a white crystalline solid (0.69 g, 16%).