Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1C[CH:2]1[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[N+:16]([C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:1][CH:2]([N:20]1[CH:21]=[CH:22][N:23]=[C:19]1[N+:16]([O-:18])=[O:17])[CH2:3][N:4]1[C:8](=[O:9])[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:14]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(O)n1ccnc1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
To a solution of N-(2,3-epoxypropyl)phthalimide (1) (Fluka, 25.0 g, 0.123 mol) in ethanol (200 mL), 2-nitroimidazole (2) (Nippon Ghosei, 14.5 g, 0.128 mol) and potassium carbonate (1.5 g) were added, and the reaction mixture was heated under reflux for 8 hrs. The reaction mixture was cooled and the yellow solid obtained was filtered and washed with ethanol (2×75 mL). The precipitate was transferred to a one liter beaker and water was added (500 mL). The mixture was stirred for 15 min. The yellow precipitate was filtered and the solid was washed with water (3×250 mL). 2-[2-hydroxy-2-(2-nitro-1H-imidazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione (3) was obtained and dried under vacuum. Yield 32.8 g (85%). The product was pure by proton NMR and HPLC, and was used in the next step without further purification. A portion (˜2 g) of the solid was recrystallized from methanol. The melting point was 213-214° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH2:23][C@H:12]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[CH2:23][C@H:12]23)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)cc1
Yield: 70 %

Procedure:
The title compound is prepared from 4-amino-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 70% of theory; LC (method 4): tR=1.77 min; Mass spectrum (ESI+): m/z=293 [M+H]+.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10]#[N:11].[H-].[Na+].[CH3:15][C:16]1[N:21]=[C:20](Cl)[C:19]([CH3:23])=[C:18]([Cl:24])[N:17]=1>C1COCC1>[Cl:24][C:18]1[N:17]=[C:16]([CH3:15])[N:21]=[C:20]([CH:9]([C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:12])[C:10]#[N:11])[C:19]=1[CH3:23]
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Reactant: Cc1nc(Cl)c(C)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(C#N)c2nc(C)nc(Cl)c2C)c(C)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 106.3 %

Procedure:
To a solution of mesitylacetonitrile (0.900 g, 5.65 mmol) in 8 ml dry THF was added sodium hydride (60% in oil, 0.250 g, 6.21 mmol) and the mixture was stirred at room temperature for 40 minutes. 2,5-Dimethyl-4,6-dichloropyrimidine (1.000 g, 5.65 mmol) was added and the resulting mixture was heated at reflux for 5 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 1.800 g of a yellow oil. The oil residue was purified through silica gel column chromatography using 10% ethyl acetate in hexane as eluent to give 0.986 g (58.3%) of the title compound as a white solid, mp 100–102° C. 1H NMR (CDCl3) δ 6.86 (s, 2H), 5.60 (s, 1H), 2.69 (s, 3H), 2.25 (s, 3H), 2.18 (s, 6H), 1.92 (s, 3H) ppm.
Reaction SMILES: Cl.C(C1C=CC2[NH:14][CH:13]([CH2:15]C(OC)=O)[C:12](=[O:20])N(C)CC=2C=1)(O)=O.O[N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:14][CH:13]([C:15]1[NH:24][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH2:12][OH:20]
Reactant: COC(=O)CC1Nc2ccc(C(=O)O)cc2CN(C)C1=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(CO)c1nc2ccccc2[nH]1

Procedure:
HCl (Maekawa; Ohtani, Agric. Biol. Chem., 40, 1976, 791) and 0.88 g of methyl 7-carboxy-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate are dissolved in 30 ml of DMF and treated with 0.49 g of 1-hydroxybenzotriazole and 0.58 g of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide.hydrochloride and 1.55 g of diiso-propylethylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[N+:21]([O-])=O)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[N:9]=1)([O-])=O>CO.[Pd]>[CH3:17][S:14]([C:10]1[N:9]=[C:8]([O:7][C:6]2[CH:5]=[C:4]([NH2:1])[C:20]([NH2:21])=[CH:19][CH:18]=2)[CH:13]=[CH:12][N:11]=1)(=[O:15])=[O:16]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)n1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1nccc(Oc2ccc(N)c(N)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(3,4-Dinitro-phenoxy)-2-methylsulfonyl-pyrimidine (Step A, 1.0 g, 2.9 mmol, 1.0 eq.) was dissolved in MeOH (50 mL) and the atmosphere was replaced by argon. A catalytic amount of 10% Pd/C was added and the argon was replaced by a H2 atmosphere. The mixture was stirred for 16 h at RT at atmospheric pressure. More Pd/C was added after the atm was replaced by argon, then the reaction was stirred under H2 at RT for 48 h. The Pd/C was filtered off and the crude aniline was purified using column chromatography (0-100% EtOAc in hexanes) to give 4-(2-methanesulfonyl-pyrimidin-4-yloxy)-benzene-1,2-diamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[NH2:11][CH:12]([CH3:15])[CH2:13][OH:14].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:11][CH:12]([CH3:15])[CH2:13][OH:14])[C:5]#[N:6]
Reactant: CC(N)CO
Reactant: N#Cc1ccc(F)c(Cl)c1
Solvent: O
Solvent: CS(C)=O
Product: CC(CO)Nc1ccc(C#N)cc1Cl
Reaction time: 2 h

Procedure:
4.00 g (25.7 mmol) 3-chloro-4-fluoro-benzonitrile are heated to 60° C. in 20 ml DMSO with 8.00 g (106.5 mmol) 2-amino-1-propanol with stirring for 2 hours. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@@:16]([OH:20])([CH3:19])[CH:17]=[O:18].[BH4-].[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@:16]([CH3:19])([OH:20])[CH2:17][OH:18]
Reactant: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)C=O)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CO)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
180 mg (0.643 mmole) of (S)-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2-hydroxy-2-methylbutanal was dissolved in 5 ml of ethanol, and 30 mg (0.79 mmole) of sodium borohydride was added, followed by stirring at room temperature for 30 minutes. Water was added to the reaction solution which was then extracted with methylene chloride. The organic extract was washed with a saturated aqueous solution of sodium chloride dried over sodium sulfate and freed from the solvent under reduced pressure. The residue was purified on silica gel column to obtain 156 mg (86%) of (S)-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2-methyl-1,2-butanediol.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].O=[C:19]1[CH2:23][CH2:22][S:21][CH:20]1[C:24](OC)=[O:25]>C(O)C>[OH:10][C:9]1[C:8]2[C:19]3[CH2:23][CH2:22][S:21][C:20]=3[C:24](=[O:25])[O:12][C:7]=2[CH:6]=[C:5]([CH:3]([CH:2]([CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4])[CH:11]=1
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: COC(=O)C1SCCC1=O
Solvent: CCO
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)SCC3
Reaction time: 72 h

Procedure:
A solution of 2.5 g. (0.011 mole) of 5-(3-methyl-2-octyl)resorcinol and 2.0 g. (0.013 mole) of the methyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylate in 50 ml. of absolute ethanol in a three-necked flask equipped with drying tube was cooled in an ice-water bath and saturated with dry hydrogen chloride. The 5-(3-methyl-2-octyl) resorcinol was prepared according to the method of Adams, Mackenzie and Loewe (J. Am. Chem. Soc. 70, 664-8 (1948). The reaction mixture was allowed to stand for 3 days at room temperature, during which time a heavy yellow solid formed. The hydrogen chloride was evaporated, the mixture was concentrated and the solid was filtered and washed with ethanol. The yield of the crude benzopyrone thus obtained was 2.6 g. (59%), m.p. 190°-205°C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([N:15]3[CH2:18][CH:17]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH2:16]3)=[O:14])=[CH:8][CH:7]=2)[CH2:2]1.[CH3:25][C@@H:26]([CH2:30][CH3:31])[C:27](O)=[O:28].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.ClCCl.O>[CH3:25][C@@H:26]([CH2:30][CH3:31])[C:27]([N:1]1[CH2:2][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([N:15]3[CH2:18][CH:17]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH2:16]3)=[O:14])=[CH:8][CH:7]=2)[CH2:4]1)=[O:28]
Reactant: CC[C@H](C)C(=O)O
Reactant: O=C(Nc1ccc(OC2CNC2)cc1)N1CC(c2cccnc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)C(=O)N1CC(Oc2ccc(NC(=O)N3CC(c4cccnc4)C3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(4-(azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide (1 g, 1.805 mmol), (S)-2-methylbutanoic acid (0.221 g, 2.166 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.519 g, 2.71 mmol) were combined in in dimethylformamide (9.03 mL) at room temperature. 1-Hydroxybenzotriazole hydrate (0.415 g, 2.71 mmol) and diisopropylethylamine (0.946 ml, 5.42 mmol) were added and the reaction mixture was stirred overnight at room temperature. Water and dichloromethane were added and the organics were removed by pipet. Concentration and reverse phase chromatography gave (S)—N-(4-(1-(2-methylbutanoyl)azetidin-3-yloxy)phenyl)-3-(pyridin-3-yl)azetidine-1-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J=2.4 Hz, 1H), 8.48 (dd, J=4.7, 1.6 Hz, 1H), 8.41 (s, 1H), 7.86 (dt, J=7.9, 2.0 Hz, 1H), 7.46-7.37 (m, 3H), 6.76 (d, J=8.9 Hz, 2H), 4.96 (dd, J=6.3, 3.4 Hz, 1H), 4.62-4.53 (m, 1H), 4.36 (d, J=15.9 Hz, 2H), 4.32-4.22 (m, 1H), 4.11-4.02 (m, 1H), 3.98-3.81 (m, 3H), 3.75 (dd, J=10.6, 3.9 Hz, 1H), 2.36-2.20 (m, 1H), 1.59-1.39 (m, 1H), 1.38-1.20 (m, 1H), 0.96 (dd, J=6.8, 3.9 Hz, 3H), 0.82 (q, J=7.2 Hz, 3H); MS (ESI(+)) m/e 409 (M+H)11.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][NH:17][C:18]([C:20]3[CH:21]=[N:22][N:23]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[C:24]=3[C:25]([F:28])([F:27])[F:26])=[O:19])[CH:12]=2)[C:7]=1[Br:36].[OH-].[Na+].O>CO>[Br:36][C:7]1[C:8]2[C:13](=[CH:12][C:11]([CH2:16][NH:17][C:18]([C:20]3[CH:21]=[N:22][N:23]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[C:24]=3[C:25]([F:26])([F:27])[F:28])=[O:19])=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[O:5][CH2:4][C:3]([OH:37])=[O:2]
Reactant: COC(=O)COc1ccc2cc(CNC(=O)c3cnn(-c4ccc(Cl)cc4)c3C(F)(F)F)ccc2c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)COc1ccc2cc(CNC(=O)c3cnn(-c4ccc(Cl)cc4)c3C(F)(F)F)ccc2c1Br
Reaction time: 8 h
Yield: 82.8 %

Procedure:
A mixture of [1-bromo-6-({[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester (0.175 g, 0.29 mmol), prepared in the previous step, 1N NaOH (323 μL, 0.323 mmol), 2 mL of H2O and 100 mL of methanol was warmed until all solids had gone into solution. When the reaction cooled a solid precipitated. After the reaction had stirred for 17 h (overnight) a solid was still present. Another 162 μL (0.162 mmol) of 1N NaOH was added. The reaction stirred for 18 h. The reaction was filtered to remove any trace particles and acidified with 1N HCl until pH 1 by litmus paper. The methanol was removed under reduced pressure. The solid formed was collected by filtration and dried under reduced pressure to give the title compound (0.14 g, 8.3%) as a white solid, mp 245° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH2:20]([NH:22][CH:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)[CH3:21]>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:25]3[CH2:26][CH2:27][CH:23]([NH:22][CH2:20][CH3:21])[CH2:24]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCNC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CC#N
Product: CCNC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC)c3c2F)C1
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To 1.0 g (3.7 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 0.56 g (3.7 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.44 g (3.7 mmol) of 3-(ethylamino)pyrrolidine. The mixture was refluxed for one hour, kept overnight at room temperature, filtered, and the solid washed with ether to give 0.81 g of 1-ethyl-7-[3-(ethylamino)-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, mp 227°-229° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][NH:5]2.Cl[C:17]([O:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18].C(N1C2C(=CC(Br)=CC=2)N(C(OC(C)C)=O)C[C@@H]1C)(=O)C>>[C:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[N:5]([C:17]([O:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:18])[CH2:6][C@@H:7]1[CH3:15])(=[O:14])[CH3:13]
Reactant: O=C(Cl)OC1CCCC1
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Agent: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC2CCCC2)C[C@@H]1C

Procedure:
Cyclopentyl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1 (2H)-carboxylate was prepared from (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone and cyclopentyl chloroformate according to the procedure outlined above for (S)-isopropyl 4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1 (2H)-carboxylate. MS (ESI, pos. ion) m/z 381, 383 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1[N:6]=[C:7]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][C:9]=1[CH3:10].[OH-].[Na+]>CO>[CH3:10][C:9]1[O:8][C:7]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:6][C:5]=1[CH2:4][C:3]([OH:19])=[O:2]
Reactant: COC(=O)Cc1nc(CCc2ccccc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(CCc2ccccc2)nc1CC(=O)O
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 63.3 %

Procedure:
(5-Methyl-2-phenethyl-oxazol-4-yl)-acetic acid methyl ester (8.75 g, 33.8 mmol), in MeOH (120 mL) was treated with 5N NaOH (40 mL) and then the solution was warmed to 40° C. After 40 min, the reaction mixture was concentrated under reduced pressure, suspended in water, and then acidified to pH=1 with 5N HCl. The mixture was extracted with EtOAc (2×), dried (MgSO4), and concentrated to provide 5.25 g (63%) of the product as an off-white solid. 1H NMR (400 MHz, CDCl3) ••1H NMR (400 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 3.52 (s, 2H), 3.06-3.03 (m, 4H), 2.24 (s, 3H).
Reaction SMILES: [CH:1]#[N:2].[CH:3]([O:6][C:7]([C:9]1[CH:10]2[CH:12]([CH2:13][N:14]=1)[CH2:11]2)=[O:8])([CH3:5])[CH3:4]>C(OCC)C.C(Cl)(Cl)Cl>[C:1]([C:9]1([C:7]([O:6][CH:3]([CH3:5])[CH3:4])=[O:8])[NH:14][CH2:13][CH:12]2[CH:10]1[CH2:11]2)#[N:2]
Reactant: CC(C)OC(=O)C1=NCC2CC12
Reactant: C#N
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(C)OC(=O)C1(C#N)NCC2CC21
Temperature: 25 °C

Procedure:
30 ml of liquid hydrogen cyanide was rapidly added drop-by-drop to a stirred and ice-cooled solution of 2 g of 2-isopropoxycarbonyl-3-azabicyclo[3.1.0]hex-2-ene in 50 ml of dry diethyl ether. The solution was stirred at 0° to 5° C. for 7 hours and then allowed to warm up to room temperature. The diethyl ether and residual hydrogen cyanide were blown off with nitrogen. The residue was taken up in diethyl ether, dried over sodium sulphate and evaporated down. An orange liquid was obtained; it was dissolved in chloroform and passed over an alumina column, eluting with chloroform. After the first 100 ml was collected, the next 300 ml was collected and evaporated down, to give 1 as a straw-colured liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=O)[CH2:14][CH:15]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[C:16]([CH3:21])([N+:18]([O-])=O)[CH3:17])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]>[Zn].C(O)(=O)C>[CH3:17][C:16]1([CH3:21])[C@@H:15]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:14][C@H:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[NH:18]1
Reactant: COc1cc(C(=O)CC(c2ccncc2)C(C)(C)[N+](=O)[O-])cc(OC)c1OC
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1cc([C@H]2C[C@H](c3ccncc3)C(C)(C)N2)cc(OC)c1OC

Procedure:
A solution of 34 g. of 3',4',5'-trimethoxy-4-methyl-4-nitro-3-(4-pyridyl)-valerophenone in 340 ml. of glacial acetic acid is heated at 50°-60° C. with stirring. There are added portionwise 34 g. of zinc dust. The resulting mixture is left to react for 1 hour. Then a further 34 g. of zinc dust are added and after another hour, the reaction mixture is filtered. The filter residue is washed with glacial acetic acid and the filtrate evaporated under reduced pressure. The residue is taken up in water, make alkaline with potassium carbonate and extracted three times with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue which results is crystallized with ether to obtain trans-4-[2,2-dimethyl-5-(3,4,5-trimethoxyphenyl)-3-pyrrolidinyl]-pyridine with a melting point of 117°-119° C. The corresponding oxalate, recrystallized from methanol, has a melting point of 228°-230° C. (decomp.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.OC1C=CC(C2SC(C3C=CC(C(O)=O)=CC=3)=NN=2)=CC=1.C(=O)([O-])[O-].[K+].[K+].[O:50]([CH2:57][CH2:58][CH2:59][CH2:60]Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.Cl>CN(C)C=O>[O:50]([CH2:57][CH2:58][CH2:59][CH2:60][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: BrCCCCOc1ccccc1
Reactant: COC(=O)c1ccc(-c2nnc(-c3ccc(O)cc3)s2)cc1
Agent: Cl
Agent: O=C(O)c1ccc(-c2nnc(-c3ccc(O)cc3)s2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2nnc(-c3ccc(OCCCCOc4ccccc4)cc3)s2)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a suspension of a mixture of methyl 4-[5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl]benzoate and 4-[5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid (600 mg), potassium carbonate (531 mg) and N,N-dimethylformamide (3 ml) was added 4-phenoxybutylbromide (880 mg) and the mixture was stirred at 100° C. (bath temperature) for 2 hours. After cooling, the mixture was added to 0.1N hydrochloric acid (100 ml). The resulting precipitate was collected by filtration and washed with water. To this material was added tetrahydrofuran (20 ml), ethanol (20 ml) and 10% sodium hydroxide aqueous solution (1.39 ml). The mixture was refluxed for 2 hours. After cooling, the reaction mixture was diluted with water (100 ml), adjusted to pH 1.8 with 1N hydrochloric acid, then extracted with a mixture of dichloromethane (1000 ml), tetrahydrofuran (200 ml) and methanol (200 ml). The organic layer was washed with brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was triturated with acetonitrile. The solid was collected by filtration and dried to give 4-[5-[4-(4-phenoxybutyloxy)phenyl]-1,3,4-thiadiazol-2-yl]benzoic acid (685 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[F:11][C:12]([F:21])([F:22])[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH:17][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[CH:3]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
Into a 500-mL round bottom flask, was placed a solution of 2-chloroisonicotinic acid (18 g, 113.92 mmol, 2.00 equiv) in dichloromethane (200 mL), 3-(trifluoromethyl)benzylamine (10 g, 57.14 mmol, 1.00 equiv), EDC.HCl (22 g, 115.18 mmol, 2.00 equiv), and 4-dimethylaminopyridine (14 g, 114.75 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 25° C. The resulting solution was diluted with 500 mL of dichloromethane. The resulting mixture was washed with 2×50 mL of aqueous NH4Cl, 1×50 mL of 10% sodium bicarbonate, and 1×50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (5:1). The product was obtained as 11.8 g (63%) of a white solid.
Reaction SMILES: [C:1]1([C@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]=[C:11]1[O:14][C:13](=[O:15])[CH2:12]1>O1CCCC1.CN(C1C=CN=CC=1)C>[O:14]=[C:11]([CH3:10])[CH2:12][C:13]([O:9][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])=[O:15]
Reactant: C[C@@H](O)c1ccccc1
Reactant: C=C1CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)O[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
To a solution of (R)-1-phenylethanol (6.0 ml, 50 mmol) in dry tetrahydrofuran (75 ml) at room temperature was added 4-(N,N-dimethylamino)pyridine (610 mg, 5.0 mmol) followed by dropwise addition of 4-methyleneoxetan-2-one (3.83 ml, 50 mmol). The reaction was stirred for 12 hours at room temperature, then the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate, poured into a separatory funnel, and washed with 1M aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, then brine. The organic phase was separated and the solvent removed under resuced pressure to provide (R)-1-phenylethyl 3-oxobutanoate as a light reddish oil (10.3 g, 100%). 1H NMR (CDCl3, 400 MHz) δ 7.4-7.2 (m, 5H); 5.94 (q, 1H, J=6.6 Hz); 3.45 (s, 2H); 2.22 (s, 3H); 1.56 (d, 3H, J=6.6 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:26])[NH:24][NH2:25])[CH:18]=[C:19]([F:21])[CH:20]=1>CO>[F:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:26])[NH:24][N:25]=[C:8]([OH:10])[C:7]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[C:11](=[O:13])[CH3:12])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: CC(=O)c1cccc(F)c1C(=O)O
Reactant: NNC(=O)Nc1cc(F)cc(F)c1
Solvent: CO
Product: CC(=O)c1cccc(F)c1C(O)=NNC(=O)Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3 g of 6-fluoro-2-acetyl benzoic acid and 3 g of 4-(3,5-difluorophenyl)semicarbazide are mixed in 20 ml of methanol and heated until clear. The solution is then stirred at R.T. for 24 hr. A white solid forms which is filtered and dried in vacuum at 60° to yield the title product m.p. 227° (decomp.). The corresponding sodium salt is made by reaction of the free acid with 25% sodium methoxylate/methanol.