Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>CN(C)C=O>[CH3:30][C:29]([CH3:32])([CH3:31])[C:28](=[O:33])[CH2:27][C:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)C(C)(C)C)(Cc1cccc2ccccc12)C(=O)OCC
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
5.00 g (16.9 mmole) of diethyl (1-naphthylmethyl)malonate were dissolved in 50 ml of anhydrous dimethylformamide, and 1.00 g (18.5 mmole) of sodium methoxide was added to the solution, whilst ice-cooling, after which the mixture was stirred for 30 minutes. At the end of this time, a solution of 3.31 g (18.5 mmole) of 1-bromopinacolone (i.e. 1-bromo-3,3-dimethyl-2-butanone) dissolved in 10 ml of anhydrous dimethylformamide was added dropwise to the mixture, which was then stirred overnight at room temperature. The solvent was then removed by distillation under reduced pressure, and the resulting residue was mixed with a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent: a 6: 1 by volume mixture of hexane and ethyl acetate), to afford 5.51 g (82%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[OH:4][CH:5]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:23]([CH2:24]Cl)=[N:22][C:21]([C:26]([NH2:28])=[O:27])=[N:20]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I-].[Na+]>CO.CCOCC>[OH:4][CH:5]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:23]([CH2:24][N:2]([CH3:3])[CH3:1])=[N:22][C:21]([C:26]([NH2:28])=[O:27])=[N:20]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(O)c2ccccc2)n1
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CN(C)Cc1nc(C(N)=O)nn1-c1ccc(Cl)cc1C(O)c1ccccc1

Procedure:
6.8 ml of 33% ethanolic dimethylamine solution is added to a solution of 5.6 g (about 0.015 mole) of 1-[2-(α-hydroxybenzyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide and 0.225 g of sodium iodide in 80 ml of methanol, and the whole is refluxed for 5 hours with stirring. The reaction mixture is thereupon concentrated in vacuo. Water and saturated sodium carbonate solution are added to the residue until the pH-value has reached 10, and extraction is performed twice with ethyl acetate. The organic phase is washed with water, and is then extracted three times with 1 N hydrochloric acid solution. Sodium carbonate is added to the aqueous acidified extracts until the pH-value of 10 is obtained. The base that the precipitated is taken up in ether; the ether solution is washed twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo to yield amorphous 1-[2-(α-hydroxybenzyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl] -1H-1,2,4-triazole-3-carboxamide. This is converted as follows into the crystalline hydrochloride: the crude base is dissolved in ethyl acetate, and ethereal hydrogen chloride solution is added until the pH-value is 4. The precipitated hydrochloride is filtered off with suction and washed with ethyl acetate and ether. After drying in vacuum, there is obtained 1-[2-(α-hydroxybenzyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxamide-hydrochloride, m.p. 155°-157° (with decomposition).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1>CN(C=O)C>[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1
Reactant: NCCCO
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCO)c1C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
3-Amino-1-propanol (6.92 mL, 90.5 mmol) was added dropwise to a stirred solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (20.0 g, 90.5 mmol) and triethylatnine (18.9 mL, 136 nmuol) in DMF (300 mL) at room temperature. After 16 hours, the solvent was removed under reduced pressure and the resulting oil was partitioned between ethyl acetate (450 mL) and water (50 mL). The layers were separated and the organic layer was washed with water (3×50 mL). The combined aqueous layers were back-extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting orange solid was triturated with hexanes/ethyl acetate (2: 1) and was isolated by filtration to yield 12.43 g of 3-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propan-1-ol as a yellow solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[N:4]1.[I-].[Na+].[CH2:12](Br)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:12]([N:3]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[N:4]1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cn[nH]c1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cnn(CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of NaH (125 mg, 3.12 mmol, 60% dispersion in mineral oil) in THF (10 mL), was added dropwise over 5 min, a solution of 1H-pyrazole-4-carbaldehyde (250 mg, 2.60 mmol) in THF (5 mL). The mixture was stirred at rt for 45 min; sodium iodide (10 mg) was added before the addition of phenethyl bromide (0.42 mL, 3.12 mmol). After 15 min, the reaction was heated at 80° C. for 4 h, then cooled to rt, quenched with saturated solution of NH4Cl and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water, brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (Isco CombiFlash) 0-40% EtOAc/heptane provided 1-phenethyl-1H-pyrazole-4-carbaldehyde: Yield 410 mg (79%). 1H NMR (400 MHz, CDCl3) δ ppm 3.20 (t, J=7.03 Hz, 2H), 4.39 (t, J=7.05 Hz, 2H), 7.06 (dd, J=7.91, 1.46 Hz, 2H), 7.22-7.32 (m, 3H), 7.63 (s, 1H), 8.00 (s, 1H), 9.79 (s, 1H); LCMS-MS (ESI+) 200.87 (M+H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1)(=O)=O.C(OC([NH:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH2:43]2)=[CH:38][C:37]=1[O:55][CH3:56])=O)(C)(C)C.FC(F)(F)C(O)=O>C(O)C(F)(F)F>[CH3:56][O:55][C:37]1[CH:38]=[C:39]([CH:42]2[CH2:43][CH2:44][NH:45][CH2:46][CH2:47]2)[CH:40]=[CH:41][C:36]=1[NH:35][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1
Reactant: COC(=O)Cc1ccccc1CCc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: OCC(F)(F)F
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C

Procedure:
Methyl 2-(2-(2-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I15) (200 mg, 0.497 mmol) and tert-butyl 4-(4-((tert-butoxycarbonyl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I19) (303 mg, 0.745 mmol) were dissolved in trifluoroethanol (4 mL). Trifluoroacetic acid (200 μL) was added and the resulting mixture was heated at 100° C. under microwave irradiation for 1 hour. The crude reaction mixture was adsorbed onto silica gel and separated by silica gel chromatography (0-20% MeOH/DCM) to give the title compound (I20) (215 mg, 82%) as a light brown liquid; 1H NMR (400 MHz, d6-Acetone) δ 8.64 (s, 1H), 8.37 (dd, J=8.3, 3.7 Hz, 1H), 7.29 (ddd, J=13.2, 6.9, 1.7 Hz, 3H), 7.22 (ddd, J=8.9, 6.1, 1.7 Hz, 1H), 7.10 (d, J=1.5 Hz, 1H), 6.97 (dd, J=8.3, 1.5 Hz, 1H), 3.98 (d, J=7.4 Hz, 3H), 3.82 (s, 2H), 3.74-3.60 (m, 5H), 3.27 (t, J=11.7 Hz, 2H), 3.22-3.06 (m, 4H), 3.00 (s, 1H), 2.34-2.17 (m, 2H), 2.12 (dd, J=4.0, 3.5 Hz, 2H), 2.08 (dt, J=6.6, 2.2 Hz, 3H). LCMS Method C: rt 5.23 min; m/z 529.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:9](Cl)([N:10]=1)[N:8]=[CH:7][N:6]=2.[CH3:12][C:13]1[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=1>C(O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:9]([NH:18][C:15]3[CH:14]=[C:13]([CH3:12])[NH:17][N:16]=3)([N:10]=1)[N:8]=[CH:7][N:6]=2
Reactant: ClC1=NC2(Cl)N=CN=C2C=N1
Reactant: Cc1cc(N)n[nH]1
Solvent: CCO
Product: Cc1cc(NC23N=CN=C2C=NC(Cl)=N3)n[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.6 %

Procedure:
To a suspension of 2,4-dichloro-purine (2.0 g, 10.6 mmol) in anhydrous ethanol (10 mL) was added 5-methyl-1H-pyrazol-3-yl amine (2.05 g, 21.2 mmol). The resulting mixture was stirred at room temperature for 48 h. The resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford 1.524 g (58% yield) of (2-chloro-purin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:21])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:8][C:4]=1[C:5]([Cl:21])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(Cn2cnnn2)cc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Cn2cnnn2)cc1C(=O)Cl
Reaction time: 4 h

Procedure:
Combine 2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoic acid (0.35 g, 1.5 mmol) and dichloromethane (25 mL). Add dropwise oxalyl chloride (0.21 mL, 2.35 mmol) followed by dimethylformamide (5 drops). After 4 hours, evaporate in vacuo and dry to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH3:15])=[C:10]([CH2:12][CH2:13][OH:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:17].O>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]1([C:7]2[O:8][C:9]([CH3:15])=[C:10]([CH2:12][C:13]([OH:17])=[O:14])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: Cc1oc(-c2ccccc2)nc1CC(=O)O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 1.0 g of 2-phenyl-4-hydroxyethyl5-methyloxazole in 20 ml of acetone was added a solution consisting of 1 g of chromium trioxide, 0.9 ml of concentrated sulfuric acid and 4 ml of water and the reaction stirred at room temperature for 40 minutes. The reaction mixture was poured into water (60 ml) and the product extracted with 150 ml of ethyl acetate. The organic layer was washed with water (2×50 ml) and dried over sodium sulfate. Removal of the solvent gave the crude product as an oil. The residue was dissolved in 80 ml of ethyl acetate and the product extracted with 100 ml of 0.25N aqueous sodium hydroxide. The aqueous layer was separated, acidified with 1N hydrochloric acid and the product extracted with 150 ml of ethyl acetate. The organic phase was separated, dried over sodium sulfate and concentrated to give a yellow solid, 500 mg.
Reaction SMILES: [OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:7][CH2:6][N:5]([C:8]([C@@:10]2([CH:23]([CH3:25])[CH3:24])[CH2:14][CH2:13][C@@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1>Cl.CCOCC.CO>[NH2:15][C@@H:12]1[CH2:13][CH2:14][C@@:10]([C:8]([N:5]2[CH2:4][CH2:3][C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([OH:1])[CH2:7][CH2:6]2)=[O:9])([CH:23]([CH3:24])[CH3:25])[CH2:11]1
Reactant: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3)CC2)CC[C@@H](N)C1
Reaction time: 3.5 h

Procedure:
tert-Butyl {(1R,3S)-3-[(4-hydroxy-4-phenylpiperidin-1-yl)carbonyl]-3-isopropyl-cyclopentyl}carbamate (0.30 g, 0.70 mmol) was dissolved in a 2.0 M solution of HCl in ether (10 mL). After being stirred for 3.5 h, a few drops of MeOH was added to get a clear solution. The mixture was concentrated to give an oil. The crude product was used in the next reaction without purification. MS calculated for C20H30N2O2: (M+H)331; found 331.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:26][CH2:27][CH2:28]I)[CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:26][CH2:27][CH2:28][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)CCC(CCCI)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCn1ccnc1

Procedure:
To a solution of 0.32 g (0.57 mmol) of t-butyl 8-(p-chlorophenylsulfonamido)-4-(3-iodopropyl)octanoate in 3 mL dry dimethylformamide is added 0.116 g (1.7 mmol) imidazole and the mixture is then refluxed with ethyl acetate and washed with water and brine. The organic layer is dried, filtered, concentrated and then subjected to chromatography using ethyl acetate as eluent to yield t-butyl 8-(p-chloro- phenylsulfonamido)-4-[3-(1-imidazolyl)propyl]octanoate; IR (neat): 1718, 1337, 1164 cm-1 ; NMR (CDCl3): delta 7.5 (br,1H), 7.1 (s,1H), 6.9 (s,1H), 4.2 (t,2H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH2:7][NH:6][C:5](=[O:9])[CH2:4][CH2:3]1.S(OC)(O[CH3:14])(=O)=O.[OH-].[K+]>CCOCC>[CH3:14][O:9][C:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:8][CH2:7][N:6]=1
Reactant: COS(=O)(=O)OC
Reactant: CC1CCNC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: COC1=NCCC(C)CC1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 5-methylazepan-2-one (1.6 g) and dimethyl sulfate (2 g, 15.9 mmol) was stirred at 120° C. for 4 h. After it was cooled to room temperature, the reaction mixture was diluted with 10 mL ether and adjusted to pH 6 with aqueous KOH. The mixture was extracted with ether (2×50 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude (E)-7-methoxy-4-methyl-3,4,5,6-tetrahydro-2H-azepine (1.2 g) was used for the next step without further purification.
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[O:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.N12CCN(CC1)CC2>C1C=CC=CC=1>[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([NH:23][C:24]([N:14]2[C:15](=[O:16])[C:6]3([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]3)[NH:7][C:8]32[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:25])=[CH:19][CH:18]=1
Reactant: O=C1NC2(CCCCC2)NC12CCCCC2
Reactant: Cc1ccc(N=C=O)cc1
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: Cc1ccc(NC(=O)N2C(=O)C3(CCCCC3)NC23CCCCC3)cc1

Procedure:
3.33 Parts of 7,14-diazadispiro[5.1.5.2]pentadecan-15-one, 2.19 parts of p-tolylisocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 150 parts of dry benzene were heated at reflux for 24 hours. The solvent was evaporated in vacuo to yield a solid material which was recrystallised from ethanol to give 4.2 parts of 14-p-tolylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one as colourless crystals of melting point 136° to 138°C. This material gave the following elemental analysis by weight:
Reaction SMILES: [F:1][C:2]1([F:13])[C:11](=[O:12])[N:5]2C(C)(C)[O:7][CH2:8][C@@H:4]2[CH2:3]1.Cl>CO.O1CCOCC1>[F:1][C:2]1([F:13])[CH2:3][C@@H:4]([CH2:8][OH:7])[NH:5][C:11]1=[O:12]
Reactant: CC1(C)OC[C@@H]2CC(F)(F)C(=O)N21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C1N[C@H](CO)CC1(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 749.9 %

Procedure:
To a solution of (S)-6,6-difluoro-3,3-dimethyl-dihydropyrrolo[1,2-c]oxazol-5(1H,3H,6H)-one (1.35 g, 0.706 mmol) in methanol (10 mL) was added HCl in dioxane (2.65 mL, 4N) under ice-water bath and then stirred at RT overnight. The reaction mixture was concentrated. The resulting residue was dissolved in THF (10 mL) and TEA (5 mL) was added. The resulting solution was stirred for 1 h. The reaction mixture was concentrated to give a crude mixture. Purification by flash column chromatography (hexanes/EtOAc) gave (S)-3,3-difluoro-5-(hydroxymethyl)pyrrolidin-2-one (0.80 g 75%). LRMS (M+H+)m/z 152.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[Cl:22])=[CH:9][S:8][C:7]=1[NH2:23])=[O:5])[CH3:2].[C:24]1(=O)[O:29][C:27](=[O:28])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:15][C:14]=2[Cl:22])=[CH:9][S:8][C:7]=1[N:23]1[C:27](=[O:28])[C:26]2[C:25](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:24]1=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=Cc2ccc(C(C)C)cc2Cl)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C=Cc2ccc(C(C)C)cc2Cl)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-[2-(2-chloro-4-isopropylphenyl)vinyl]-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 31, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][C:4]([NH:6][C:7]1([C:10]([O-:12])=[O:11])[CH2:9][CH2:8]1)=[O:5]>C(Cl)Cl.FC(F)(F)C(O)=O>[F:1][C:2]([F:13])([F:14])[CH2:3][C:4]([NH:6][C:7]1([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]1)=[O:5]
Reactant: O=C(CC(F)(F)F)NC1(C(=O)[O-])CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CC(F)(F)F)NC1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
tert-Butyl (±)-cis-(acetyloxy)methyl]-1-[(3,3,3-trifluoropropanoyl)-amino]cyclopropane carboxylate (489 mg, 1.44 mmol) was dissolved in a mixture of 4 mL of methylene chloride and 1.22 mL of trifluoroacetic acid. The reaction mixture was allowed to stir at ambient temperature for 3.5 hours. The solvents were removed in vacuo and the residue was azeotroped with toluene (450 ml) to afford 408 mg of (±)-cis-(acetyloxy)methyl]-1-[(3,3,3-trifluoropropanoyl)amino]cyclopropane-carboxylic acid.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:21][O:22][C:23](=[O:25])[N:24]=2)[CH:15]=1.[CH2:28]([N:31]([CH2:35][CH:36]=[CH2:37])[C:32](Cl)=[O:33])[CH:29]=[CH2:30]>N1C=CC=CC=1>[F:27][C:13]([F:12])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[N:24]([C:32]([N:31]([CH2:35][CH:36]=[CH2:37])[CH2:28][CH:29]=[CH2:30])=[O:33])[C:23](=[O:25])[O:22][N:21]=2)[CH:15]=1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: C=CCN(CC=C)C(=O)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To 1 ml of pyridine were added 0.28 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.29 g of N,N-diallylcarbamoyl chloride was added at room temperature. After stirring for 8 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.34 g of 3-(4-trifluoromethylpyridin-2-yl)-N,N-diallyl-1,2,4-oxadiazol-5-one-4-carboxamide (present compound (17)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:27]=[N+:28]=[N-:29].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][N:27]=[N+:28]=[N-:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CN=[N+]=[N-]
Temperature: 25 °C

Procedure:
In a flask protected by a safety screen, a solution of N-t-butoxycarbonyl-4(S)-t-butyldimethylsilyloxy-2(S)-methane-sulfonyloxy methyl pyrrolidine(10.40 g, 25.39 mmol) and tetrabutyl-ammonium azide (8.18 g, 28.7 mmol) in toluene (250 mmol was stirred at 80° C. for 5 hr. The reaction was cooled to room temperature and diluted with EtOAc (250 mn), washed with water and brine and dried (Na2SO4). The solvent was evaporated in vacuo to afford the title compound as a yellow oil which was used in the next step without furthur purification.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH:23]1[CH2:26][N:25]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24]1>CN(C=O)C>[C:28]1([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:25]2[CH2:26][CH:23]([N:11]3[C:7]([CH2:6][C:5]4[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:8][C:9]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)=[N:10]3)[CH2:24]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Fc1ccc(Cc2cc(-c3ccncc3)n[nH]2)cc1
Reactant: IC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Cc2cc(-c3ccncc3)nn2C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-[5-(4-fluorobenzyl)-1H-pyrazol-3-yl]pyridine (3.7 g, 14.6 mmol) in DMF (40 mL) was added NaH (0.584 g, 14.6 mmol) and the solution was stirred for 10 minutes under nitrogen. 3-Iodo-N-benzhydryl-azetidine (5.61 g, 16.1 mmol) was then added and the reaction mixture was heated to 110° C. for 2 hours under nitrogen. The solvent was removed in-vacuo and the residue was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O, brine, dried over MgSO4, filtered and stripped to yield a crude mix of regioisomers. The residue was purified by flash chromatography (5:95 MeOH/CH2Cl2) to yield a clean mix of regioisomers that were separated by SF chromatography to yield the title compound as a lyophilized solid (2.35 g, 34%. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 8.62 (d, 2 H), 7.69 (d, 2 H), 7.42 (d, 4 H), 7.24-7.31 (m, 4 H), 7.14-7.24 (m, 2 H), 7.02-7.09 (m, 2 H), 6.97 (s, 2 H), 6.36-6.39 (m, 1 H), 4.74-4.87 (m, 1 H), 4.57 (s, 1 H), 3.94 (s, 2 H), 3.51-3.62 (m, 4 H); m/z (APCI+) for C32H27N4F 475.3 (M+H)+.