Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10].[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[S:6][C:5]([CH:7]=[CH:12][N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)s1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C=C[N+](=O)[O-])s1
Temperature: 0 °C
Yield: 72.3 %

Procedure:
Cool a solution of 5-methylthiophene-2-carbaldehyde (1 g, 7.9 mmol, 1 eq) and nitromethane (484 mg, 7.9 mmol, 1 eq) in methanol (3 mL) to 10° C. Add sodium hydroxide (332 mg, 8.3 mmol, 1.05 eq) as an aqueous solution (1.5 mL) to the reaction mixture. Stir reaction for 15 minutes and add ice water. Add this mixture to an aqueous HCl solution (1.67 mL concentrated HCl in 2.4 mL water) and stir overnight. Extract product with ethyl acetate, separate organics, dry with magnesium sulfate, and concentrate on rotovap to give 2-methyl-5-(2-nitrovinyl)thiophene (966 mg, 72% yield) as a crude solid.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](F)[CH:16]=[C:15]([F:23])[C:14]=1[F:24].[C:25](OCC)(=[O:27])C>C1COCC1.CCCCCC>[F:24][C:14]1[C:15]([F:23])=[CH:16][C:17]([O:27][CH3:25])=[C:18]([N+:19]([O-:21])=[O:20])[C:13]=1[NH:12][C:6]1[CH:7]=[CH:8][C:9]([I:11])=[CH:10][C:5]=1[F:4]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A mixture of sodium methoxide (32.0 g, 600 mmol) in dry THF (500 mL) at −78° C. was added to (2-fluoro-4-iodo-phenyl)-(2,3,5-trifluoro-6-nitro-phenyl)-amine (25 g, 60 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mixture was quenched with 200 mL of water and concentrated. The concentrate was acidified with cold 2N HCl (pH=2) and extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (1-5% ethyl acetate in hexane) afforded 18 g of the product (70.6% yield). H1NMR (CDCl3, 300 MHz): δ 7.42 (dd, 1H), 7.34 (d, 1H), 6.9 (s, 1H), 6.64-6.54 (m, 2H), 3.92 (s, 3H). LCMS: 94.1%, m/z=422.9 (M−1). HPLC: 98.8%.
Reaction SMILES: [H][H].N#N.[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:5]1(=[O:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH:5]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: Oc1ccccc1
Agent: N#N
Product: O=C1CCCCC1
Product: OC1CCCCC1
Reaction time: 4 h

Procedure:
The catalyst from Example 7b was regenerated by passing over air at 350° C. for 4 hours and, after the air had been displaced by nitrogen, was reduced by passing over 10% of hydrogen/90% of N2 at 150° C. for 4 hours. Hydrogen and phenol in a molar ratio of 4:1 were passed over the catalyst at 150° C. under a loading of 1.0 g of phenol/ml of catalyst×hour. After a run-in time of 150 hours, a cyclohexanone/cyclohexanol ratio of 18 to 30 was obtained at a conversion of 95 to 97% and a selectivity of 99.7 to 99.9%. The experiment was discontinued after 2,600 hours (cf. comment on Example 5).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C([O-])C.[Na+].C(O)C.Br[CH2:24][CH2:25][CH2:26][CH2:27][Cl:28]>C(OCC)(=O)C.CO>[Cl:28][CH2:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: ClCCCCBr
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(c1ccccc1)c1ccc(OCCCCCl)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Combine 4-hydroxybenzophenone (347 g, 1.75 mol) and methanol (3.5 L). Heat to 50° C. and add a solution of sodium ethanolate in ethanol (718 mL, 21% by weight, 1.92 mol) over 20 minutes. Heat to reflux and add 1-bromo-4-chlorobutane (600 g, 3.5 mol) over 30 minutes. After 18 hours, cool the reaction mixture and evaporate in vacuo to obtain a residue. Add ethyl acetate (5 L) to give a solid. Filter and extract the filtrate with aqueous 10% sodium hydroxide solution and aqueous saturated sodium chloride solution. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 4-(4-chlorobutoxy)benzophenone.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])[CH:5]=1.Cl.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl>CN(C=O)C.CCOC(C)=O.O>[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])=[CH:17][CH:18]=2)([CH3:11])[CH3:12])[CH:5]=1
Reactant: CN(C)CCCCl
Reactant: CC(C)(c1ccc(O)cc1)c1cc(Br)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCOc1ccc(C(C)(C)c2cc(Br)ccn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
Sodium hydroxide (pellets are finely grinded, 0.488 g, 12.2 mmol, 5 eq) is added to a solution of 4-[1-(4-bromo-pyridin-2-yl)-1-methyl-ethyl]-phenol (Step 55.2) (0.714 g, 2.44 mmol) in DMF (5 mL). The mixture is stirred for 20 min at rt. 3-Dimethylamino-1-propylchloride hydrochloride (0.611 g, 3.87 mmol, 1.6 eq) is added. The reaction mixture is heated to 90° C., stirred for 10 h, allowed to cool, diluted with EtOAc/H2O and extracted with EtOAc. The organic phase is washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) to afford 0.398 g of the title compound as an impure brown oil which is used without further purification: ESI-MS: 377.1/379.0 [M+H]+; TLC: Rf=0.22 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Li]CCCC.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1)([O-:8])=[O:7].[CH:21]1([CH2:26]I)[CH2:25][CH2:24][CH2:23][CH2:22]1.Cl>C1COCC1.CN1C(=O)N(C)CCC1>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=1)[CH2:26][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:20]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: ICC1CCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 1 L round bottom flask containing 250 mL of 9:1 THF/DMPU at −78° C. are added under nitrogen 11 mL (78.6 mmol) anhydrous DIEA followed by rapid addition of 32 mL of 2.5 M n-BuLi in hexanes. After 10 min at −78° C. a solution of 15.4 g (74 mmol) of p-nitrophenylacetic acid, ethyl ester in 100 mL of 9:1 THF/DMPU is added dropwise over 30 min. A deep purple solution results, and the reaction mixture is stirred at −78° C. for 30 min and then cyclopentyl methyl iodide (17.6 g, 78 mmol) in 50 mL of 9:1 THF/DMPU is added. The reaction is stirred while warming slowly to RT overnight. The mixture is poured into 1 L of 1 N HCl and extracted twice with MTBE. The combined MTBE extracts are washed with brine, dried over anhydrous magnesium sulfate, filtered and reduced to an orange oil. Flash chromatography over silica eluting with 4:1 hexane/MTBE affords 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester as an orange oil: 1H NMR (400 MHz, CDCl3) δ 1.0-1.1 (m, 2H), 1.2 (t, 3H, J=7.2), 1.4-1.8 (m, 5H), 1.8-1.9 (m, 2H), 2.1-2.25 (m, 2H), 3.74 (t, 1H, J=7.8), 4.1 (m, 2H), 7.51 (d, 2H, J=8.8), 8.19 (d, 2H, J=8.8); LC/MS 290 (M−1).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]2[N:12]([CH2:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)[N:13]=[N:14][C:9]2=[N:8][CH:7]=1)=[CH2:5])C.Cl>C(O)(=O)C>[N:22]1[C:23]2[C:18](=[CH:17][C:16]([CH2:15][N:12]3[C:10]4=[N:11][C:6]([C:4](=[O:3])[CH3:5])=[CH:7][N:8]=[C:9]4[N:14]=[N:13]3)=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: C=C(OCC)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of the 6-((6-(1-ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (150 mg, 0.451 mmol) in acetic acid was added 3N HCl (0.1 mL). After stirring at it for 2 h, solvent was removed under reduced pressure. The residue was diluted with water and its pH was adjusted to basic with aqueous NaHCO3, and extracted with DCM. The combined organic layers were washed with NaHCO3 (aq) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 131 mg (91%) of the title compound as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 9.45 (s, 1H), 8.95 (d, 1H), 8.14 (m, 2H), 7.95 (s, 1H), 7.84 (d, 1H), 7.45 (m, 1H), 6.19 (s, 2H), 2.75 (s, 3H). LCMS (method B): [MH]+=305, tR=2.95 min.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:27]([N:34]1[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:37]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:36]=[C:35]1[CH2:49][CH3:50])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N1C(C(OCC)=O)=C(C(OCC)=O)N=C1CBr)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:27]([N:34]1[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:37]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:36]=[C:35]1[CH:49]([Br:1])[CH3:50])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc(CC)n(Cc2ccccc2)c1C(=O)OCC
Agent: CCOC(=O)c1nc(CBr)n(Cc2ccccc2)c1C(=O)OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(C(C)Br)n(Cc2ccccc2)c1C(=O)OCC
Yield: 97.8 %

Procedure:
3.08 g of N-bromosuccinimide and 0.51 g of benzoyl peroxide were added to a solution of 5.19 g of diethyl 1-benzyl-2-ethylimidazole-4,5-dicarboxylate [prepared as described in step (i) above] in 100 ml of carbon tetrachloride, and the resulting mixture was heated under reflux for 1 hour. Following a procedure similar to that described in Preparation 42(ii), 6.29 g of the title compound were obtained as a syrup from the resulting reaction solution.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].B.C1COCC1.O>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(CO)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of 3-nitro-5-(trifluoromethyl)benzoic acid (2.0 g, 8.5 mmol) in THF (100 mL) was added borane-THF (17 mL of a 1 M solution in THF, 17 mmol). The reaction was stirred at 60° C. for 24 hours and then poured into H2O (50 mL). The resultant mixture was extracted with EtOAc (100 mL) and the organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 50% EtOAc/hexanes afforded [3-nitro-5-(trifluoromethyl)phenyl]methanol. Rf=0.35 (75% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) 8.44 (s, 1H), 8.40 (s, 1H), 7.98 (s, 1H), 4.91 (s, 2H), 2.07 (bs, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].[S-:15][C:16]#[N:17].[K+]>C(O)C.O>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[CH2:2][S:15][C:16]#[N:17]
Reactant: N#C[S-]
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
A solution of 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (20 g) in ethanol (100 mL) was heated to 60-70° C., and aqueous solution (10 mL) of potassium thiocyanate (8 g) was added dropwise. The reaction mixture was heated at 80° C. for 10 min, and the mixture was stirred at room temperature for 4 hr and diluted with water. The precipitate was collected by filtration, dissolved in ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated to give 2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl thiocyanate (14 g) as a solid. This solid (10 g) was dissolved in acetic acid (50 mL), and 48% hydrogen bromide-acetic acid solution (10 mL) was added. The reaction mixture was heated at 70-80° C. for 3 hr, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and water, sodium bicarbonate was added, and the mixture was adjusted to pH 7. The ethyl acetate layer was separated, washed with saturated brine and dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (4.2 g) as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[C:8]([O:12][C:13]([N:15]1[CH2:18][C:17](=O)[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(OC)(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CC(O)=O.ClCCCl>[C:8]([O:12][C:13]([N:15]1[CH2:18][CH:17]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)[CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C1CNCCN1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: COC(OC)OC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CCNC(=O)C2)C1
Reaction time: 16 h
Yield: 27.9 %

Procedure:
A mixture of piperazin-2-one (1.52 g, 15.1 mmol), 3-oxoazetidine-1-carboxylic acid tert-butyl ester (2.0 g, 11.6 mmol) and trimethyl orthoformate (12.8 mL, 12.4 g, 117 mmol) in AcOH (0.7 mL) and DCE (50 mL) was stirred for 5 h before the addition of triacetoxyborohydride (4.9 g, 23.2 mmol). The resulting mixture was stirred for 16 h then partitioned between DCM and H2O. The organic layer was dried (Na2SO4) and concentrated in vacuo. The resulting oil was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound as a foam (827 mg, 28%). 1H NMR (CDCl3, 300 MHz): δ 6.24 (s, 1H); 3.97 (dd, J=8.9, 7.1 Hz, 2H); 3.82 (dd, J=5.2, 2.2 Hz, 2H); 3.40 (td, J=5.2, 2.2 Hz, 2H); 3.24-3.15 (m, 1H); 3.07 (s, 2H); 2.60 (t, J=5.4 Hz, 2H); 1.44 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][C:14](O)=[O:15]>O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]2[C:4]=1[CH2:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][C:14]2=[O:15]
Reactant: COc1cccc(CC(CC(=O)O)c2ccccc2)c1OC
Solvent: O
Product: COc1ccc2c(c1OC)CC(c1ccccc1)CC2=O
Temperature: 100 °C
Yield: 80.6 %

Procedure:
4-(2',3'-Dimethoxyphenyl)-3-phenylbutyric acid (37 g, 123 mmol), from Step 5, was added dropwise to 200 g of polyphosphoric acid heated to 100° C. The resultant mixture was stirred and heated at 100° C. for 0.25 h. A mixture of 100 g of ice and 200 mL of water was added to the reaction mixture. The precipitate which formed was filtered, washed with 3×75 mL of water and dissolved in 300 mL of methylene chloride. The methylene chloride solution was dried over anhydrous magnesium sulfate, filtered and concentrated to give 28 g (81% yield) of 5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one, m.p; 127°-128° C.; 1H NMR (CDCl3) δ: 2.75-3.0 (m, 3H), 3.3-3.5 (m, 2H), 3.8 (s, 3H), 3.95 (s, 3H), 693 (d, 1H), 7.25-7.4 (m, 5H), 7.9 (d, 1H).
Reaction SMILES: C[Si](Br)(C)C.[CH2:6]([O:8][CH2:9][N:10]1[C:18]2[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][CH2:23][P:24](=[O:27])([O-:26])[O-:25])[C:15](=[O:28])[N:14]([CH3:29])[C:13]=2[N:12]=[CH:11]1)[CH3:7].CO.[NH3:32]>ClCCl>[CH2:6]([O:8][CH2:9][N:10]1[C:18]2[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][CH2:23][P:24](=[O:25])([O-:27])[O-:26])[C:15](=[O:28])[N:14]([CH3:29])[C:13]=2[N:12]=[CH:11]1)[CH3:7].[NH4+:32].[NH4+:10]
Reactant: N
Agent: CCOCn1cnc2c1c(=O)n(CCCCP(=O)([O-])[O-])c(=O)n2C
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Product: [NH4+]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.4 ml (0.026 mol) of trimethylsilyl bromide were slowly added dropwise at 0° C., under an argon atmosphere, to a solution of 4.16 g (0.01 mol) of [4-(7-ethoxymethyl-3-methylxanthin-1-yl)butyl]phosphonate in 5 ml of dichloromethane. The solution was stirred at 0° C. for 1 hour and at room temperature for 2 hours. The dichloromethane was then evaporated and the oily residue which remained was dried in a bulb tube in an oil pump vacuum to remove excess trimethylsilyl bromide and ethyl bromide formed. The residue was taken up in a little methanol and treated with 1 ml of concentrated ammonia solution and stirred at room temperature for 2 hours. After evaporating the solvent, the diammonium salt was crystallized from a methanoltdiisopropyl ether mixture.
Reaction SMILES: [C:1]([O:20]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14]CCCC.[H-].[Na+].C(N(CCCC)CCCC)CCC.C([O:39]CC)=C>>[CH2:4]([OH:39])[CH:3]=[CH:2][CH2:1][OH:20].[CH3:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: C=COCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCN(CCCC)CCCC
Product: CCCCCCCCCCCCCC
Product: OCC=CCO
Reaction time: 0.03 h

Procedure:
Route with additives: In a test tube the mixture of 1 ml (2.95 mmol) of methyl oleate, the corresponding amount of 2-butene-1,4-diol (0.24 ml or 0.73 ml) and 0.1 ml of tetradecane (internal standard) is prepared and mixed. If the reaction is being carried out without solvent, a blank sample is taken for GC measurement. In the case of the procedure with solvent, a blank sample for GC measurement is taken only after the addition of 1 ml of the corresponding solvent. After sampling has taken place, the test tube is placed in the thermally conditioned oil bath. The mixture is stirred for about 2 minutes using a magnetic stirrer. When the desired temperature of the mixture has been reached, the catalyst (2 mol %) is added. The reaction mixture is heated and stirred for 4 hours more. After 4 hours of reaction the next GC sample is taken. After sampling has taken place, the corresponding additive is added. The additives used were sodium hydride and tributylamine (respectively 1 and 10 mol %, based on the catalyst). After 24 hours the final GC sample is taken and the reaction is halted by addition of 1 ml of ethyl vinyl ether.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH2:5]([O:4][C:2]([NH:12][C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC1(C(=O)O)CCCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC1(C(=O)O)CCCC1)OCc1ccccc1
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A solution of benzyl chloroformate (0.290 g, 1.1 mmol) in dioxane (2.5 cm3) was added dropwise to a solution of 1-aminocyclopentanecarboxylic acid (Fluka) (0.2 g, 1.54 mmol) and sodium carbonate (0.490 g, 4.64 mmol) in water (5 cm3) at 0° C. Stirring was continued at room temperature overnight and the reaction mixture washed with ether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate, dried (Na2SO4), filtered and the solvent removed to afford carbamate 21 (0.253 g, 62%) as an oil which solidified on standing. Carbamate 21 was shown to be a 70:30 mixture of conformers by 1H NMR analysis (the ratio was estimated from the integration of the resonances at δ 5.31 and 7.29-7.40, assigned to the N—H protons of the major and minor conformers, respectively): mp 70-80° C. (lit.1 82-86° C., ethyl acetate, petroleum ether); δH (400 MHz; CDCl3; Me4Si) 1.83 (4H, br s, 2× cyclopentyl-H2), 2.04 (2H, br s, cyclopentyl-H2), 2.20-2.40 (2H, m, cyclopentyl-H2), 5.13 (2H, br s, OCH2Ph), 5.31 (0.7H, br s, N—H) and 7.29-7.40 (5.3H, m, Ph and N—H*); δC (100 MHz; CDCl3) 24.6 (CH2, cyclopentyl-C), 37.5 (CH2, cyclopentyl-C), 66.0 (quat., cyclopentyl-C), 66.8 (CH2, OCH2Ph), 128.0 (CH, Ph), 128.1 (CH, Ph), 128.4 (CH, Ph), 136.1 (quat, Ph), 155.8 (quat., NCO2) and 179.5 (quat, CO2H).
Reaction SMILES: ClC1C(Cl)=NC2C(C=1)=CC=CC=2.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(C([O-])=O)#CC([O-])=O.ClC1C=C(C=C(Cl)C=1)N.[C:37]([C:43]([O:45][CH3:46])=[O:44])#[C:38][C:39]([O:41][CH3:42])=[O:40]>>[NH:13](/[C:38](=[CH:37]\[C:43]([O:45][CH3:46])=[O:44])/[C:39]([O:41][CH3:42])=[O:40])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C#CC(=O)OC
Agent: Clc1cc2ccccc2nc1Cl
Agent: Nc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])C#CC(=O)[O-]
Product: COC(=O)/C=C(\Nc1ccccc1)C(=O)OC
Yield: 80 %

Procedure:
The dichloroquinoline (represented by 4) may be synthesized as described by Heindel, N. D., et al., “CYCLIZATION OF ANILINE-ACETYLENE DICARBOXYLATE ADDUCTS: A MODIFIED CONRAD-LIMPACH METHOD FOR THE SYNTHESIS OF POTENTIAL ANTIMALARIALS,” J. Med. Chem. 11 1218–1221 (1968). 3,5-Dichloroaniline, (1) a dihaloaniline, is refluxed with dimethyl acetylenedicarboxylate to produce substituted diester (3) in approximately 80% yield. Upon heating in diphenyl ether, the fumarate ester under goes cyclization to the quinoline carboxylate (4). The ester (4) can be readily aminated to the tosylamine (5) as described by Harrison, B. L., et al., “4-[(CARBOXYMETHYL)OXYL]-AND 4-[(CARBOXYMETHYL)AMINO]-5,7-DICHLOROQUINOLINE-2-CARBOXYLIC ACID: NEW ANTAGONISTS OF THE STRYCHNINE-INSENSITIVE GLYCINE BINDING SITE ON THE N-METHYL-D-ASPARTATE RECEPTOR COMPLEX,” J. Med. Chem. 33 3130–3132 (1990). The tosylamine (5) was acylated with diphenylcarbamoyl chloride (6), followed by hydrolysis, to form the diphenyl urea derivative (7).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[O:6][C:7]1[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([Cl:16])[N:10]=[C:9]([Cl:17])[N:8]=1.[C:22]([O-:25])(=[O:24])[CH3:23].[Na+]>CN(C=O)C>[Cl:17][C:9]1[N:8]=[C:7]([O:6][C:5]2[CH:4]=[C:3]([CH:20]=[C:19]([CH3:21])[CH:18]=2)[CH2:2][O:25][C:22](=[O:24])[CH3:23])[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([Cl:16])[N:10]=1
Reactant: CC(=O)[O-]
Reactant: Cc1cc(CBr)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(C)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a stirred solution of 4-(3-bromomethyl-5-methyl-phenoxy)-2,6-dichloro-5-isopropyl-pyrimidine (14.4 g, 36.9 mmol) in anhydrous DMF (50 ml), was added sodium acetate (6.05 g, 73.8 mmol) and the mixture was stirred in an oil bath (90˜100° C.) for overnight. After cooling to room temperature, the mixture was partitioned between ether and water. The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether: hexanes (from 1:9 to 1:4)) to afford 10 g (73%) of a white solid. m.p. 76-77° C.; 1H NMR (200 MHz, CDCl3) δ 1.41 (6H, d, J=7.2 Hz), 2.12 (3H, s), 2.39 (3H, s), 3.58 (1H, m), 5.09 (2H, s), 6.88 (1H, s), 6.93 (1H, s), 7.08 (1H, s).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:15]O>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:15])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: Cl
Product: COC(=O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of quinoline-6-carboxylic acid (1.00 g, 5.77 mmol) in MeOH (10 mL) was added hydrogen chloride (2.00 mL, 8.00 mmol) (4.0M in 1,4-dioxane). The reaction was stirred 18 h at rt, LCMS shows <10% conversion. Additional hydrogen chloride (2.00 mL, 8.00 mmol) was added and the reaction heated to 50° C. in an oil bath 36 h. The reaction was cooled to rt and concentrated in vacuo. The solid was dissolved in DCM and extracted with sat. aqueous NaHCO3 (2×50 mL). The organic layer was dried (MgSO4), and concentrated to give the product which was used without further purification in the next step.