Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6]>C(O)(=O)C>[CH3:3][O:4][C:5]([C:7]1[C:16]2[C:11](=[C:12]([Br:1])[C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: COC(=O)c1cccc2cc(OC)ccc12
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c(Br)c(OC)ccc12
Yield: 67.6 %

Procedure:
A solution of bromine (26.6 g, 0.167 mole) in glacial acetic acid (25 ml) was added dropwise to a cooled suspension of 6-methoxy-1-naphthalenecarboxylic acid methyl ester (30 g, 0.13 9 moles) in glacial acetic acid (2.75 ml). The precipitate was collected, washed with water and crystallized from ethanol to give 33.3 g of 5-bromo-6-methoxy-1-naphthalenecarboxylic acid methyl ester; mp 119° C.; NMR (CDCl3) δ 3.97 (s, 3H), 4.03 (s, 3H), 7.35 (d, J=9.25 Hz, 1H), 7.4 (m, 1H), 8.05 (d, J=6.75 Hz, 1H) 8.45 (d, J=8.25 Hz, 1H), 8.9 (d, J=9.25, 1H). The latter ester (10.1 g, 34 mmoles) and Cu2 (CN)2.H2O (3.4 g, 17 mmoles) in distilled dimethylformamide (75 ml) containing 15 drops of pyridine was heated at 180° C. for 5 hr. The hot mixture was poured into a mixture of ice (50 g) and conc. NH4OH (50 ml). The resulting precipitate was collected, washed with water, dried and recrystallized from chloroform-ethyl acetate to afford 5.6 g of 5-cyano-6-methoxy-1-naphthalenecarboxylic acid methyl ester: mp 210°-211° C., NMR (CDCl3)δ 3.95 (s, 3H), 4.15 (s, 3H). To a stirred solution of the latter ester (5.95 g, 24.66 mmoles) in 2-methoxyethanol (100 ml) at 20°-22° C., 4N aqueous NaOH solution (12.3 ml) was added. The reaction mixture was stirred at 20°-22° C. for 60 hr, diluted with water, cooled to 0° C. and rendered acidic with 1N aqueous HCl. The precipitate was collected and dried to yield 5.6 g of the title compound; mp>290° C.; NMR (DMSO-d 6) δ 4.1 (s, 3H), 8.1 (m, 5H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH2:13]([B:15]([CH2:18][CH3:19])OC)[CH3:14].O>C(OCCCC)CCC.[Cl-].[Na+].O>[CH2:13]([B:15]([CH2:18][CH3:19])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:14]
Reactant: Brc1cccnc1
Reactant: CCB(CC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCOCCCC
Product: CCB(CC)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
Into a solution of n-butyl lithium (165 ml, 264 mmol) in butyl ether (250 ml) at −78 degrees under nitrogen was added 3-bromopyridine (25.4 ml, 264 mmol). After 1 h, added diethylmethoxyborane (52 ml, 396 mmol). The mixture was allowed to warm to room temperature. After 16 h, added water and brine, separated organic layer, dried over sodium sulfate, then concentrated. The resulting slurry was dissolved in isopropanol (500 ml), cooled and the product isolated by filtration give diethyl(3-pyridyl)borane (29.8 g).
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:22])[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][OH:32]>CC(C)=O>[CH2:1]([C:5]1[C:6](=[O:22])[N:7]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:8]2[C:13]([C:14]=1[O:15][CH2:30][CH2:31][OH:32])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: OCCBr
Reactant: CCCCc1c(O)c2cccnc2n(-c2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCc1c(OCCO)c2cccnc2n(-c2ccccc2)c1=O
Yield: 58.5 %

Procedure:
Reflux a stirred solution of 16.2 gm of 3-(n-butyl)-4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one and 11.4 gm of anhydrous potassium carbonate powder in 600 ml of dry acetone for 30 minutes. 95% 2-bromoethanol (10.3 gm) is added dropwise to the solution. The reaction is refluxed for 26 hours, cooled and the solvent removed by stripping. The resulting solid is dissolved in 500 ml chloroform and the chloroform solution is washed with 300 ml water, twice with 100 ml of 0.5N sodium hydroxide solution and finally with 100 ml of water. The chloroform solution is dried over magnesium sulfate, filtered and the solvent is removed to give the crude product. The crude product is triturated with warm isopropyl ether to give 10.9 gm of the 3-(n-butyl)-4-(2-hydroxyethoxy)-1-phenyl-1,8-naphthyridin-2(1H)one; which after recrystallization from acetone melts at 138°-140° C.
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH:2]=[CH2:3].CC([O-])(C)C.[K+].[Si:19]([O:26][CH2:27][C@@H:28]1[CH:33]=[C:32]([CH2:34][O:35][CH3:36])[C@H:31](OS(C)(=O)=O)[CH2:30][N:29]1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].ON>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]([C:6]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:12])[C@H:31]1[CH2:30][N:29]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[C@H:28]([CH2:27][O:26][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:33]=[C:32]1[CH2:34][O:35][CH3:36])[CH:2]=[CH2:3]
Reactant: COCC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1OS(C)(=O)=O
Reactant: C=CCONC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: NO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCON(C(=O)OC(C)(C)C)[C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1COC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl allyloxycarbamate (7.39 g, 42.66 mmol) in DMF (150 mL) at rt, potassium 2-methylpropan-2-olate (42.66 mL, 42.66 mmol) was added and gave a purple solution. After 30 min at rt, the mixture was cooled to 0° C. and (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-(methoxymethyl)-5-(methylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (crude, 16.55 g, 35.55 mmol) in 50.0 mL DMF was added. The mixture was then warmed up to rt for 1 h. It was then diluted with ethyl acetate (200 mL) and washed aqueous sat. NaHCO3 solution, brine, dried over MgSO4, filtered and concentrated to give a residue which contains some starting material. The crude was purified on a silica gel column yielding a colorless oil. (19.3 g). 1HNMR shows still a mixture (with hydroxyamine starting material). It was used directly in TBS deprotection.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1)=[O:15].[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C>ClCCl>[O:24]=[C:23]([O:25][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1)[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:17][CH:18]=1
Reactant: C1=COCCC1
Reactant: COC(=O)c1ccc(CC(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CC(=O)OC2CCCCO2)cc1
Yield: 170.8 %

Procedure:
To a saturated solution of anhydrous p-toluenesulphonic acid in dry dichloromethane (35 ml) successively 2-[4-(methoxycarbonyl)phenyl]acetic acid (E11) (0.671 g, 3.45 mmol) and 3,4-dihydro-2H-pyran (3 ml, 32.9 mmol) were added, and the resultant solution was stirred for 45 minutes at room temperature. To the reaction mixture triethylamine (1 ml, 7.2 mmol) was added and the volatiles were evaporated. The obtained crude title product (1.64 g) was immediately utilized in the next step of the synthesis.
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[C:13]2[C:12](=[O:14])[NH:11][N:10]=[CH:9][C:8]=2[N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:6]=1.[Br:23]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:23][C:6]1[N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]2[CH:9]=[N:10][NH:11][C:12](=[O:14])[C:13]=2[C:5]=1[Cl:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)CCOCn1cc(Cl)c2c(=O)[nH]ncc21
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1c(Br)c(Cl)c2c(=O)[nH]ncc21
Reaction time: 8.5 h
Yield: 83 %

Procedure:
To 30 ml of acetonitrile solution containing 903 mg (3.00 mmol) of 3-chloro-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 16-(c) was added 703 mg (3.95 mmol) of N-bromosuccinimide at room temperature, and the mixture was stirred for 8.5 hours. After completion of the reaction, ethyl acetate was added to the reaction mixture, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogencarbonate, 5% aqueous sodium hydrogen sulfite solution and then a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the obtained concentrate were added diisopropyl ether and cyclohexane, precipitated solid was collected by filtration. The obtained solid was washed with cyclohexane and then with hexane, and dried under reduced pressure to obtain 943 mg of the title compound as a pale yellowish solid. (Yield: 83%)
Reaction SMILES: [CH2:1]1[C@@H:6](O)[C@@H:5](O)[C@H:4](O)[CH2:3][C@@:2]1([C:11]([OH:13])=[O:12])O.C(OCC)C>S1(CCCC1)(=O)=O>[C:11]([OH:13])(=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:1]=1
Reactant: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Product: O=C(O)c1ccccc1
Temperature: 210 °C

Procedure:
The reaction is performed using the following set-up and procedure: quinic acid (20 mmol) was first dissolved in sulfolane at room temperature in a 50 ml three neck flask fitted with a fractioning column connected to a collecting flask through a U-shaped tube. The temperature in the reaction mixture is indicated by an immersed thermometer and nitrogen is bubbled through the mixture using a perforated tube immersed in the solution. Formic acid is then added and the mixture is heated over a preheated oil bath to 200-220° C. for a sufficient period of time. After that, the procedure is repeated adding another aliquot of formic acid. The reaction can be monitored by 1H NMR taking aliquots from the reaction mixture. Eventually the conversion of quinic acid is complete. Benzoic acid is isolated from the reaction mixture by extraction with ethyl ether and isolated removing the solvent at reduced pressure to give the product in a yield of over 75%.
Reaction SMILES: Br[CH2:2][C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([CH3:14])([CH3:13])[C:3](=[O:15])[CH2:2][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:7][CH:8]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(Cc1ccc(Cl)cc1)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(Cc1ccc(Cl)cc1)C(=O)Cn1cncn1
Yield: 52 %

Procedure:
37 (0.13 mol) of 4-bromo-1-(4-chlorophenyl)-2,2-dimethyl-3-butanone, 13.3 g (0.019 mol) of 1,2,4-triazole and 53.8 g (0.39 mol) of potassium carbonate are heated under reflux in 300 ml of acetone for 8 hours. The mixture is allowed to cool, the inorganic residue is filtered off with suction and the filtrate is concentrated. The residue is taken up in chloroform and the mixture is washed with water, dried over sodium sulphate and concentrated. The residue is stirred with diethyl ether, filtered off with suction and dried at 50° C. in vacuo. 18.8 g (52% of theory) of 1-(4-chlorophenyl)-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-3-butanone of melting point 127° C. are obtained. ##STR18##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:14])([CH2:12][F:13])[CH2:10][F:11].CCN(C(C)C)C(C)C.[CH2:24](Cl)[O:25][CH3:26].[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:14][CH2:24][O:25][CH3:26])([CH2:10][F:11])[CH2:12][F:13]
Reactant: Cc1ccc(C(O)(CF)CF)c(Br)c1
Reactant: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC(CF)(CF)c1ccc(C)cc1Br
Temperature: 25 °C
Reaction time: 11 h
Yield: 79.2 %

Procedure:
To a stirring solution of 2-(2-bromo-4-methylphenyl)-1,3-difluoropropan-2-ol (1.3 g, 4.9 mmol) in DCM (10 mL) at rt were successively added DIPEA (3.4 mL, 19.6 mol) and MOMCl (0.6 mL, 7.4 mmol) over a 10 min period. The solution was stirred 11 h at rt followed by addition of a saturated aqueous NH4Cl solution (20 mL). The aqueous phase was segregated, and the organic one was washed with water (20 mL), brine (20 mL), dried with anhydrous Na2SO4, filtered, and concentrated to give pure 2-bromo-1-(1,3-difluoro-2-(methoxymethoxy)propan-2-yl)-4-methylbenzene (1.2 g, yield 80%) 1H NMR (400 MHz, CDCl3): δ 7.50 (s, 1 H), 7.38 (d, 1 H), 7.15 (d, 1 H), 5.15-5.12 (m, 1 H), 5.03-5.00 (m, 2 H), 4.91-4.88 (m, 1 H), 4.62 (s, 2 H), 3.43 (s, 3 H), 2.32 (s, 3 H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:6][C:7](O)=[O:8])=[O:4].CN(C=O)C.C(Cl)(=O)C([Cl:29])=O>C1COCC1>[CH2:14]([O:13][C:11]([NH:10][C@@H:5]([CH2:6][C:7]([Cl:29])=[O:8])[C:3]([O:2][CH3:1])=[O:4])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(=O)Cl)NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Z-asp-OMe (175 g, 622 mmol) was dissolved in THF (1750 ml) and admixed with 2 ml of DMF. 86.9 g (684 mmol) of oxalyl chloride were dissolved in 200 ml of THF (slightly exothermic), cooled back to room temperature (RT) and added dropwise to the solution of the amino acid over 1 hour (h). After a further hour at RT, the solution was initially sparged with nitrogen for 10 min, concentrated on a rotary evaporator at a maximum of 30° C. and coevaporated repeatedly with toluene. The resulting dirty white solid was dried to constant weight under in-house vacuum (about 1.5 mbar) and reacted further without further purification. Yield: 186.6 g (quantitative).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].CCCCCC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23])[CH:6]=[CH:5]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
200 g 6-bromonaphthalen-2-ol, 143 g imidazole and 151 g tert.-butylchlorodimethylsilane were dissolved in 1,000 ml dimethylformamide, stirred for two hours at ambient temperature, the solution largely concentrated (506 g), the residue dissolved in ethyl acetate and water, 1,500 ml saturated sodium chloride solution added, the phases separated, the aqueous phase extracted twice with ethyl acetate and the organic phases combined and concentrated. The crude product obtained was dissolved in boiling hexane and subsequently kept overnight at 4° C. After filtration, 158 g (6-bromonaphthalen-2-yloxy)-tert.-butyldimethylsilane were isolated. Repeated concentration of the mother liquor and recrystallisation from methanol yielded a further 54 g (6-bromonaphthalen-2-yloxy)-tert.-butyldimethylsilane.
Reaction SMILES: Br.[C:2]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>CN(C)C=O.CC1C=CC(S(NC2C=CC(NC3C=CC=CC=3)=CC=2)(=O)=O)=CC=1>[C:2]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH2:10][CH2:9]1)(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5]
Reactant: CC(=O)CC(=O)N1CCNCC1
Reactant: C=C(C)C(=O)Cl
Agent: Br
Agent: Cc1ccc(S(=O)(=O)Nc2ccc(Nc3ccccc3)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(C)C(=O)N1CCN(C(=O)CC(C)=O)CC1
Reaction time: 20 h
Yield: 56 %

Procedure:
Crude 1-acetoacetylpiperazine hydrobromide (50 g, 0.2 mole) was dissolved in N,N-dimethylformamide (300 ml) with Aranox® (50 mg) (available from U.S. Rubber Co.). Triethylamine (50 g, 0.5 mole) was added at 0° C., followed immediately by the dropwise addition of methacryloyl chloride (20.8 g, 0.2 mole) at 0° C. The reaction solution was then allowed to reach 20° C. over a 20 hour period. The reaction solution was filtered and the solvent was removed at low vacuum. The residue was distilled to give 4-acetoacetyl-1-methacryloylpiperazine (b.p.=110°-129° C./10-8μ) at a yield of 56%.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[NH:6][C:7]([NH2:16])=[C:8]2[C:12]([N:13]=1)=[N:11][C:10]([O:14][CH3:15])=[N:9]2)[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1>CN(C=O)C.ClCCl>[NH2:16][C:7]1[N:6]=[C:5]([O:4][CH:2]([CH3:1])[CH3:3])[N:13]=[C:12]2[C:8]=1[N:9]=[C:10]([O:14][CH3:15])[N:11]2[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCBr)CC1
Reactant: COc1nc2nc(OC(C)C)[nH]c(N)c-2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1nc2c(N)nc(OC(C)C)nc2n1CCCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.7 %

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine (37 mg, 0.166 mmol) in DMF (0.5 ml) was added potassium carbonate (55 mg, 0.398 mmol) followed by a solution of 1,1-dimethylethyl 4-(4-bromobutyl)-1-piperidinecarboxylate (58 mg, 0.181 mmol) in DMF (0.2 ml) and the mixture was stirred at room temperature for 72 hours. The mixture was diluted with dichloromethane (5 ml) and washed with water (5 ml). The layers were separated using a hydrophobic frit, the aqueous layer was extracted again with dichloromethane (5 ml) and the combined organic extracts were evaporated. The residue was dissolved in methanol (0.6 ml) and purified by MDAP (Method A). The appropriate fractions were combined and evaporated under a stream of nitrogen in a blowdown apparatus to give the title compound as a colourless gum (32 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.C([N:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]([CH2:35]Br)[NH:27][C:26]1=[O:37])(=O)C.[ClH:38]>C(O)C>[ClH:38].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:35][C:28]2[NH:27][C:26](=[O:37])[NH:25][C:29]=2[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)c1c(CBr)[nH]c(=O)n1C(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1[nH]c(=O)[nH]c1CN1CCN(c2ccccc2OC)CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a cooled solution (0° C.) of 2 g of 1-(2-methoxyphenyl)piperazine and 2.1 g of triethylamine in 40 ml of ethanol is added 2.9 g of ethyl 3-acetyl-5-(bromomethyl)-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate. The resulting solution is stirred at 0° C. for 4 hours, 30 ml of ice-water is added and the mixture is filtered. One equivalent of hydrochloric acid is added to the filtrate and it is evaporated to dryness. The residue crystallizes from a mixture of ethanol and ethyl acetate (1:1) and is recrystallized from that solvent mixture to give ethyl 2,3-dihydro-5-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxylate hydrochloride melting at about 227° C. (dec.). The free base of this compound has the following structural formula: ##STR6##
Reaction SMILES: [Cl-].[NH4+].[F:3][CH:4]([F:23])[C@H:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([F:22])[CH:14]=2)=[CH:9][CH:8]=1)[OH:6]>C(O)C.O.[Fe]>[NH2:19][C:17]1[CH:18]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([C@H:5]([OH:6])[CH:4]([F:23])[F:3])=[CH:12][CH:11]=2)[CH:14]=[C:15]([F:22])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(F)cc(-c2ccc([C@H](O)C(F)F)cc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(F)cc(-c2ccc([C@H](O)C(F)F)cc2)c1
Temperature: 25 °C

Procedure:
Ammonium chloride (24.2 mg, 0.453 mmol) was added to a mixture of (1S)-2,2-difluoro-1-(3′-fluoro-5′-nitrobiphenyl-4-yl)ethanol (269 mg, 0.905 mmol) and iron (253 mg, 4.53 mmol) in ethanol (6 mL) and water (3 mL). The mixture was heated to reflux for 1.5 hours. Upon cooling to room temperature, the reaction mixture was filtered through CELITE and washed with ethyl acetate. The filtrate was washed with saturated aqueous NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to yield (1S)-1-(3′-amino-5′-fluorobiphenyl-4-yl)-2,2-difluoroethanol. MS ESI calc'd. for C14H13F3NO [M+H]+ 268, found 268.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH2:11][CH2:10]1
Reactant: c1ccc(CN2CCNCC2)nc1
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N1CCN(Cc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1 eq 1-(pyridin-2-ylmethyl)piperazine hydrochloride in dry dichloromethane are added 1.5 eq butanoyl chloride and 2.5 eq triethylamine. After stirring for 6 hours at room temperature the solvent is removed in vacuo and the residue re-dissolved in ethyl acetate. The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, ethyl acetate is removed in vacuo and the crude product is purified by column chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][C:13]([N:15]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=1)=[O:14]>O1CCCC1>[CH3:23][N:22]([CH3:24])[C:19]1[CH:18]=[CH:17][C:16]([N:15]([CH2:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C:13](=[O:14])[CH2:12][NH:11][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:10])=[CH:21][CH:20]=1
Reactant: CN(C)c1ccc(N(CC(=O)OC(C)(C)C)C(=O)CN)cc1
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccc(N(C)C)cc2)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 697.8 %

Procedure:
3-Methylphenyl isocyanate (0.35 g) is added at a temperature in the region of 20° C. to a solution of tert-butyl 2-[2-amino-N-(4-dimethylaminophenyl)acetamido]acetate (0.7 g) in anhydrous tetrahydrofuran (15 cc). The solution obtained is stirred for 3 hours at a temperature in the region of 20° C. and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallisation of the residual solid in ethyl acetate, tert-butyl 2-{N-(4-dimethylaminophenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (0 7 g), m.p 105° C., is obtained.