Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccccc2s1)c1ccccc1
Temperature: 3 °C
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
In a 100 ml three-necked flask equipped with magnetic stirrer, thermometer, dropping funnel and nitrogen inlet, 5.34 g (35.6 mmol) of 2-amino-benzothiazole are dissolved in 50 ml of pyridine and cooled to 3° C. using an ice bath. 5.0 g of benzoylchloride (35.6 mmol) are added dropwise within 20 minutes, keeping the temperature within the mixture below 5° C. Stirring is continued for another 15 minutes, then the mixture is poured on 500 ml of water. The white suspension is stirred for 1 hour, filtered, the white residue is washed 3 times with 100 ml of water, respectively, and dried over night at 50° C. and 30 mbar. 7.5 g crude product obtained are purified by flash-chromatography using hexane/ethylacetate 3:1 (v/v), yielding 5.8 g of the title product.
Reaction SMILES: [C:1]1([C:11](=[O:14])[CH2:12][CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br-:15].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>COCCOC>[Br:15][CH:12]([CH3:13])[C: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)=[O:14]
Reactant: CCC(=O)c1cccc2ccccc12
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: COCCOC
Product: CC(Br)C(=O)c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 118.2 %

Procedure:
To a solution of 1-naphthalen-1-yl-propan-l-one (37.8 g) in 1,2-dimethoxyethane (350 mL) at 0° C. was added phenyl trimethylammonium tribromide (83 g). The mixture was stirred at 0° C. for 10 minutes and then at room temperature for 24 hours. The mixture was washed with water (500 mL) and the aqueous phase was extracted with ethyl acetate (2×500 mL). The combined organics were washed with water (2×200 mL), brine (500 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to afford an orange gum. The gum was triturated with diethyl ether and filtered to afford 2-bromo-1-naphthalen-1-yl-propan-1-one (39.8 g, 74%) as an orange solid, 1H NMR (CDCl3): 1.95 (3H, d, J=6.6 Hz), 5.35 (1H, q, J=6.6 Hz), 7.45-7.60 (3H, m), 7.85-7.90 (2H, m), 8.0 (1H, d, J=8.1 Hz), 8.4 (1H, d, J=7.9 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:16][O:17][CH2:18][CH2:19]Br>CC#N>[CH3:16][O:17][CH2:18][CH2:19][O:9][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=1
Reactant: OCc1cccc(O)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COCCOc1cccc(CO)c1
Temperature: 110 °C

Procedure:
A mixture of 10 g (80.6 mmol) of 3-(hydroxymethyl)phenol, 78.4 g (241.7 mmol) of Cs2CO3 and 8.4 mL (88.6 mmol) of bromoethyl methyl ether in 150 mL of CH3CN is heated for 12 hours at 110° C. After cooling to room temperature, the medium is filtered, concentrated under reduced pressure, taken up in 500 mL of DCM, washed with brine (2×100 mL) dried over Na2SO4, filtered and then concentrated under reduced pressure. 10.9 g of 3-(2-methoxyethoxy)phenyl]methanol are obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH:12]1([Mg]Br)[CH2:14][CH2:13]1.[Cl-].[NH4+]>CCOCC>[CH:12]1([C:7]2([OH:11])[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)[CH2:14][CH2:13]1
Reactant: Br[Mg]C1CC1
Reactant: O=C1CCc2cc(F)ccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(C2CC2)CCc2cc(F)ccc21
Reaction time: 8 h
Yield: 106.8 %

Procedure:
To a solution of 5-fluoroindanone (0.95 g, 6.33 mmol) in anhydrous ether (30 ml) under nitrogen at room temperature add cyclopropyl magnesium bromide (9.1 ml, 7.28 mmol, 1.15 equivalents, 0.80 M in tetrahydrofuran) dropwise while maintaining a gentle reflux. After stirring overnight, quench the reaction at room temperature via dropwise addition of 10% aqueous ammonium chloride. Dilute the reaction with ether, wash with water (2×), dry over anhydrous sodium sulfate, filter, and concentrate to give the title compound (1.30 g, ˜100%). NMR (CDCl3, 400 MHz): δ 0.26 (m, 1H), 0.36-0.51 (m, 3H), 1.21 (m, 1H), 2.13 (m, 1H), 2.28 (m, 1H), 2.80 (m, 1H), 2.95 (m, 1H), 6.88 (m, 2H), 7.29 (m, 1H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(N(CC)CC)C.[NH2:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][CH:21]=[N:22]2)=[C:18]([Cl:25])[N:17]=1>C1(C)C=CC=CC=1>[C:5]([N:22]1[CH:21]=[N:20][C:19]2[C:23]1=[N:24][C:16]([NH2:15])=[N:17][C:18]=2[Cl:25])(=[O:7])[CH3:6]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)n1cnc2c(Cl)nc(N)nc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 204.2 g (2.00 mol) of acetic anhydride, 202.4 g (2.00 mol) of triethylamine and 169.6 g (1.00 mol) of 2-amino-6-chloropurine was stirred at 80° C. for 1 hour. The resulting suspension was cooled at 25° C., and thereafter diluted with 400 mL of toluene, and the diluted solution was filtered. The resulting crystals were suspended in 300 mL of isopropanol, and the suspension was filtered again. The resulting crystals were dried at 60° C. under reduced pressure, to give 211.8 g of white powder of 9-acetyl-2-amino-6-chloropurine (yield 100%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[OH-].[K+].[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CS(C)=O>[CH3:11][C:4]1[CH:3]=[C:2]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc(-n2ccnc2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 82.9 %

Procedure:
To a solution of 4-fluoro-2-methyl-1-nitro-benzene (300 mg, 1.84 mmol) in DMSO (2 mL) were added KOH (20 mg, 3.87 mmol) and imidazole (263 mg, 3.88 mmol). The reaction mixture was heated to 100° C. for 3.5 h, cooled to room temperature, and diluted with ice-cold water. The resulting precipitate was filtered, washed with ice-cold water, and dried under vacuum to give the title compound (310 mg, 80%) as a yellow powder. 1H NMR (300 MHz, DMSO-d6) δ 8.46 (1H, s), 8.16 (1H, d, J=8.9 Hz), 7.90-7.92 (2H, m), 7.78 (1H, dd, J=2.5, 8.9 Hz), 7.17 (1H, s), 2.61 (3H, s). LRMS (M+H)+ m/z 204.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:15])([CH3:14])[CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]([CH3:14])([CH3:15])[CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH:8]([OH:13])[CH2:7]1
Reactant: COC(C)(C)CCC1CC(=O)CC(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(C)(C)CCC1CC(C)CC(O)C1
Reaction time: 16 h
Yield: 77.8 %

Procedure:
A solution of 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohexan-1-one (0.50 g, 0.0024 mol) in tetrahydrofuran (1 mL) was added to a suspension of lithium aluminum hydride (0.10 g, 0.0027 mol) in tetrahydrofuran (1 mL) cooled to 0~C. The mixture was stirred at 20~C for 16 h. Subsequent workup yielded 3-(3-methoxy-3-methylbutyl)-5-methylcyclohexanol (0.40 g) as a mixture of four diastereoisomers (ratio 2.8:15.3:79.2:2.8).
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].CN([CH:31]=[O:32])C>C1COCC1>[Cl:15][C:16]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:23]([F:27])[C:24]([CH:31]=[O:32])=[CH:25][CH:26]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1c(F)cccc1Cl
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)ccc(C=O)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution DIPEA (6.6 mL, 46.0 mmol) in THF (15 mL) was added nBuLi (27 mL, 43.0 mmol, 1.6 M in hexane) at −78° C. and the reaction mixture was warmed to 0° C. over a period of 1 h. Then the reaction mixture was cooled to −78° C. and a solution of ethyl 2-chloro-6-fluorobenzoate (3.50 g, 19.0 mmol) in THF (56 mL) was added to the reaction mixture dropwise over 30 mins. The resulting mixture was stirred at −78° C. for 2 h before DMF (14 mL, 186 mmol) was added to the reaction mixture. The resulting mixture was stirred at −78° C. for 1 h and then gradually warmed to 0° C. over 1 h. The reaction mass was quenched with 10% aq. AcOH and was extracted with EtOAc. The organic layer was washed with water and brine, separated, dried, filtered and concentrated to provide ethyl 6-chloro-2-fluoro-3-formylbenzoate. 1H NMR (300 MHz, DMSO-d6): δ 10.27 (s, 1H), 8.05-8.00 (t, J=7.8 Hz, 1H), 7.72-7.69 (d, J=8.4 Hz, 1H), 4.53-4.46 (q, J=6.9, 14.4 Hz, 2H), 1.41-1.37 (t, J=6.6 Hz, 3H). A mixture of ethyl 6-chloro-2-fluoro-3-formylbenzoate (4.04 g, 17.52 mmol) and hydroxylamine (50% aq, solution, 4.29 mL, 70 mmol) in MeOH (60 mL) was stirred at 55° C. for 1.5 h. Then the mixture was concentrated and the residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to provide ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate. 1H NMR (300 MHz, DMSO-d6): δ 11.89 (s, 1H), 8.20 (s, 1H), 7.88-7.83 (t, J=8.1 Hz, 1H), 7.49-7.46 (d, J=8.4 Hz, 1H), 4.44-4.37 (q, J=7.5, 14.1 Hz, 2H), 1.34-1.29 (t, J=7.2 Hz, 3H). A mixture of ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate (4.21 g, 17.14 mmol), Zn (4.48 g, 68.56 mmol), and 10N HCl in EtOH (51.42 mL, 514.2 mmol) in MeOH (200 mL) was heated at reflux for 3 h. Additional Zn (2.24 g, 34.25 mmol) was added to the reaction mixture and it was heated at reflux for 2 h and then stirred at rt for 16 h. Then the reaction mixture was concentrated. The residue was diluted with EtOAc and was treated with a saturated solution of NaHCO3. The mixture was filtered and the organic layer was separated, dried, filtered and concentrated to provide 3.5 g of the title product. 1H NMR (300 MHz, CDCl3): δ 7.54 (t, J=7.8 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 4.45 (q, J=7.5, 14.1 Hz, 2H), 4.11 (d, J=3.6 Hz, 2H), 3.37 (br s, 2H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C@H:9]2[C@H:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:14]([CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:13][C@@H:10]2[CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:35](=O)([O-])[O-:36].[K+].[K+]>CO>[OH:12][CH2:11][C:10]1([O:13][C@H:14]([CH2:24][O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:9]1[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:35][OH:36]
Reactant: O=C([O-])[O-]
Reactant: O=C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: C=O
Agent: [K+]
Solvent: CO
Product: OCC1(CO)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
In accordance with Flowchart F, 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose 29 is reacted with formalin and potassium carbonate in methanol at about 85° C. under an inert atmosphere, then acidified, giving 2,5-anhydro-2-C-(hydroxymethyl)-3,4,6-tris-O-(phenylmethyl)-D-glucitol 42. which is reacted with borontrifluoride etherate in acetic anhydride at reduced temperature followed by treatment with sodium bicarbonate, giving 2-C-[(acetyloxy)methyl]-2,5-anhydro-3,4-bis-O-(phenylmethyl)-D-glucitol, 1,6-diacetate 43. Compound 43 is reacted with aqueous potassium carbonate in methanol at reflux, giving 2,5-anhydro-2-C-(hydroxymethyl)-3,4-bis-O-(phenylmethyl)-D-glucitol 44, which is reacted with benzaldehyde dimethyl acetal and p-toluenesulfonic acid in dimethylformamide at about 60° C. under reduced pressure, giving a mixture of [R] and [S]-2,5-anhydro-2-C-(hydroxymethyl)-3,4-bis-O-(phenylmethyl)-1,21 -O-(phenylmethylene)-D-glucitol 45 and 46. The mixture 45 and 46 is reacted with aluminum chloride and lithium aluminum hydride in ether/dichloromethane under an inert atmosphere, giving a mixture of 2,5-anhydro-2-C-[(phenylmethoxy)methyl]-3,4-bis-O-(phenylmethyl)-D-glucitol and 2,5-anhydro-2-C-(hydroxymethyl)-1,3,4 -tris-O-(phenylmethyl)-D-glucitol 47, which is reacted with diphenyl phosphorochloridate in pyridine at reduced temperature, giving a mixture of 2,5-anhydro-2-C-[(phenylmethoxy)methyl]-3,4-bis-O-(phenylmethyl)-D-glucitol, 1,6-bis (diphenyl phosphate) and 2,5-anhydro-2-C-[[(diphenoxyphosphinyl)oxy]methyl]-1, 3,4-tris-O-(phenylmethyl)-D-glucitol, 6-diphenyl phosphate 48. The mixture 48 is hydrogenated in methanol and acetic acid over palladium on carbon, giving, after chromatography, the product of Formula I where R', R", R'" and R"" are phenyl, 2,5-anhydro-2-C-(hydroxymethyl)-D-glucitol, 1,6-bis(diphenyl phosphate) 49. Substitution of other esterifying agents as described in Flowchart A will result in the corresponding tetraesters. Compound 49 may then be hydrogenated in methanol over platinum oxide, giving the product of Formula I where R', R", R'" and R"" are hydrogen, 2,5-anhydro-2-C-(hydroxymethyl)-D-glucitol, 1,6-bis(dihydrogen phosphate) 50. ##STR19##
Reaction SMILES: [NH3:1].[NH:2]1[CH:6]=[N:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[N:3]1>>[NH:2]1[CH:6]=[N:5][C:4]([S:7]([NH2:1])(=[O:9])=[O:8])=[N:3]1
Reactant: O=S(=O)(Cl)c1nc[nH]n1
Reactant: N
Product: NS(=O)(=O)c1nc[nH]n1

Procedure:
Liquid ammonia is reacted with 1,2,4-triazol-3- sulfonylchloride to give 1,2,4-triazol-3-sulfonamide in U.S. Pat. No. 2,554,816.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2cccn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A mixture of 3,4-difluoronitrobenzene (1.00 mL, 9.03 mmol), pyrazole (0.615 g, 9.04 mmol) and K2CO3 (2.50 g, 18.1 mmol) in DMF (10 mL) was stirred at room temperature overnight. Water (30 mL) was added to induce precipitation. The precipitate was collected, dried on vacuum to give 1-(2-fluoro-4-nitrophenyl)-1H-pyrazole as a solid (1.80 g). MS 208.3 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CCN)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(C)=O)cc1
Temperature: 20 °C
Reaction time: 0.67 h
Yield: 175.3 %

Procedure:
To 100 g of 2-(4-methoxyphenyl)ethylamine in 500 mL of chloroform was slowly added 100 mL of triethylamine acetic anhydride (72 g), and this was stirred at 20° C. for 40 minutes. The mixture was then extracted twice with a dilute aqueous solution of HCl (0.4 N, 400 mL) followed by a saturated aqueous solution of NaHCO3 (2×400 mL). The solvent was removed by rotary evaporation, and the residue was dried in a vacuum oven (45° C.), resulting in an off-white powder, N-[2-(4-methoxyphenyl)ethyl]acetamide (120 g, 93.9% yield). 1HNMR (DMSO-d6) spectrum was consistent with the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>C1COCC1>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25](=[O:26])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1Cl
Reaction time: 6 h
Yield: 92.7 %

Procedure:
To a stirred mixture of tert-butyl 4-amino-3-methylphenylacetate (1.00 g, 4.52 mmol), 2-chlorophenyl isocyanate (0.55 ml, 4.52 mmol) in THF (10 ml) was added Et3 N (0.13 ml, 0.90 mmol) at room temperature. After 6 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2-chlorophenyl) ureido]-3-methylphenylacetate (1.57 g, 93%) as a pale yellow powder. mp 104–106° C. (dec.); 1H-NMR (CDCl3) δ 1.45 (s, 9H), 2.28 (s, 3H), 3.51 (s, 2H), 6.33 (br, 1H), 6.96 (t, J=7.6 Hz, 1H), 7.08 (br, 1H), 7.16–7.30 (m, 4H), 7.42 (m, 1H), 8.2 (d, J=8.1 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([O:21][C:22]3[CH:36]=[CH:35][C:25]([C:26]([O:28]CC[Si](C)(C)C)=[O:27])=[CH:24][CH:23]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2.C(OCC)(=O)C>C1COCC1>[CH3:1][C:2]1([CH3:37])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:35][CH:36]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)Oc4ccc(C(=O)OCC[Si](C)(C)C)cc4)cc32)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)Oc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 110.0 mg (0.213 mmol) 2- trimethylsilylethyl 4[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]oxy]-benzoate (Compound 38) and 167.3 mg of tetrabutylamrnmonium flouride (0.640 mmol, 0.64 ml of a 1M solution in THF) in 2.0 ml THF was stirred at room temperature for 22 hours. Ethyl acetate was added and the resulting solution washed with H2O and saturated aqueous NaCl then dried over MgSO4. Removal of the solvents under reduced pressure and washing of the residual solid with EtOAc and CH3CN afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 8.10 (2H, d, J=8.8 Hz), 8.06 (1H, dd, J=2.0, 8.1 Hz), 7.82 (1H, d, J=1.9 Hz), 7.64 (1H, d, J=8.1 Hz), 7.35 (2H, d, J=8.6 Hz), 7.25 (4H, m), 6.08 (1H, t, J=4.7 Hz), 2.42 (2H, d, J=4.7 Hz), 2.35 (3H, s), 1.39 (6H, s).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][C@H:7]1[C:15]2[C:14](O)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9][CH2:8]1.C([O-])(O)=O.[Na+]>ClCCCl>[Cl:3][C:14]1[C:15]2[C@H:7]([CH3:6])[CH2:8][CH2:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: C[C@@H]1CCc2ncnc(O)c21
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@@H]1CCc2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 61.1 %

Procedure:
Neat POCl3 (463.9 ml, 5067 mmol) was added slowly by addition funnel to a 0° C. solution of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (152.2 g, 1013 mmol) in DCE (1.2 L). After the addition was complete, the reaction mixture was warmed to room temperature, then heated to reflux and stirred for 70 minutes. The reaction was complete as determined by HPLC. The reaction mixture was cooled to room temperature, and the excess POCl3 was quenched in 4 portions as follows: Reaction mixture transferred to separatory funnel and dripped into a beaker containing ice and saturated NaHCO3 solution cooled in an ice bath. Once the addition of each portion of the reaction mixture was completed, the quenched mixture was stirred for 30 minutes to ensure complete destruction of POCl3 prior to transfer to separatory funnel. The mixture was transferred to the separatory funnel and extracted twice with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel as follows: silica gel (1 kg) was slurried in 9:1 hexane:ethyl acetate onto a 3 L fritted funnel, silica settled under vacuum, topped with sand. The crude was loaded with a DCM/hexane mixture, and the compound was eluted using 1 L sidearm flasks under vacuum. High Rf byproducts eluted first, then (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (104.4 g, 61.09% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
4-Methylbenzenesulfonyl chloride (52.1 g) was added to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (50.0 g) in pyridine (248 mL) at room temperature. The mixture was stirred at room temperature overnight. After evaporation of the solvent, water and ethyl acetate were added to the residue. The organic layer was separated, washed with 1M hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was triturated in diisopropyl ether at 0 C (“C” represents “degrees Celsius”) to give the title compound (76.1 g).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].C(=O)([O-])[O-].[Cs+:17].[Cs+].C(O)(C)C.C(=O)=O>O>[O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-:6])=[C:3]1[OH:4].[Cs+:17]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Cs+]
Solvent: O
Solvent: CC(C)O
Product: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Yield: 192 %

Procedure:
Ascorbic acid (5 g, 28.4 mmol) was dissolved in 20 ml of water, followed by slow addition of cesium carbonate (4.63 g, 14.2 mmol) in the temperature range of 0 to 5° C. 40 ml of isopropyl alcohol was slowly added to the reaction mixture when the generation of carbon dioxide completely stopped. After standing for several hours, the precipitate was filtered and washed with isopropyl alcohol, and dried to give 8.4 g of the cesium ascorbate as a white solid (yield 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13].[BH4-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of 6.5 g of methyl 2-(2,6-dichloroanilino)phenylglyoxylate in 130 ml of ethanol was added 0.5 g of sodium borohydride while cooling at -15° to -20° C., and the mixture was stirred at 0° C. for 2 hours and then at room temperature for further 1 hour. Thereafter, the reaction mixture was mixed with diluted hydrochloric acid for decomposition, diluted with 500 ml of water and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate and then concentrated without heating. The resulting residue was recrystallized from ethanol to give 6.2 g of methyl 2-(2,6-dichloroanilino)phenylglycolate. m.p. 123°-124° C. Yield: 95% of theoretical amount