Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)(=O)=O.C(O)[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH2:18](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)CO.[S:30](=[O:33])(=[O:32])=[O:31].[CH3:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])C>N1C=CC=CC=1>[CH3:18][C:35]1([CH3:34])[C:36]([CH3:38])([CH3:39])[O:31][S:30](=[O:33])(=[O:32])[O:40]1
Reactant: O=S(=O)=O
Reactant: OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)CO
Reactant: CC(=O)C(C)(C)C
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)OS(=O)(=O)OC1(C)C
Yield: 36 %

Procedure:
The parent compound 1,3,2-dioxathiolane 2,2-dioxide (ethylene cyclic sulfate) was prepared by Baker and Field from 1,2-dibromoethane and silver sulfate in 23% yield whereas the reaction failed with 1,2-dibromopropane (Baker, W., Field, F. B., J. Chem. Soc., 1932, 86). Alternatively, ethylene sulfate is obtained by the treatment of glycol diacetate with dimethyl sulfate (Breslow, D. S., Skolnik, H., In Heterocyclic Compounds Interscience: 1966, p1 and references cited therein). Unlike the synthesis of ethylene sulfite from ethylene glycol and thionyl chloride or ethylene oxide and sulfur dioxide (vide supra), the corresponding reaction with sulfuryl chloride or sulfur trioxide gave only low yields of ethylene sulfate. Thus, the treatment of ethylene glycol with sulfuryl chloride gave only 4% yield of ethylene sulfate (Pritchard, J. G.; Lauterbur, P. C., J. Am. Chem. Soc., 1961, 83, 2105). Several cyclic sulfates of sugars and other polyhydroxylated compounds have been prepared with sulfuryl chloride and pyridine (Bragg, P. D.; Jones, J. K. N.; Turner, J. C., Can. J. Chem., 1959, 37, 1412, and Jones, J. K. N.; Perry, M. B.; Turner, J. C., Can. J. Chem., 1960, 38, 1122), however, the reaction has never been clean and several side products were isolated. For example, D-mannitol and dulcitol yielded tetrachloro-substituted cyclic sulfates (Robertson, F. M.; Neish, A. C., Can. J Res. 1947, 25B, 491). This is apparently due to the chlorinating nature of sulfuryl chloride (Tewson, T. J., J. Org. Chem., 1983, 48, 3507, Tabushi, I.; Kitaguchi, H., In Synthetic Reagents, Pizey, J. S., Ed.; Ellis Horwood: Chichester, 1981, 4, 336). Similarly, the reaction of liquid sulfur trioxide with pinacolone gave only 36% yield of 4,4,5,5-tetramethyl-1,3,2-dioxathiolane 2,2-dioxide (Sheehan, J. C.; Zoller, U., J. Org. Chem., 1974, 39, 3415). Garner and Lucas prepared trans-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide by oxidizing the corresponding cyclic sulfite prepared from (R,R)-(-)-2,3-butanediol with calcium permanganate (Garner, H. K.; Lucas, H. J., J. Am. Chem. Soc., 1950, 72, 5497). The cis isomer was prepared using meso-2,3-butanediol (Robertson, F. M.; Neish, A. C., Can. J. Res., 1947, 25B,491, Lichtenberger, J.; Hinckey, J., Bull. Soc. Chim. Fr., 1961, 1495). Similarly, tetramethylene sulfate (Baker, W.; Burrow, B. F., J. Chem. Soc., 1961, 2257) and cyclohexane 1,2-cyclic sulfate (Brimacombe, J. S.; Foster, A. B.; Hanwek, E. B.; Overend, W. G.; Staceus, M., J. Chem. Soc., 1960, 201) were prepared by oxidizing the corresponding cyclic sulfites in moderate yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][CH2:10][OH:11].CC(C)=O>C(N(CC)CC)C>[OH:11][CH2:10][CH2:9][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCNCC1
Reactant: OCCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN1CCN(CCO)CC1
Yield: 75 %

Procedure:
N-methyl-piperazine (10 g, 100 mmoles) and 2-chloroethanol (8.5 g,100 mmoles) are stirred at 100° C. for 4 hours. 250 ml of acetone are added to the very viscous reaction mixture and the resulting suspension is neutralised with 15 ml of triethylamine. After filtration of the triethylammonium chloride, the solvent is evaporated under reduced pressure. The desired compound is obtained after purification by chromatography on an alumina column (eluent:ethyl acetate) as a colourless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH2:16]([O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)[CH3:17]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:13]([O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:23]3[CH:24]=[CH:25][C:20]([C:19]([O:18][CH2:16][CH3:17])=[O:27])=[CH:21][CH:22]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)([CH3:15])[CH3:14]
Reactant: C#Cc1ccc(C2(OC(C)C)CC2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 66, 114.0 mg, 0.57 mmol) and ethyl-4-iodo benzoate (Reagent A, 731.0 mg, 0.63 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (36.0 mg, 0.19 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (133 mg, 0.19 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 151.0 mg (76%) of the title compound as an orange solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH2:10]([Sn](CCCC)(CCCC)C=C)[CH2:11]CC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH:10]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)=[CH2:11]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C#N)cn1
Temperature: 25 °C
Yield: 113.9 %

Procedure:
A 100 mL round bottom flask equipped with a condenser was charged with 6-Chloro-nicotinonitrile (500 mg, 3.61 mmol), Pd(PPh3)4 (42 mg, 0.036 mmol), PPh3 (28.4 mg, 0.11 mmol), toluene (20 mL) and tributyl-vinyl-stannane (1.37 g, 4.33 mmol) under argon. The mixture was heated to reflux for three hours, then cooled to RT, quenched with water (12 mL), and extracted with EtOAc (30 mL) three times. The organic layer was combined and dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (5% EtOAc/Hexane) to afford compound 384A as a light yellow oil (535 mg). HPLC retention time=1.43 min. (condition A), M+=131.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]=[O:12])=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C>C(Cl)Cl.CCCCCC>[CH2:13]([O:1][C:2]1[C:3]([CH:11]=[O:12])=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cc2c(cc1O)CCO2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCCCC
Product: O=Cc1cc2c(cc1OCc1ccccc1)CCO2
Temperature: 0 °C
Yield: 78.7 %

Procedure:
A 2-liter, 3-neck flask equipped with a nitrogen inlet, internal thermometer, mechanical stirrer, and reflux condenser was charged with 5-hydroxy-2,3-dihydrobenzofuran-6-carboxaldehyde (50.00 g; 0.30 moles), benzylbromide (38.6 ml, 0.34 moles), and crushed anhydrous K2CO3 (165.84 g, 1.20 moles). The reaction mixture was refluxed for 16 hours, cooled to room termperature and suction filtered. The filtrate was concentrated in vacuo to afford a yellow solid. The solid was dissolved in methylene chloride (600 ml) and washed sequentially with 0.5 N sodium hydroxide solution (3×250 ml) and brine (2×250 ml). The organic phase was dried over MgSO4, suction filtered, and the filtrate concentrated in vacuo to yield a crude solid (85 g). The solid was dissolved in methylene chloride (300 ml)/n-hexane (200 ml), treated with charcoal and suction filtered through a bed of celite. The filtrate was evaporated in vacuo to approximately 300 ml and slowly cooled to 0° C. to produce yellowish flat needles (60 g, 78%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]12[CH2:17][CH2:16][CH:15]1[CH2:14][NH:13][CH2:12]2.C(N(CC)CC)C>O1CCOCC1>[CH:11]12[CH2:17][CH2:16][CH:15]1[CH2:14][N:13]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH2:12]2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C1CC2CNCC12
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(N2CC3CCC3C2)nc1
Temperature: 65 °C
Yield: 87.6 %

Procedure:
A mixture of 0.1 g (0.63 mmol) of 2-chloro-5-nitropyridine, 0.1 g (0.75 mmol) of 3-aza-bicyclo[3.2.0]heptane (J. Med. Chem. 1967, 10(4), 621) and 0.26 mL (0.19 mmol) of triethylamine in 10 mL of dioxane, is heated at 65° C. for 4 h. The reaction mixture is then poured into 50 mL of ice water. The mixture is stirred until the ice has melted completely, then a yellow precipitate is collected by filtration and is dried at reduced pressure. In this way we isolate 0.121 g of the expected product in the form of a yellow powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH:10](C2C=CC=CC=2)[C:9]2[C:4](=CC(=O)NC=2)[CH2:3]1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:26][N:27]([CH3:31])[CH2:28]2)=[CH:23][N:22]=1.[CH3:38][Si](Cl)(C)C.[Na+].[I-]>CC#N>[CH3:31][N:27]1[CH2:26][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:19][CH2:38][CH2:1][N:2]3[CH2:11][CH2:10][CH2:9][CH2:4][CH2:3]3)=[N:22][CH:23]=2)[CH2:28]1
Reactant: COc1cc2c(cn1)C(c1ccccc1)CN(C)C2
Reactant: CN1Cc2cc(=O)[nH]cc2C(c2ccccc2)C1
Reactant: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN1Cc2cc(OCCCN3CCCCC3)ncc2C(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
6-Methyl-8-phenyl-5,6,7,8-tetrahydro-2H-[2,6]naphthyridin-3-one. A 0° C. solution of 7-methoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydro-[2,6]naphthyridine (74.5 mg, 0.293 mmol) in CH3CN (1 mL) was treated with TMSCl (1 mL) and NaI (˜10 mg). The resulting mixture was stirred at 0° C. for 30 min, then at 50° C. for 18 h. The mixture was concentrated, diluted with satd. aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated. 1H NMR indicated ˜30% conversion to the desired product. The material was diluted with CH3CN (2 mL), treated with TMSCl (1 mL) and NaI (˜10 mg) and heated at 60° C. for 18 h. The mixture was concentrated, neutralized with satd. aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated. The crude mixture was chromatographed (SiO2; 1-10% 2 M NH3 in MeOH/DCM) to give the title compound (29.6 mg, 42%). 1H NMR (CDCl3): 7.33-7.23 (m, 3H), 7.20-7.16 (m, 2H), 6.83 (s, 1H), 6.26 (s, 1H), 4.06-4.00 (m, 1H), 3.73 (d, J=15.9, 1H), 3.40 (d, J=15.2, 1H), 3.03-2.97 (m, 1H), 2.46 (dd, J=11.6, 10.0, 1H), 2.41 (s, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[OH:26]OS([O-])=O.[K+]>C(Cl)(Cl)Cl>[O-:26][N+:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=2)=[O:13])[CH:1]=1
Reactant: O=S([O-])OO
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2cnccc12
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2c[n+]([O-])ccc12
Yield: 10.5 %

Procedure:
To a suspension of N-isoquinolin-5-yl-N′-[4-(trifluoromethyl)benzyl]urea (Example 14; 100 mg, 0.29 mmol) in chloroform (25 ml) was added Oxone (541 mg, 0.87 mmol), followed by wet alumina Grade III (1 g), and the resulting suspension heated at reflux for 60 minutes. Whilst the mixture was still hot it was filtered to remove alumina and Oxone, the solids were washed with more chloroform, then methanol, and the filtrate evaporated to dryness. The residue was purified by preparative TLC eluting with 10% MeOH in dichloromethane+0.5% NH4OH, and the product triturated with a mixture of dichloromethane/iso-hexanes, filtered and dried to give the title compound (11 mg, 10%) as a white solid. m/z (ES+) 362 (M+H)+.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[CH3:7][O:8][C:9]([C:11]1[N:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=2)=[O:10].BrC(C)C>CS(C)=O>[CH3:7][O:8][C:9]([C:11]1[N:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13]2[C:18]([C:19]=1[O:20][CH:2]([CH3:3])[CH3:1])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=2)=[O:10]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1c(O)c2cc(OC)ccc2n1-c1ccccc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)Br
Product: COC(=O)c1c(OC(C)C)c2cc(OC)ccc2n1-c1ccccc1
Reaction time: 0.75 h

Procedure:
A stirred mixture of 24.8 g (0.22 mole) of potassium tert-butoxide in 100 ml of dimethyl sulfoxide (under a nitrogen atmosphere) was placed in a cold water bath. A solution of 44.6 g (0.15 mole) of 3-hydroxy-5-methoxy-1-phenyl-1H-indole-2-carboxylic acid methyl ester [P. C. Unangst and M. E. Carethers, J. Heterocyclic Chem., 21, 709 (1984)] in 100 ml of dimethyl sulfoxide was added over 30 minutes. The new mixture was stirred for an additional 45 minutes, and 25.0 ml (32.8 g, 0.27 mole) of 2-bromopropane was added in one portion. The cooling bath was removed, and the mixture was stirred at room temperature for 45 hours, then added to 2.5 kg ice water. The crude ester intermediate was removed by extracting with dichloromethane (4×800 ml). The combined organic layers were washed with water (1×2.0 l), 5% aqueous sodium bicarbonate (2×2.0 l), and water again (1×2.0 l), before being dried with anhydrous sodium sulfate. Evaporation (vacuum) yielded a crude residue of 5-methoxy-3-(1-methylethoxy)-1-phenyl-1H-indole-2-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:29]([C:32](=O)[CH2:33]Br)=[CH:28][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([NH2:39])(=[S:38])[CH3:37].C(=O)([O-])O.[Na+].C(O)C>O>[CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:29]([C:32]2[N:39]=[C:36]([CH3:37])[S:38][CH:33]=2)=[CH:28][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:25])[F:26])[CH:15]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: CC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccc(OCc3ccccc3)c(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2)cs1
Yield: 67.5 %

Procedure:
A mixture of 2-benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)-phenyl]benzamide (280 mg, 0.5 mmol), thioacetamide (41 mg, 0.55 mmol), sodium hydrogen carbonate (50 mg, 0.6 mmol) and ethanol (15 mL) was refluxed for 1 hour. The reaction mixture was poured into water, neutralized by sodium hydrogen carbonate, and extracted with ethyl acetate. After the organic layer was washed with water and saturated brin, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound (181 mg, 67.5%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:12]2([CH:17]=[CH:16][C:15](=[O:18])[CH:14]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:13]2[OH:27])[CH2:11][C:10]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31](C#N)=[O:32].C1N2C[CH2:42][N:37](CC2)C1>>[CH2:1]([O:8][N:9]1[C:12]2([CH:17]=[CH:16][C:15]([C:42]#[N:37])([O:18][C:31]([O:30][CH3:29])=[O:32])[CH:14]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[CH:13]2[O:27][C:31]([O:30][CH3:29])=[O:32])[CH2:11][C:10]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CN2CCN1CC2
Reactant: COC(=O)C#N
Reactant: CC(C)(C)[Si](C)(C)OC1C(=O)C=CC2(CC(=O)N2OCc2ccccc2)C1O
Product: COC(=O)OC1C(O[Si](C)(C)C(C)(C)C)C(C#N)(OC(=O)OC)C=CC12CC(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 874.9 %

Procedure:
To a mixture of rac-(4R,5S,6S)-1-benzyloxy-6-tert-butyldimethylsilyloxy-5-hydroxy-1-azaspiro[3.5]nona-8-ene-2,7-dione (3) (95 mg, 0.235 mmol) and methylcyanoformate (169 μl, 2.115 mmol) was added at room temperature DABCO (3 mg, 0.023 mmol). The mixture was stirred at room temperature for 14 h and then concentrated under reduced pressure. The residue was triturated with Et2O, filtered and the solvent was evaporated under reduced pressure to give rac-(4R,5S,6S,7S)-1-benzyloxy-7-cyano-6-tert-butyldimethylsilyloxy-5,7-bis(methoxycarbonyloxy)-1-azaspiro[3.5]nona-8-ene-2-one (9) as a brown oil (110 mg, 86%), was used in the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=3)[O:12]2)=[C:4]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[N:3]=1.[N:31]1([CH2:37][CH2:38][NH2:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.CS(C)=[O:42]>>[CH:18]([OH:22])=[O:42].[CH2:23]([C:20]1[N:19]=[C:18]([C@@H:13]2[C@@H:14]([OH:17])[C@@H:15]([OH:16])[C@H:11]([N:8]3[CH:7]=[N:6][C:5]4[C:9]3=[N:10][C:2]([NH:39][CH2:38][CH2:37][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[N:3][C:4]=4[NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[O:12]2)[O:22][N:21]=1)[CH3:24]
Reactant: NCCN1CCCCC1
Reactant: CS(C)=O
Reactant: CCc1noc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Product: CCc1noc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)n1
Product: O=CO
Temperature: 80 °C

Procedure:
Intermediate 9 (0.070 g, 0.161 mmol) and 2-piperidinoethylamine (0.115 ml, 0.807 mmol) were dissolved in DMSO (0.03 ml) and heated at 80° C. in a sealed vial (eg Reacti vial™), for 40 h, a further portion of 2-piperidinoethylamine (0.057 ml, 0.403 mmol) was added after the first 20 h. The product was purified by Autoprep. HPLC to give the title compound after freeze drying as a brown gum (0.035 g). LC/MS system B Rt=2.33 min, m/z=530 MH+.
Reaction SMILES: [CH2:1]([Si:11]([CH3:14])([CH3:13])O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].CN(C)C=O.C(Cl)([Cl:22])=O>ClCCCl>[CH2:1]([Si:11]([CH3:14])([CH3:13])[Cl:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC[Si](C)(C)O
Reactant: O=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCCCCCCC[Si](C)(C)Cl
Yield: 88 %

Procedure:
To the same reactor as used in Example 1 were added 54.1 g (0.25 mole) of decyldimethylsilanol, 215 g of 1,2-dichloroethane and 1.83 g (0.025 mole) of N,N-dimethylformamide, and 27.2 g (0.275 mole) of phosgene was introduced into the resulting mixture at a temperature of from 40° to 45° C. over 2 hours with stirring. After completion of the introduction, the same procedure as in Example 7 was carried out to obtain 51.7 g of decyldimethylchlorosilane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18](O)=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:44][C@@H:45]([C:48]1[CH:49]=[N:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=1)[CH2:46][OH:47].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:47][CH2:46][C@@H:45]([NH:44][C:18]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=1)=[O:19])[C:48]1[CH:49]=[N:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)cc1
Reactant: COc1ccc([C@H](N)CO)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc([C@@H](CO)NC(=O)c2cc(-c3ccc(C)cc3)cc(S(C)(=O)=O)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(methylsulfonyl)biphenyl-3-carboxylic acid (35 mg, 0.12 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (46 mg, 0.24 mmol), 1-hydroxybenzotriazole hydrate (18 mg, 0.12 mmol), and CH2Cl2 (3 mL) were added (S)-2-amino-2-(6-methoxypyridin-3-yl)ethanol (30 mg, 0.18 mmol) and N,N-diisopropylethylamine (42 μL, 0.24 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-80% CH3CN-water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:7]([CH:13]2[CH2:15][CH2:14]2)=[N:8][NH:9][C:10]=1[CH2:11][CH3:12])C.C(OC(=O)C[C:24]1[C:25]([CH2:31][CH3:32])=N[NH:27][C:28]=1[CH2:29][CH3:30])(C)(C)C.CCC(=O)CC(=O)CC.C(OC(=O)CC1C(C2CCCCC2)=NNC=1C)(C)(C)C>>[NH2:27][C:28]1[CH:24]=[CH:25][C:31]([CH2:32][N:9]2[C:10]([CH2:11][CH3:12])=[C:6]([CH2:5][C:4]([OH:3])=[O:16])[C:7]([CH:13]3[CH2:14][CH2:15]3)=[N:8]2)=[CH:30][CH:29]=1.[NH2:27][C:28]1[CH:24]=[CH:25][C:31]([CH2:32][N:8]2[C:7]([CH:13]3[CH2:14][CH2:15]3)=[C:6]([CH2:5][C:4]([OH:3])=[O:16])[C:10]([CH2:11][CH3:12])=[N:9]2)=[CH:30][CH:29]=1
Reactant: CCc1n[nH]c(CC)c1CC(=O)OC(C)(C)C
Reactant: CCOC(=O)Cc1c(C2CC2)n[nH]c1CC
Agent: CCC(=O)CC(=O)CC
Agent: Cc1[nH]nc(C2CCCCC2)c1CC(=O)OC(C)(C)C
Product: CCc1c(CC(=O)O)c(C2CC2)nn1Cc1ccc(N)cc1
Product: CCc1nn(Cc2ccc(N)cc2)c(C2CC2)c1CC(=O)O

Procedure:
The following examples can be prepared in analogous fashion to example 2.7, employing in the alkylation step (3-cyclopropyl-5-ethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (preparation according to the preparation of (3,5-diethyl-1H-pyrazol-4-yl)-acetic acid tert-butyl ester, WO2007/141267, employing 2-cyclopropyl-6-ethyl-3,5-dione instead of heptane-3,5-dione) instead of (3-cyclohexyl-5-methyl-1H-pyrazol-4-yl)-acetic acid tert-butyl ester and employing in the amide coupling the corresponding carboxylic acids as coupling partners. Each example is a single regioisomer; the required intermediates [1-(4-amino-benzyl)-3-cyclopropyl-5-ethyl-1H-pyrazol-4-yl]-acetic acid and [1-(4-amino-benzyl)-5-cyclopropyl-3-ethyl-1H-pyrazol-4-yl]-acetic acid are obtained in a single reaction and are separable by MPLC.
Reaction SMILES: [C:1]12([O:8][C:7]3[CH:9]=[CH:10][C:11]([C:13]4([C:16]([O:18]C)=[O:17])[CH2:15][CH2:14]4)=[CH:12][C:6]=3[O:5]1)[CH2:4][CH2:3][CH2:2]2.[Li+].[OH-].Cl>C1COCC1.O>[C:1]12([O:8][C:7]3[CH:9]=[CH:10][C:11]([C:13]4([C:16]([OH:18])=[O:17])[CH2:15][CH2:14]4)=[CH:12][C:6]=3[O:5]1)[CH2:2][CH2:3][CH2:4]2
Reactant: COC(=O)C1(c2ccc3c(c2)OC2(CCC2)O3)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(c2ccc3c(c2)OC2(CCC2)O3)CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 58.3 %

Procedure:
To a mixture of methyl 1-(spiro[benzo[d][1,3]dioxole-2,1′-cyclobutane]-5-yl)cyclopropanecarboxylate (0.60 g, 2.3 mmol) in THF/H2O (4:1, 10 mL) was added LiOH (0.30 g, 6.9 mmol). The mixture was stirred at 60° C. for 24 h. HCl (0.5 N) was added slowly to the mixture at 0° C. until pH 2-3. The mixture was extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine, dried over anhydrous MgSO4, and washed with petroleum ether to give 1-(spiro[benzo[d][1,3]-dioxole-2,1′-cyclobutane]-5-yl)cyclopropane carboxylic acid (330 mg, 59%). 1HNMR (400 MHz, CDCl3) δ 6.78-6.65 (m, 3H), 2.65-2.58 (m, 4H), 1.86-1.78 (m, 2H), 1.63-1.60 (m, 2H), 1.26-1.19 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH2:13]([NH2:15])[CH3:14].C(O)C>>[BrH:1].[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:15][CH2:13][CH3:14])=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: CCN
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Solvent: CCO
Product: Br
Product: CCNCCc1ccc([N+](=O)[O-])cc1

Procedure:
1-Bromo-2-(4-nitrophenyl)ethane (Aldrich, 10 g, 50 mmol) was stirred overnight at ambient temperature with a solution of ethylamine in ethanol (33%, 25 ml, ~180 mmol). The orange solution was evaporated to leave a crystalline residue. The solid material was collected with the aid of ethanol (10 ml). Concentration of the filtrate yielded a second batch of product, identical on t.l.c., which was combined with the first.