Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CS(C)=O.[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([CH2:18]OC)[O:16]C>>[CH2:7]([O:16][CH2:15][C:18]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COCCOC
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
S-α,β-Isopropylidene glycerol (2.53 g, 0.0191M) was added dropwise to a stirred slurry of sodium hydride (1.08 g of a 50% dispersion in oil, 0.021M) in dry dimethoxyethane (15 ml) containing dry dimethylsulphoxide (3 ml). The reaction mixture was stirred at room temperature for 0.25 hours and then treated with benzyl chloride (2.66 g, 0.021 M). The reaction mixture was heated at 80° C. for 3 hours. The solvent was evaporated off under reduced pressure and the residue was treated with water and extracted with ether. The combined extracts were dried (MgSO4) and the solvent was evaporated off under reduced pressure to give the crude S-α,β-isopropylidene glycerol, benzyl ether. The crude product was dissolved in acetone (4 ml) and treated with hydrochloric acid (2 ml of 1 Ml-1) and heated at 70° C. for 2 hours. The solvent was evaporated off under reduced pressure and the residue was dissolved in ethyl acetate (120 ml), washed with saturated aqueous sodium hydrogen carbonate solution and dried (MgSO4). The solvent was evaporated off under reduced pressure to give the crude product which was further purified by chromatography (silica gel, 10% ethanol in chloroform) to give R-1-benzyloxy-2,3-dihydroxypropane (3.2 g) as an oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:45](=[O:46])[N:13]3[C:14]([C:29]([O:31][CH:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])=[C:15]([CH2:19][S:20][C:21]4[N:25]([CH2:26][C:27]#[CH:28])[N:24]=[N:23][N:22]=4)[CH2:16][S:17](=O)[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.P(Cl)(Cl)Cl>O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:45](=[O:46])[N:13]3[C:14]([C:29]([O:31][CH:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])=[C:15]([CH2:19][S:20][C:21]4[N:25]([CH2:26][C:27]#[CH:28])[N:24]=[N:23][N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: C#CCn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Temperature: -30 °C
Reaction time: 0.67 h
Yield: 89 %

Procedure:
A mixture of benzhydryl 7-(2-phenylacetamido)-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate-1-oxide (9.3 g) and dry N,N-dimethylformamide (93 ml) was cooled to -30° C. and thereto was added phosphorus trichloride (3.9 g). The resulting solution was stirred for 40 minutes at -30° C. The reaction mixture was allowed to warm to ambient temperature, added to water (150 ml) and then extracted with ethyl acetate (×3). The extracts were combined, washed successively with a saturated aqueous solution of sodium bicarbonate (×2) and water (×3), dried over magnesium sulfate, treated with activated charcoal and then evaporated. The residue was pulverized in a mixture of isopropyl ether and n-hexane, collected by filtration, washed with n-hexane and then dried to give benzhydryl 7-(2-phenylacetamido)-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (8.07 g).
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Br-].[CH2:16]([C:19]1[C:27]2[O:26][N:25]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:23]=2[CH:22]=[CH:21][C:20]=1[O:34][CH2:35][CH2:36][CH2:37]Br)[CH2:17][CH3:18].C(C1C2ON=C(C3C=CC=CC=3)C=2C=CC=1O)CC>>[CH3:1][C:2]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:6][C:5](=[O:7])[N:4]([CH2:37][CH2:36][CH2:35][O:34][C:20]2[CH:21]=[CH:22][C:23]3[C:24]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:25][O:26][C:27]=3[C:19]=2[CH2:16][CH2:17][CH3:18])[C:3]1=[O:8]
Reactant: CC1(c2ccccc2)NC(=O)NC1=O
Reactant: CCCc1c(OCCCBr)ccc2c(-c3ccccc3)noc12
Agent: CCCc1c(O)ccc2c(-c3ccccc3)noc12
Agent: [Br-]
Product: CCCc1c(OCCCN2C(=O)NC(C)(c3ccccc3)C2=O)ccc2c(-c3ccccc3)noc12

Procedure:
rac-5-Methyl-5-phenyl-3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione was prepared as for Example 10 from 5-methyl-5-phenylimidazolidine-2,4-dione and the appropriate bromide. The bromide, 7-propyl-3-phenyl-6-(3-bromopropyloxy)-1,2-benzisoxazole, was prepared as for Example 7 using the 7-propyl-3-phenyl-6-hydroxy-1,2-benzisoxazole prepared in Example 6.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:2]=12.C(Cl)(=O)C(Cl)=O.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:23][CH2:22]1>C(Cl)Cl.CN(C)C=O>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:23][CH2:22]3)=[O:12])[CH:8]=[CH:9][C:2]=12
Reactant: NCC1CCN(CCc2ccccn2)CC1
Reactant: O=C(O)c1ccc2nonc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCC1CCN(CCc2ccccn2)CC1)c1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a suspension of benzofurazan-5-carboxylic acid (150 mg, 0.91 mmol) in methylene chloride (3.3 ml) was added dimethylformamide (1 drop) followed by dropwise addition of oxalyl chloride (89 μl, 1.0 mmol). The resulting solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The brown oil was redissolved in methylene chloride (3.3 ml) and was added to a cooled (0° C.) solution of 4-(aminomethyl)-1-(2-pyridylethyl)piperidine (0.21 g, 0.95 mmol) in methylene chloride (1.6 ml). The reaction mixture was stirred at 0° C. for 11/2 hours. Solvent evaporation, flash chromatography (silica gel, chloroform-methanol-ammonium hydroxide, 95/5/1/2) and trituration with hexane-ethyl acetate gave 4-[N-(benzofurazan-5-carbonyl)aminomethyl]-1-(2-pyridylethyl)piperidine (133 mg, 40%);
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[N+:7]([O-:9])=[O:8].[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O>C(Cl)Cl>[O:1]([CH2:2][CH2:3][O:4][CH2:5][C:6]([N+:13]([O-:15])=[O:14])([N+:7]([O-:9])=[O:8])[N+:10]([O-:12])=[O:11])[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])C(COCCO)([N+](=O)[O-])[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=[N+]([O-])OCCOCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The dried solution of 2,2,2-trinitroethyl 2-hydroxyethyl ether produced in example 3 was diluted to 200 ml with methylene chloride and this solution was slowly added with cooling below 5° C. (ice bath) to a vigorously stirred nitrating solution (prepared by slowly adding 136 ml of 90% nitric acid to 272 ml of concentrated sulfuric acid with cooling). The nitration mixture was vigorously stirred at room temperature for 3 hours before it was poured onto ice. The organic layer was separated, washed with 3×100 ml of water, dried over magnesium sulfate and allowed to stand in a hood to evaporate volatiles to give 75 g (65%) of essentially pure 2,2,2-trinitroethyl 2-nitroxyethyl ether (TNEN). The TNEN can be further purified by dissolving it in 300 ml of diethyl ether, adding 300 ml of hexanes, cooling the solution in a dry ice-acetone bath until it begins to cloud, adding seed crystals, continuing cooling in the dry ice-acetone bath for 20 minutes, removing the crystals by filtration through a precooled filter funnel, washing the crystals with cold (-40° C.) hexanes and quickly redissolving the cold crystals into methylene chloride. The pure product has mp 10°-11° C.; 1H NMR (CDCl3): δ4.10 (m,2H), 4.70 (m,2H) 4.88 (s,2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[C:17]([C:20]1SC(CC(O)=O)=C(C2C=CC=CC=2)[N:24]=1)([CH3:19])[CH3:18].C(N1C=CN=C1)(N1C=CN=C1)=O.C1(CO)CCCCC1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[C:17]([CH3:19])([CH3:18])[C:20]#[N:24]
Reactant: CC(C)(c1nc(-c2ccccc2)c(CC(=O)O)s1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: OCC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C#N)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 113.6 %

Procedure:
A mixture of intermediate (10) (0.00387 mole) and 1,1′-carbonylbis-1H-imidazole (0.0058 mole) in dichloromethane (40 ml) was stirred at RT for 90 minutes, then cyclohexylmethanol (0.0058 mole) was added. The mixture was stirred at RT overnight, diluted with CH2Cl2 and washed twice with an aqueous solution of NaCl. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/EtOAc 50/50). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from EtOAc. The precipitate was filtered off, washed with DIPE and dried at 50° C. overnight, yielding 1.43 g of compound 7 with a molecular weight of 613.5, a melting point of 180° C. and represented by the formula wherein R14 is cyclohexylmethyl.
Reaction SMILES: [CH2:1]([C:3]([C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[C:27]([CH3:40])[CH:26]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH3:24])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:41][O:42][C:43](=[O:52])[CH2:44][C:45]1[CH:50]=[CH:49][C:48](Br)=[CH:47][N:46]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[CH3:41][O:42][C:43](=[O:52])[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:28]2[CH:29]=[CH:30][C:25]([C:3]([CH2:1][CH3:2])([C:6]3[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]4([O:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[CH2:18][CH2:17][CH2:16][CH2:15]4)=[C:8]([CH3:24])[CH:7]=3)[CH2:4][CH3:5])=[CH:26][C:27]=2[CH3:40])=[CH:47][N:46]=1
Reactant: COC(=O)Cc1ccc(Br)cn1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)nc2)c(C)c1
Yield: 31.1 %

Procedure:
A solution of 2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 32-(4); 60.8 mg, 0.10 mmol), (5-bromo-pyridin-2-yl)acetic acid methyl ester (Example 44-(2); 43.5 mg, 0.18 mmol), tetrakistriphenylphosphine palladium (17.3 mg, 0.015 mmol) and potassium phosphate (34.1 mg, 0.16 mmol) in N,N-dimethylformamide (0.6 mL) was stirred at 85° C. for four hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% ethyl acetate/hexane to 60% ethyl acetate/hexane) to give the title compound (18.1 mg, 28%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH3:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[C:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([OH:31])=[O:30].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:35]3[CH:36]=[CH:37][C:32]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=3)=[CH:7][CH:6]=2)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:22]([CH3:28])[CH:23]=1
Reactant: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 166, step 1, 5-{3-(4-bromo-phenyl)-3-(4-chloro-2-methyl-phenyl)-1-[(E)-hydroxyimino]-propyl}-1-methyl-1H-pyridin-2-one (example 226, step 4) was reacted with 4-carboxyphenylboronic acid in the presence of dichloro(1,1′-bis(diphenylphosphino) ferrocene)palladium(II) dichloromethane adduct in a mixture of 1,4-dioxane, water and 2 M aqueous sodium carbonate solution to give the title compound containing 10% of the corresponding Z isomer as a light brown solid, MS (ESI+): m/z=501.16 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C@@H:6]3[CH2:20][O:21][CH2:22][CH2:23][N:5]3[C:4]=2[N:3]=1.[NH:24]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[C:27]=2[CH:26]=[CH:25]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.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>[NH:24]1[C:32]2[C:27](=[C:28]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C@@H:6]5[CH2:20][O:21][CH2:22][CH2:23][N:5]5[C:4]=4[N:3]=3)[CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21
Temperature: 120 °C
Yield: 89.1 %

Procedure:
A mixture of (R)-tert-butyl 2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetate (PREPARATION x24, 100 mg, 0.293 mmol), indole-4-boronic acid (70.8 mg, 0.440 mmol), tetrakis(triphenylphosphine)palladium(0) (33.9 mg, 0.029 mmol) and sodium carbonate (62.2 mg, 0.587 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) was heated to 120° C. for 30 minutes in a microwave. After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered through Celite, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 20-80% EtOAc/hexane gradient) to afford the title compound as an off-white solid (110 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 9 H), 3.07-3.36 (m, 3 H), 3.42-3.51 (m, 1 H), 3.62-3.79 (m, 3 H), 3.93 (dd, J=10.86, 3.28 Hz, 1 H), 4.01-4.16 (m, 2 H), 4.77 (dd, J=13.39, 2.02 Hz, 1 H), 7.22-7.31 (m, 2 H), 7.39-7.46 (m, 2 H), 7.66 (s, 1 H), 8.01 (dd, J=7.45, 0.88 Hz, 1 H), 8.26 (br s, 1H). ESI-MS m/z [M+H]+ calc'd for C23H27N5O3, 422.21; found 422.3.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=O)C.CO.[OH-].[Na+]>O1CCCC1>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:12]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[N:9]1[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]1
Reactant: CCOC(=O)N1CCN(C(c2ccc(Cl)cc2)c2ccccc2Cl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Clc1ccc(C(c2ccccc2Cl)N2CCNCC2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 62.3 %

Procedure:
To a stirred solution of 0.9 gram (0.002 mole) of N-(ethoxycarbonyl)-N′-[(2-chlorophenyl)(4-chlorophenyl)methyl]piperazine in 10 mL of tetrahydrofuran was added 10 mL of methanol and 10 mL of aqueous 50% sodium hydroxide. Upon completion of the addition the reaction mixture was warmed to 80° C., where it stirred for 24 hours. At the end of this time the reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in chloroform, and the solution was stirred for 40 minutes. The resulting precipitate was collected by filtration. The filtrate was concentrated under reduced pressure, yielding 0.6 gram of crude material. The crude material was purified by preparative thin layer chromatography (TLC). Elution was accomplished with 1:1 acetone: methanol. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.4 gram of N′-[(2-chlorophenyl)(4-chlorophenyl)-methyl]piperazine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[F:35])#[N:28]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:31]2[CH:32]=[CH:33][C:34]([F:35])=[C:29]([C:27]#[N:28])[CH:30]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: N#Cc1cc(B(O)O)ccc1F
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(F)c(C#N)c2)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3-cyano-4-fluoro-phenylboronic acid, 5-(3-cyano-4-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=66%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C.O>[N:13]1([CH2:2][CH2:3][O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=Cc1ccccc1OCCCl
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCN1CCCC1
Yield: 55 %

Procedure:
A solution of 2-(2-chloroethoxy)benzaldehyde (40; 2.5 g, 13.5 mmol), pyrrolidine (172; 1.9 g, 26.8 mmol), K2CO3 (3.8 g, 27.2 mmol) and NaI (0.6 g, 4.2 mmol) in DMF (50 mL) was stirred at 80° C. for 12 h. Water (200 mL) was added and the mixture was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed brine (3×50 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (dichloromethane:methanol=100:1) to give 2-(2-(pyrrolidin-1-yl)ethoxy)benzaldehyde 41 (1.63 g, 7.43 mmol, 55%) as a pale yellow solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:34]([O:38][C:39](=[O:46])[NH:40][C@@H:41]1[CH2:45][CH2:44][NH:43][CH2:42]1)([CH3:37])([CH3:36])[CH3:35].[Br:47][C:48]1[CH:49]=[N:50][C:51]([N:54]2[C:62]3[C:57](=[CH:58][CH:59]=[C:60]([C:63](O)=[O:64])[CH:61]=3)[C:56]([S:66][CH3:67])=[CH:55]2)=[N:52][CH:53]=1>CN(C=O)C>[Br:47][C:48]1[CH:49]=[N:50][C:51]([N:54]2[C:62]3[C:57](=[CH:58][CH:59]=[C:60]([C:63]([N:43]4[CH2:44][CH2:45][C@@H:41]([NH:40][C:39](=[O:46])[O:38][C:34]([CH3:37])([CH3:35])[CH3:36])[CH2:42]4)=[O:64])[CH:61]=3)[C:56]([S:66][CH3:67])=[CH:55]2)=[N:52][CH:53]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)O)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
HATU (2.41 g, 6.363 mmol), diisopropylethylamine (3.02 ml, 17.355 mmol) and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (1.18 g, 6.363 mmol) were added to an ice cooled suspension of 223a) (2.1 g, 5.787 mmol) in DMF (20 mL). The resulting mixture was stirred at room temperature for 16 h and then diluted with ice cold water (40 mL). The precipitate was filtered off, washed with water and hexane (3 times) and dissolved in dichloromethane. The solution was successively washed with saturated ammonium chloride solution (2×30 mL), saturated sodium hydrogen solution (2×30 mL), and brine (30 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was triturated with ether. White solid. Yield: 3 g (97% of theory)
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([OH:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1>C(OCC)C.[Ag]=O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C@H:14]([O:19][CH2:2][CH:3]2[CH2:5][CH2:4]2)[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](O)Cc1ccc(Br)cc1
Reactant: BrCC1CC1
Agent: O=[Ag]
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)OCC1CC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 121.8 %

Procedure:
0.11 ml (1.15 mmol) of bromomethylcyclopropane are added to a mixture of 267 mg (3.48 mmol) of silver oxide and 100 mg (0.38 mmol) of methyl (S)-3-(4-bromophenyl)-2-hydroxypropionate in 2 ml of diethyl ether. The reaction mixture is stirred at 50° C. for 24 hours. The mixture is filtered and then the solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 85/15). 145 mg of methyl (S)-3-(4-bromophenyl)-2-(cyclopropylmethoxy)propanoate are obtained in the form of an oil. Yield=50%.
Reaction SMILES: [O:1]1CCCC1.B.[O:7]1[C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:11][CH:10]=[CH:9][CH2:8]1.[OH-].[Na+].OO>O1CCCC1.C(OCC)C.O>[OH:1][CH:9]1[CH2:10][CH2:11][C:12]2([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)[O:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC=CCO2)CC1
Reactant: C1CCOC1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CCC(O)CO2)CC1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 24.3 %

Procedure:
Borane tetrahydrofuran complex (1M in tetrahydrofuran, 23.68 mL, 23.68 mmol) was added dropwise to a solution of 1,1-dimethylethyl 1-oxa-9-azaspiro[5.5]undec-3-en-9-carboxylate (Description 131, 2.0 g, 7.89 mmol) in tetrahydrofuran (30 mL) and the mixture was stirred at room temperature for 6.5 hours. Water (25 mL), aqueous sodium hydroxide (4M, 25 mL) and hydrogen peroxide (37%, 25 mL) were added and the mixture was stirred at room temperature for 20 minutes. Water (100 mL) and diethyl ether (100 mL) were added and the layers were separated. The aqueous fraction was extracted with diethyl ether (100 mL) and the combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate. The residue was purified by MPLC on silica gel, eluting with ethyl acetate, to give 1,1-dimethylethyl 3-hydroxy-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate (520 mg, 24%); 1H NMR (360 MHz, CDCl3) δ 3.76–3.71 (4H, m), 3.50–3.45 (1H, m), 3.16–3.07 (2H, m), 1.92–1.85 (3H, m), 1.75–1.63 (2H, m), 1.46 (9H, s), and 1.45–1.35 (3H, m); and 1,1-dimethylethyl 4-hydroxy-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate (200 mg, 9%);. 1H NMR (400 MHz, CDCl3) δ 4.02–3.93 (1H, m), 3.87–3.83 (1H, m), 3.75–3.71 (2H, m), 3.57 (1H, dt, J 2.3, 11.7 Hz), 3.19 (1H, t, J 11.3 Hz), 3.03 (1H, t, J 11.7 Hz), 1.95–1.87 (2H, m), 1.86–1.81 (1H, m), 1.68–1.65 (1H, m), 1.57–1.47 (2H, m), 1.45 (9H, s), and 1.41–1.28 (2H, m).