Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[S:2]([C:5]1[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]([Br:13])[C:6]=1[NH2:7])(=[O:4])=[O:3].[CH3:14][Li]>CCOCC>[Br:13][C:8]1[CH:9]=[C:10]([Br:12])[CH:11]=[C:5]([S:2]([CH3:14])(=[O:4])=[O:3])[C:6]=1[NH2:7]
Reactant: [Li]C
Reactant: Nc1c(Br)cc(Br)cc1S(=O)(=O)F
Solvent: CCOCC
Product: CS(=O)(=O)c1cc(Br)cc(Br)c1N
Temperature: 0 °C

Procedure:
A solution of 2-fluorosulfonyl-4,6-dibromoaniline (7.19 g; 0.0216 mol) in ether (100 ml) is cooled to -65° C. under a nitrogen atmosphere and a solution of methyllithium in ether (37.5 ml of 1.8 M; 0.0675 mol) is added via a syringe. The mixture is allowed to warm to 0° C., the solution is poured into ice, and the ether layer is separated. The aqueous layer is extracted with ether (3×100 ml) and the ether layers are combined. The solvent is removed under reduced pressure and the residue crystallized from petroleum ether to afford the title product.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:5]2[C:16](=[O:26])[CH:17]([NH:18][C:19](=[O:25])[CH2:20][C:21](=[O:24])[CH2:22][Br:23])[C@H:4]2[S:3]1.O.[N:28]([O-])=[O:29].[Na+]>C(O)(=O)C.O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:13])([Cl:15])[Cl:14])=[O:9])[N:5]2[C:16](=[O:26])[CH:17]([NH:18][C:19](=[O:25])[C:20](=[N:28][OH:29])[C:21](=[O:24])[CH2:22][Br:23])[C@H:4]2[S:3]1
Reactant: O=N[O-]
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2S1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(=NO)C(=O)CBr)[C@H]2S1

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-7-(3-oxo-4-bromobutyramido)-3-cephem-4-carboxylate (2.54 g.) in glacial acetic acid (25 ml.) was added dropwise a solution of sodium nitrite hydrate (0.33 g.) in water (1 ml.) over 3 minutes with stirring at 10° to 15° C., and then the mixture was stirred for 1 hour at the same temperature. After the reaction mixture was poured into cold water (70 ml.), the precipitates were collected by filtration and then dried to give brown powder of 2,2,2-trichloroethyl 2-methyl-7-(2-hydroxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylate (a mixture of syn and anti isomers) (2.0 g.), mp 76° to 80° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:16]([N:19]1[CH2:23][CH2:22][CH:21](O)[CH2:20]1)([CH3:18])[CH3:17].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:21]1[CH2:22][CH2:23][N:19]([CH:16]([CH3:18])[CH3:17])[CH2:20]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)N1CCC(O)C1
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)C3)ccc2[nH]1

Procedure:
A mixture of 3.08 g (15 mmol) 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester, 2.51 g (20 mmol) 1-isopropyl-3-pyrrolidinol and 8.7 ml (30 mmol) tri-N-butyl phosphine in 75 ml was treated at room temperature with 7.57 g (30 mmol) 1,1′-(azodicarbonyl)-dipiperidine in 75 ml THF. The mixture was allowed to stir for a prolonged period of time and subsequently evaporated to dryness. The residue was suspended in 40 ml DCM/n-heptane 1/1, filtered and again washed with 40 ml DCM/n-heptane 1/1. The filtrate was evaporated and purified on silica eluting with a gradient of DCM/2N NH3 in methanol 99/1 to DCM/2N NH3 in methanol 93/7. The product fractions were evaporated and the residue was titurated with diethyl ether to yield after filtration, washing and drying of the residue at 50° C. under vacuum 2.1 g (44%) of the title compound as off-white solid. MS (m/e): 317.1 (MH+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].O.B1(C=C)OB([CH:29]=[CH2:30])OB(C=C)O1.C1C=CN=CC=1>C(COC)OC.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>[CH:29]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=2)[CH:3]=1)=[CH2:30]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: COC(=O)c1ccc2cc(Br)ccc2c1
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: [K+]
Solvent: COCCOC
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1ccc2cc(C(=O)OC)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
Methyl 6-bromo-2-naphthalene carboxylate (98 g) was dissolved in dimethoxyethane (2 1) and tetrakis(triphenylphosphine)palladium (44 g) was added in nitrogen atmosphere. The mixture was stirred for 30 minutes at room temperature. Potassium carbonate (52 g), water (1 1) and 2,4,6-trivinylcyclotriboroxane-pyridine complex (91 g) were added and the mixture was stirred for 24 hours while refluxing with heating. There action mixture was cooled to room temperature and treated with activated alumina to obtain methyl 2-vinyl-6-naphthalene carboxylate (77 g).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH2:6]1[CH:11]2[C:12]3[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=3[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:10]2[CH2:9][CH2:8][NH:7]1>C(O)C>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][N:7]1[CH2:8][CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][C:13]3[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=3[CH:11]2[CH2:6]1
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNCC21
Reactant: ClCC1CO1
Solvent: CCO
Product: OC(CCl)CN1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.9 %

Procedure:
0.832 g of epichlorohydrin was added to a mixture of 4.5 ml of ethanol and 1.5 g of 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine, whilst ice-cooling, and the mixture was stirred at room temperature for 5 hours. At the end of this time, it was concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 1.56 g (yield 76%) of the title compound as a colorless foam.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)([Cl:17])=[O:16]>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:15]([Cl:17])=[O:16])[CH2:4][CH2:3]1
Reactant: O=C(Cl)Cl
Reactant: CC1CCNCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
9 g (90.75 mmol) of 4-methylpiperidine and 13.9 ml (100 mmol) of triethylamine were added at −30° C. to 54.9 ml (100 mmol) of phosgene in toluene (20 percent) and 100 ml of THF and, after stirring for 2.5 h, the reaction mixture was allowed to warm to room temperature. The reaction mixture was concentrated and the residue was mixed with methylene chloride and filtered off, and the filtrate was concentrated. The crude product (12.7 g) was reacted without further purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[O:40]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41]1>O1CCCC1.O>[F:3][C:4]1[C:9]([C:10]2[N:14]([S:45]([C:42]3[CH:43]=[CH:44][O:40][CH:41]=3)(=[O:47])=[O:46])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH:11]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=S(=O)(Cl)c1ccoc1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccoc2)c1)C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 72.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 48 mg) in tetrahydrofuran (2 mL) were added dropwise a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (244 mg) in tetrahydrofuran (1 mL), 15-crown-5 (266 mg) and furan-3-sulfonyl chloride (147 mg) under ice-cooling and the mixture was stirred for 1.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:1) to give the title compound as a pale-yellow oil (yield 253 mg, 73%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C([N-]C(C)C)(C)C.[Li+].IC>O1CCCC1>[F:13][C:14]([F:22])([F:23])[CH2:15][CH:16]([CH3:1])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CCC(F)(F)F
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A solution of diisopropylamine (19.5 mL) in tetrahydrofuran (200 mL) at 0° C. was treated with n-butyllithium (71 mL, 1.5M in hexanes). The resulting solution was stirred for 30 minutes at 0° C., then was cooled to -70° C. A solution of ethyl 4,4,4-trifluorobutyrate (14 mL) in tetrahydrofuran (150 mL) was slowly added to the lithium diisopropylamide solution and the resulting mixture was stirred at -70° C. for 30 minutes. A solution of iodomethane (11.5 mL) in tetrahydrofuran was added in one portion, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched with water and evaporated. The residue was dissolved in methylene chloride, washed (10% (w/v) hydrochloric acid, water, and brine), dried (MgSO4), filtered, and evaporated. The resulting pale yellow liquid was purified by distillation to yield ethyl 4,4,4-trifluoro-2-methylbutyrate as a colorless liquid (7.8 g, 46%); bp 125°-128 ° C.; partial NMR: (300 MHz, CDCl3): 1.30 (m, 6H, CH3), CH2CH3), 2.15 (m, 1H, H-C(3)), 2.64 (m, 1H, H-C(3)), 2.72 (m, 1H, H-C(2)), 4.16 (q, 2H, OCH2).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[BH3-]C#N.[Na+]>CO>[C:21]([O:20][C:18]([N:12]1[CH2:17][CH2:16][N:15]([CH2:1][C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=2)[C:6]([OH:8])=[O:7])[CH2:14][CH2:13]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)O)c2)CC1
Temperature: 27 °C
Reaction time: 6 h
Yield: 54.6 %

Procedure:
The solution of 3-formylbenzoic acid (300 mg, 1.83 mmol) and tert-butyl piperazine-1-carboxylate (340 mg, 1.83 mmol) in MeOH (10 mL) was stirred at 27° C. for 1 h. Then NaBH3CN (138 mg, 2.19 mmol) was added to the solution and stirred at 27° C. for 6 h. The solution was concentrated and the residue was purified by column to give the title product (320 mg, Yield 50%). LCMS (m/z): 321.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+].Cl[C:21]1[N:26]=[C:25]2[O:27][C:28]([C:30]3[CH:35]=[C:34]([CH3:36])[C:33]([O:37][CH3:38])=[C:32]([CH3:39])[CH:31]=3)=[N:29][C:24]2=[CH:23][CH:22]=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:21]1[N:26]=[C:25]2[O:27][C:28]([C:30]3[CH:35]=[C:34]([CH3:36])[C:33]([O:37][CH3:38])=[C:32]([CH3:39])[CH:31]=3)=[N:29][C:24]2=[CH:23][CH:22]=1
Reactant: Oc1ccccc1F
Reactant: COc1c(C)cc(-c2nc3ccc(Cl)nc3o2)cc1C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1c(C)cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc1C
Temperature: 180 °C

Procedure:
In a microwaveable vessel, 0.75 g of 5-chloro-2-(4-methoxy-3,5-dimethylphenyl)oxazolo[5,4-b]pyridine were dissolved in 12 ml of absolute N,N-dimethylformamide, and 0.30 g of 2-fluorophenol and 1.02 g of cesium carbonate were added. In a microwave reactor, the reaction was heated at 180° C. for 45 min. For work-up, the mixture was added to saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium bisulaite solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by precipitation from acetonitrile, giving, from solid and mother liquor, a total of 0.52 g (55%) of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13]([C:15]1[N:16]=[CH:17][C:18]2[NH:19][C:20]3[C:25]([C:26]=2[C:27]=1[CH2:28][O:29][CH3:30])=[CH:24][C:23]([OH:31])=[CH:22][CH:21]=3)=[O:14])[CH3:11]>N1C(C)=CC(C)=CC=1C.[Cu-]=O>[CH2:10]([O:12][C:13]([C:15]1[N:16]=[CH:17][C:18]2[NH:19][C:20]3[C:25]([C:26]=2[C:27]=1[CH2:28][O:29][CH3:30])=[CH:24][C:23]([O:31][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[CH:22][CH:21]=3)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(O)cc3c2c1COC
Reactant: COc1ccc(Br)cc1
Agent: O=[Cu-]
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)c1ncc2[nH]c3ccc(Oc4ccc(OC)cc4)cc3c2c1COC
Reaction time: 35 h
Yield: 41.9 %

Procedure:
0.2 g of 4-methoxybromobenzene, 0.3 g of 6-hydroxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, and 0.15 g of copper(I) oxide are heated in 5 ml of collidine to boiling for 35 hours. After cooling, the mixture is filtered and evaporated under vacuum. The residue is taken up in ethyl acetate, extracted repeatedly with ice-cold 25% ammonia solution and then washed with saturated sodium chloride solution, dried over calcium sulfate, and evaporated. Chromatography on silica gel with methylene chloride-ethanol (10:1) yields 0.17 g of 6-(4-methoxyphenoxy)-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, mp 154.0° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[F:9][C:10]([F:22])([F:21])[C:11]([NH:13][C@@H:14]1[C:19](=[O:20])[O:18][C:16](=[O:17])[CH2:15]1)=[O:12].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[F:9][C:10]([F:21])([F:22])[C:11]([NH:13][C@@H:14]([CH2:15][C:16](=[O:17])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([F:8])[CH:4]=1)[C:19]([OH:20])=[O:18])=[O:12]
Reactant: Fc1ccccc1F
Reactant: O=C1C[C@H](NC(=O)C(F)(F)F)C(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C[C@H](NC(=O)C(F)(F)F)C(=O)O)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 45.6 %

Procedure:
To an ice-cooled solution of 1,2-difluorobenzene (25 ml; 0.256 mol) in dry dichloromethane (170 ml), (S)-N-trifluoroacetylaspartic anhydride (12 g.; 0.054 mol) was added in one portion. To the resulting solution, anhydrous aluminium trichloride (21.5 g; 0.16 mol.) was slowly added portionwise, under vigorous stirring and dry nitrogen atmosphere, maintaining the temperature below 10° C. The so obtained deep-yellow suspension was stirred at room temperature for 3 hrs. and then at 50° C. for 5 hrs. The resulting reaction mixture was then poured into ice (400 g), and extracted with dichlorometane (3×100 ml), the collected organic extracts were washed with brine (2×50 ml ), dried (Na2SO4), and evaporated in vacuum to afford the crude product (7.3 g) as an oily material. Recrystallisation from hexane/ethyl ether afforded the pure titled compound as colourless prisms (8 g; 47%), m.p. 136°-137° C.
Reaction SMILES: [Cl-].[Li+].[BH4-].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]2[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([O:35][C@H:36]3[C@H:40]4[O:41][CH2:42][CH:43]([CH2:44][C:45](OCC)=[O:46])[C@H:39]4[O:38][CH2:37]3)=[N:24][C:9]2=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>C(O)C>[Cl:5][C:6]1[CH:7]=[C:8]2[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([O:35][C@H:36]3[C@H:40]4[O:41][CH2:42][CH:43]([CH2:44][CH2:45][OH:46])[C@H:39]4[O:38][CH2:37]3)=[N:24][C:9]2=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)CC1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@@H]3C(CCO)CO[C@@H]32)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Reaction time: 2.5 h

Procedure:
Lithium chloride (2 mg, 0.047 mmol) and sodium borohydride (90 mg, 2.38 mmol) were added to a solution of ethyl 2-[(3aR,6R,6aS)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxy-methyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]acetate (133 mg, 0.205 mmol) in ethanol (2.0 mL). After 2.5 hours, additional sodium borohydride (34 mg, 0.9 mmol) was added and the mixture was stirred for an additional 20 hours. The mixture was partitioned between ethyl acetate (20 mL)/1N aqueous HCl (4.5 mL) and water (5 mL). The organic layer was washed with brine (1×5 mL), dried with MgSO4, filtered and the solvents were removed under vacuum. The crude residue was purified on preparative silica gel plates (1×1000 u prep tlc—developed with 5% methanol/DCM and eluted with 10% methanol/DCM) to give the title compound. C32H38ClN3O5Si 607.23 observed m/e: minor isomer 608.23 (M+H)+ (Rt 0.98/2 min) and major isomer 608.23 (M+H)+ (Rt 1.04/2 min)
Reaction SMILES: ClC1C=C(C=CC=1Cl)C([NH:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N+:44]([C:47]1[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=1[CH:49]=O)([O-:46])=[O:45].C(=O)(O)[O-].[Na+]>ClCCl.C(O)(=O)C>[N+:44]([C:47]1[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=1[CH2:49][NH:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:9]1)([O-:46])=[O:45]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccc(Cl)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1Nc2ccccc2C(c2ccccc2)=NC1NCc1ccccc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 72.5 %

Procedure:
A solution of Intermediate 3 (50 mg) and sodium (triacetoxy)borohydride (106 mg) in dichloromethane (6 ml) and acetic acid (1 ml) was treated with 2-nitro-benzaldehyde (45 mg). The resulting mixture was stirred under nitrogen for 18 h. Saturated sodium bicarbonate solution was carefully added, and the mixture extracted with dichloromethane. The organic layer was passed through a hydrophobic frit, and evaporated. The residue was then purified on a silica gel SPE cartridge. Gradient elution with 10-18% ethyl acetate in petrol gave the title compound as a colourless solid (33 mg) LC/MS RT=4.83 min Found ES+=387
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][N:9]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[N:10]2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[N:3]=1>[Pd].CO>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2n1CCn1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: Cc1nc2ccccc2n1CCn1cc(N)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a round bottom flask was added 2-methyl-1-(2-(4-nitro-1H-pyrazol-1-yl)-ethyl)-1H-benzoimidazole (5.23 g, 19.28 mmol), Pd/C (523 mg) and MeOH (100 mL, degassed). The flask was evacuated and backfilled with H2 and the reaction mixture was stirred under H2-atmosphere at rt for 5 h. The reaction mixture was filtered over celite, washed with MeOH and the solvent was removed under reduced pressure. Purification was performed by dissolving the desired compound at 40° C. in DCM (60 mL) and filtering off the insoluble impurities. By adding heptane (150 mL) to the remaining solution, the title compound precipitated out as a pink solid. LC-MS conditions B: tR=0.17 min, [M+H]+=242.00.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)CC(CCCC(F)(F)F)c2ccc(Br)cc2)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(CCCC(F)(F)F)c2ccc(Br)cc2)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-7,7,7-trifluoro-heptanoyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 14% of the corresponding Z isomer as a colorless solid, MS (ESI+): m/z=445.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2=[C:7]([C:13](O)=[O:14])[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:4]2[O:3]1.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2=[C:7]([C:13]([Cl:19])=[O:14])[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:4]2[O:3]1
Reactant: COc1ccc(C(=O)O)c2c1OC(C)(C)C2
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Cl)c2c1OC(C)(C)C2

Procedure:
0.8 g of 2,3-dihydro-2,2-dimethyl-7-methoxybenzofuran-4-carboxylic acid is heated to boiling under reflux for 1 h in a mixture of 50 ml of abs. toluene and 3 ml of thionyl chloride. The solvent is distilled off in a rotary evaporator and toluene (about 30 ml) is then added a further 2 times and the mixture is concentrated again. The residue is dried in a high vacuum and employed in Example 1 without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:4][OH:5].[CH3:12][O:13][CH:14]([OH:19])[C:15](OC)=O.C(O)(=O)C>CO.[Pd]>[CH:6]1([CH:3]([CH2:4][OH:5])[CH2:2][NH:1][CH2:15][C:14]([O:13][CH3:12])=[O:19])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NCC(CO)C1CCCCC1
Reactant: COC(=O)C(O)OC
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CNCC(CO)C1CCCCC1
Yield: 53.4 %

Procedure:
A solution of 3-amino-2-cyclohexyl-1-propanol (1 g, 6.37 mmole) and methyl glyoxylate methylhemiacetal (790 mg, 6.56 mmole; see Tetrahedron, 881, 1977) in methanol (9 ml) was stirred at room temperature under argon for 24 hours. The resulting solution was transferred to a Parr bottle, treated with additional methanol (22 ml), acetic acid (3.6 ml), and 10% Pd on carbon (857 mg) and hydrogenated at 50 psi overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo. Acetic acid was removed by evaporation from toluene. The residue was partitioned between ethyl acetate and 1N HCl. The organic layer was extracted with additional HCl and the combined aqueous extracts were washed with ethyl acetate. The pH of the product rich aqueous solution was raised to 10.2, and sodium chloride was added to saturation. Extraction with ethyl acetate followed by drying (sodium sulfate), filtration and concentration in vacuo produced 780 mg (53%) of the title compound as an oil.