Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([CH2:10][CH2:11]Br)[C:3]([NH:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[O:4].[OH-].[Na+]>ClCCl>[Br:1][CH:2]1[CH2:10][CH2:11][N:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]1=[O:4]
Reactant: CC(C)CNC(=O)C(Br)CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)CN1CCC(Br)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4.48 g (14.9 mmol) rac-2,4-Dibromo-N-isobutyl-butyramide were dissolved in 40 ml dichloromethane, then 17.3 ml of 50% sodium hydroxide solution and 0.48 g Dowex 2×10 were added. The mixture was stirred vigorously for 4 h at room temperature. Afterwards the mixture was poured into 50 ml ice/water an the phases were separated. The aqueous phase was extracted thrice with 20 ml dichloromethane, and the combined organic phases were washed once with 20 ml water, once with 20 ml brine and dried over magnesium sulfate. After evaporation of the solvent, the resulting colourless oil was chromatographed or silica gel (0.040-0.063 mm) with ethyl acetate/n-hexane 1:1 as eluent.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[NH:5][C:4](=[O:13])[C:3]=1[C:14]1[NH:18][C:17]2[CH:19]=[C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:21]=[CH:22][C:16]=2[N:15]=1.[F:29][C:30]([F:37])([F:36])[C:31](OCC)=[O:32]>CN(C)C(=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[NH:5][C:4](=[O:13])[C:3]=1[C:14]1[NH:18][C:17]2[CH:19]=[C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:31](=[O:32])[C:30]([F:37])([F:36])[F:29])[CH2:25][CH2:24]3)[CH:21]=[CH:22][C:16]=2[N:15]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: Nc1c(-c2nc3ccc(N4CCNCC4)cc3[nH]2)c(=O)[nH]c2cccc(F)c12
Solvent: CC(=O)N(C)C
Product: Nc1c(-c2nc3ccc(N4CCN(C(=O)C(F)(F)F)CC4)cc3[nH]2)c(=O)[nH]c2cccc(F)c12
Temperature: 130 °C

Procedure:
4-Amino-5-fluoro-3-(6-piperazin-1-yl-1H-benzoimidazol-2-yl)-1H-quinolin-2-one was taken up in ethyl trifluoroacetate and N,N-dimethylacetamide (DMA). The resulting solution was heated at 130° C. in a sealed tube for 30 minutes. The reaction was cooled to room temperature and quenched by addition of saturated aqueous sodium bicarbonate followed by pouring the mixture into water. The resulting solid was collected by filtration and washed with diethyl ether to afford 4-amino-5-fluoro-3-{6-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-1H-benzoimidazol-2-yl}-1H-quinolin-2-one (Rt 2.63 minutes, MH+=457.1), which was immediately taken up in THF. Borane-THF complex (3.3 equivalents) was added and the reaction was stirred at room temperature overnight. After quenching the excess borane with water, the mixture was extracted into ethyl acetate, dried over magnesium sulfate, filtered and concentrated to a brown solid which was purified by reverse phase HPLC to yield the desired compound. MH+=461.1.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:20]([NH:22][C@@H:23]([C:25]([NH:27][CH2:28][C@H:29]([NH2:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[CH3:24])=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])=O)(C)(C)C.Cl>O1CCOCC1>[CH3:19][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[CH2:10][C@@H:9]([C:20]([NH:22][C@@H:23]([C:25]([NH:27][CH2:28][C@H:29]([NH2:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[CH3:24])=[O:21])[NH2:8]
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NC[C@H](N)Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(O)cc(C)c1C[C@H](N)C(=O)N[C@H](C)C(=O)NC[C@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.9 %

Procedure:
N-(tert-Butoxycarbonyl)-2,6-dimethyl-L-tyrosyl-N-{(2R)-2-amino-3-phenylpropyl}-D-alaninamide (203 mg, 0.36 mmol) was dissolved in 1 mL dioxane and hydrogen chloride (4M solution in dioxane, 1 mL, 4 mmol) added and the mixture stirred at room temperature for 16 h. The mixture was evaporated under reduced pressure and the residue purified by preparative HPLC and then freeze dried to provide the title compound (83 mg, 56%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:44])([CH3:43])[CH2:34][O:35][Si](C(C)(C)C)(C)C)=[CH:29][CH:28]=2)[S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)Cl>C1COCC1>[C:1]([O:5][C:6](=[O:45])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([CH3:44])([CH3:43])[CH2:34][OH:35])=[CH:31][CH:32]=2)[S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(C(C)(C)CO[Si](C)(C)C(C)(C)C)cc2)S(=O)(=O)c2cccnc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(C(C)(C)CO)cc2)S(=O)(=O)c2cccnc2)c1
Temperature: 25 °C
Yield: 62.2 %

Procedure:
To a solution of (3-{[{4-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-benzyl}-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic acid tert-butyl ester (210 mg, 0.321 mmol) in THF (2 mL) was added tetrabutylammonium fluoride (1M in THF, 0.34 mL, 0.34 mmol). The reaction was heated at reflux for 1 h and additional tetrabutylammonium fluoride (1M in THF, 0.34 mL, 0.34 mmol) was added. The reaction was heated at reflux for 24 h and additional tetrabutylammonium fluoride (1M in THF, 0.34 mL, 0.34 mmol) was added. The reaction was heated for 45 minutes and was cooled to room temperature. Water and CH2Cl2 were added and the layers were separated. The aqueous solution was washed with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered and concentrated. Medium pressure chromatography (1:1 hexanes:EtOAc to 3:2 EtOAc: hexanes) provided (3-{[[4-(2-hydroxy-1,1-dimethyl-ethyl)-benzyl]-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic acid tert-butyl ester (108 mg). MS 541 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[OH:9][N:10]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12]([NH:14][CH3:15])=[O:13].Cl[CH2:23][C:24]1[N:29]=[C:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=[CH:26][CH:25]=1>C(#N)C.CN(C=O)C>[CH3:15][NH:14][C:12](=[O:13])[C:11](=[N:10][O:9][CH2:23][C:24]1[N:29]=[C:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH:27]=[CH:26][CH:25]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNC(=O)C(=NO)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CNC(=O)C(=NOCc1cccc(NC(=O)OC(C)(C)C)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
37.4 g (114 mmol) of caesium carbonate and 0.91 g, (5.47 mmol) of potassium iodide were added to a solution of 10.7 g (60.1 mmol) of 2-(hydroxyimino)-N-methyl-2-phenylacetamide (81:19 mixture of the Z and E diastereoisomers) and 13.3 g (54.7 mmol) of tert-butyl [6-(chloromethyl)pyridin-2-yl]carbamate in 100 ml of acetonitrile: DMF 75:25. After stirring for 3 h at room temperature, the mixture was concentrated by evaporation in vacuo and the residue was admixed with 250 ml of ethyl acetate. Then, 500 ml of water were added, the phases were separated and the aqueous phase was extracted again with 250 ml of ethyl acetate. The combined organic phases were dried with MgSO4 and concentrated by evaporation in vacuo. This gave 16.8 g (95% purity; 89:11 mixture of Z and E isomers) of tert-butyl {6-[({[2-(methylamino)-2-oxo-1-phenylethylidene]amino}oxy)methyl]pyridin-2-yl}carbamate.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][C:4]([CH3:14])([CH3:13])[CH2:5][NH:6][C:7](=[O:12])[CH2:8][CH2:9]OC.[OH-].[Na+]>>[CH3:15][N:2]([CH3:1])[CH2:3][C:4]([CH3:14])([CH3:13])[CH2:5][NH:6][C:7](=[O:12])[CH:8]=[CH2:9]
Reactant: COCCC(=O)NCC(C)(C)CN(C)C
Agent: [Na+]
Agent: [OH-]
Product: C=CC(=O)NCC(C)(C)CN(C)C
Temperature: 300 °C

Procedure:
A total of 820 g (3.8 moles) N-(N',N',2,2-tetramethyl-3-aminopropyl)-3-methoxypropionamide was fed continuously to an evaporator flask heated to 170° to 180° C., and the vapors were conducted under a vacuum of 14 millibars to a reaction tube 1 meter long and 3 cm in diameter which was heated externally, by means of a strip heater, to 300° C. and was filled with alumina beads impregnated with 10% sodium hydroxide. With a head temperature ranging from 150° to 220° C., about 475 g of a yellow oil was collected over a period of 2 hours, which for further purification was distilled once more in a high vacuum. 383 g (2.1 moles=52% of theory, based on 3-methoxypropionamide) of a product having a boiling point0.2 of 98° to 102° C. was obtained.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[OH:5].[OH-].[Na+]>CCO>[CH:11]1([C:4]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)([OH:5])[C:3]([OH:17])=[O:2])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)C(O)(c1ccco1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(O)(c1ccco1)C1CCCCC1
Reaction time: 1 h

Procedure:
1 g (0.0042 mol) of 2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid methyl ester was dissolved in 12 ml of EtOH and 6 ml of a solution of NaOH 2N were added. This mixture was stirred at 600 for 1 hour. After this time, the EtOH was evaporated and the residue was acidified with HCl 10%. The aqueous solution was extracted with AcOEt (2×100 ml). The organic layers were combined, dried and evaporated to obtain a residue (2-cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid) which was used without further purification. The acid obtained was dissolved in dry DMF (12 ml) and 0.817 g (0.005 mol) of 1,1′-carbonildimidazol were added. The mixture was stirred for 1 h at room temperature. After this time the sodium salt of 1-ethylpyrrolidin-3-ol (prepared by addition of HNa (0.1 g, 0.0046 mol) to a solution of 1-ethylpyrrolidin-3-ol (0.5319, 0.0046 mol) in 5 ml of dry DMF) was added. After stirring 15 h at room temperature the reaction mixture was treated with water, and the aqueous phase was extracted with Et2O (2×100 ml). The organic phases were combined, washed with water and dried. After removal of the solvent the product obtained was purified by chromatography on silica gel eluting with chloroform plus isopropanol (5%→15%). The yield was 460 mg (34% related to starting methyl ester) of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:22][CH2:23][N:24]3[CH:29]4[CH2:30][CH2:31][CH:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[S:42]([NH2:45])(=[O:44])=[O:43].[C:46](Cl)(=[O:50])[CH:47]([CH3:49])[CH3:48]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:11][CH2:12][C:13]([CH2:22][CH2:23][N:24]3[CH:29]4[CH2:30][CH2:31][CH:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)=[O:9])=[CH:4][C:3]=1[S:42]([NH:45][C:46](=[O:50])[CH:47]([CH3:49])[CH3:48])(=[O:43])=[O:44]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)CC1
Reactant: CC(C)C(=O)Cl
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccc(Cl)c(S(=O)(=O)NC(=O)C(C)C)c2)CC1
Yield: 80 %

Procedure:
2-Chloro-N-isobutyryl-5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene-sulfonamide (19 mg, 80%) was obtained as amorphous solid from 2-chloro-5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzenesulfonamide and isobutyryl chloride following the procedure outlined in example 476. 1H NMR (300 MHz, DMSO-d6, 100° C.) δ 7.85-7.76 (m, 2H), 7.60-7.50 (m, 2H), 7.42-7.28 (m, 5H), 7.26 (m, 1H), 7.18-7.12 (m, 2H), 4.76 (br, 1H), 3.36-3.08 (m, 7H), 2.53-2.27 (m, 7H), 2.04-1.82 (m, 10H), 1.69 (d, J=7.6 Hz, 2H), 0.95 (d, J=6.6 Hz, 6H). HRMS m/z (M+H)+ calcd: 716.3037, obsd: 716.3013.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[C:22]2[O:21][CH:20]=[CH:19][O:18][C:17]=2[CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl>ClCCl>[CH:12]([C:13]1[C:22]2[O:21][CH:20]=[CH:19][O:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)=[O:11]
Reactant: OCc1cccc2c1OC=CO2
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cccc2c1OC=CO2
Reaction time: 0.25 h

Procedure:
A solution of 1.27 g (10.05 mmol) of oxalyl chloride in 30 ml of anhydrous dichloromethane is cooled to -60° C. and then 1.57 g (20.1 mmol) of dimethyl sulphoxide are added to the mixture. After 5 minutes' stirring under an inert atmosphere, 1.1 g of 5-hydroxymethyl-1,4-benzodioxin (6.7 mmol) dissolved in 15 ml of dichloromethane are slowly added to the mixture which is then stirred for a further 15 minutes. 4.66 ml (33.5 mmol) of triethylamine are subsequently added to the mixture which is then allowed to return to room temperature. The solution is then acidified with a 1N hydrochloric acid solution and the aqueous phase is subsequently extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrated under reduced pressure. The title aldehyde is obtained pure in the form of a yellow solid after passage over a silica column (eluant:AcOEt/PE:10/90).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[N+:18]([O:21][CH:22]1[O:29][CH:28]2[CH:24]([O:25][CH2:26][C@@H:27]2O)[CH2:23]1)([O-:20])=[O:19].Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][C@@H:27]1[CH2:26][O:25][CH:24]3[CH:28]1[O:29][CH:22]([O:21][N+:18]([O-:20])=[O:19])[CH2:23]3)=[O:15])[CH:7]=[CH:6]2
Reactant: O=[N+]([O-])OC1CC2OC[C@H](O)C2O1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)O[C@@H]3COC4CC(O[N+](=O)[O-])OC43)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 1 g, 4.43 mmol) and (2S)-7-(nitrooxy)-4,8-dioxabicyclo(3.3.0) octan-2-ol (isosorbide 5-mononitrate, 1 g, 5.21 mmol) in anhydrous dichloromethane (25 mL) were added 1-(3-(dimethylamino) propyl)-3-ethylcarbodiimide hydrochloride (EDAC, 1.17 g, 1.4 eq) and a catalytic amount of N,N-dimethylaminopyridine (DMAP) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 and washed H2O, brine, dried over sodium sulfate, filtered, and the organic extracts were evaporated. The product was purified by column chromatography on silica gel eluting with EtOAc:hexane (3:7 to 1:1) to give the title compound (1.71 g, 97.6% yield) as a white crystalline solid. Mp 112-113° C. 1H NMR (300 MHz, CDCl3) δ 7.67 (m, 3H), 7.37 (m, 1H), 7.14 (m,2H), 5.26 (m, 2H), 4.78 (t, J=5.2 Hz, 1H), 4.21 (d, J=4.9 Hz, 1H), 4.02-3.77 (m, 5H), 3.92 (s, 3H), 1.56 (d, 3H, J=7.1 Hz); LRMS (APIMS) m/z 404 (MH+).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[C:17]([CH2:23][C:24]3[CH:33]=[CH:32][C:27]4[O:28][CH2:29][CH2:30][O:31][C:26]=4[CH:25]=3)[CH:16]=2)[O:8][CH:7]([O:34][CH3:35])[C@H:6]1[O:36]C(=O)C)(=O)C.[OH-].[Li+]>CO.C1COCC1.O>[O:28]1[C:27]2[CH:32]=[CH:33][C:24]([CH2:23][C:17]3[CH:16]=[C:15]([C@H:9]4[C@H:10]([OH:11])[C@@H:5]([OH:4])[C@H:6]([OH:36])[C@@H:7]([O:34][CH3:35])[O:8]4)[CH:20]=[CH:19][C:18]=3[CH2:21][CH3:22])=[CH:25][C:26]=2[O:31][CH2:30][CH2:29]1
Reactant: CCc1ccc([C@@H]2OC(OC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1Cc1ccc2c(c1)OCCO2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCc1ccc([C@@H]2O[C@H](OC)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
Step-IV: To a stirred solution of acetic acid (3S,4R,5S,6S)-4,5-diacetoxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-2-methoxy-tetrahydro-pyran-3-yl ester (300 mg, 0.55 mmol) in methanol:THF:water (3:2:1 mixture, 6 ml) was added lithium hydroxide (46 mg, 1.10 mmol). After stirring for 2 h at room temperature, volatiles were evaporated under reduced pressure. The resulting residue was taken in ethyl acetate (10 ml) and washed with brine (5 ml), brine containing 1 ml of 5% aqueous KHSO4 (5 ml), brine (5 ml), dried over sodium sulfate, concentrated and purified by preparative HPLC to furnish 90 mg (2S,3R,4R,5S,6S)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol as white solid. 1H NMR (400 MHz, CD3OD): δ 0.56-0.58 (m, 2H), 0.84-0.87 (m, 2H), 1.80-1.85 (m, 1H), 3.27-3.44 (m, 3H), 3.48 (s, 3H), 4.05 (d, J=6.4 Hz, 2H), 4.10 (d, J=9.3 Hz, 1H), 4.17 (s, 4H), 4.30 (d, J=7.8 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.69 (d, J=8.4 Hz, 2H), 6.98 (d, J=7.8 Hz, 1H), 7.16-7.19 (m, 2H). MS (ES) m/z 446.3 (M+18).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[S:17][C:18]([C:24]#[C:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:26]([C:25]#[C:24][C:18]1[S:17][C:16]([NH:15][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:7]=2)=[C:20]([C:21]([NH2:23])=[O:22])[CH:19]=1)([C:29]([CH3:31])([CH3:32])[CH3:30])([CH3:28])[CH3:27]
Reactant: Brc1cccc(CN2CCOCC2)n1
Reactant: CC(C)(C)[Si](C)(C)C#Cc1cc(C(N)=O)c(N)s1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)[Si](C)(C)C#Cc1cc(C(N)=O)c(Nc2cccc(CN3CCOCC3)n2)s1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-[(6-Bromopyridin-2-yl)methyl]morpholine (Example 45, Step 1) (340 mg, 1.32 mmol), 2-amino-5-{[tert-butyl(dimethyl)silyl]ethynyl}thiophene-3-carboxamide (445 mg, 1.59 mmol), Pd2dba3 (121 mg, 0.13 mmol), X-Phos (315 mg, 0.66 mmol), and K2CO3 (201 mg, 1.46 mmol) were combined in a vial, sealed, and evacuated/backfilled with nitrogen. Degassed t-amyl alcohol (3.3 ml), and the reaction was vigorously stirred at 100° C. overnight. The reaction mixture was then diluted with MeOH, combined with silica, and evaporated. Flash chromatography (dry load, 0-10% MeOH/EtOAc) afforded the title compound as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][O:13][C:9]=2[C:8]=1[Cl:23])C.Cl>O>[Cl:23][C:8]1[C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[C:10]=2[CH:21]=[CH:22][C:7]=1[O:6][CH2:5][C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)COc1ccc2c(-c3ccc(Cl)cc3)noc2c1Cl
Agent: Cl
Solvent: O
Product: O=C(O)COc1ccc2c(-c3ccc(Cl)cc3)noc2c1Cl
Reaction time: 0.5 h

Procedure:
A mixture of 25 g of ethyl{[7-chloro-3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, Example 14, and 20 ml of 50% The hot mixture is diluted with 300 ml of water and then acidified with concentrated hydrochloric acid. The acidified mixture is stirred for 30 minutes and then filtered and the filter cake is recrystallized from a dimethylformamide-ethylacetate mixture to yield the product {[7-chloro-3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid having a melting point of 254° to 257° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.Cl[Si:12]([CH3:15])([CH3:14])[CH3:13]>N1C=CC=CC=1.C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([Si:12]([CH3:15])([CH3:14])[CH3:13])=[O:7])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[Si](C)(C)C(=O)c1ccc(N)nc1
Reaction time: 6 h

Procedure:
6-Aminonicotinic acid (86 mg, 0.6 mmol) was taken up in 0.65 mL pyridine and 10 mL CH2Cl2. Chlorotrimethylsilane (0.65 mL, 7 mmol) was added and the mixture stirred for 6 h. Solvent was evaporated and the product was used without purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]([C@H:15]3[O:27][C@@H:26]([CH2:28][O:29]C(=O)C)[C@H:21]([O:22]C(=O)C)[C@@H:16]3[O:17]C(=O)C)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O.CO>C(O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]([C@H:15]3[O:27][C@@H:26]([CH2:28][OH:29])[C@H:21]([OH:22])[C@@H:16]3[OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(NC(C)C)nc3c(Cl)cccc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CC(C)Nc1nc2c(Cl)cccc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 68.4 %

Procedure:
4-Chloro-2-(isopropylamino)-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (2.24 g, 4.79 mmol), sodium carbonate (0.67 g, 6.32 mmol), water (7 mL), methanol (14 mL) and ethanol (20 mL) were used according to general procedure III. The product was purified by silica gel chromatography using 10:1 dichloromethane/methanol to afford 1.12 g (68%) of a white solid: m.p. 225-227° C. Anal. calcd for C15H20ClN3O4: C, 52.77; H, 5.91; N, 12.32. Found: C, 52.79; H, 5.96; N, 12.25.
Reaction SMILES: [CH3:1][N:2]([NH:4][C:5]([C:7]1[N:8]([CH3:13])[CH:9]=[C:10]([NH2:12])[N:11]=1)=[O:6])[CH3:3].[CH3:14][N:15]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=[C:16]1[C:23](Cl)=[O:24]>C1COCC1.C(Cl)Cl>[CH3:3][N:2]([NH:4][C:5]([C:7]1[N:8]([CH3:13])[CH:9]=[C:10]([NH:12][C:23]([C:16]2[N:15]([CH3:14])[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=2)=[O:24])[N:11]=1)=[O:6])[CH3:1]
Reactant: CN(C)NC(=O)c1nc(N)cn1C
Reactant: Cn1cc([N+](=O)[O-])nc1C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)NC(=O)c1nc(NC(=O)c2nc([N+](=O)[O-])cn2C)cn1C
Temperature: -20 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
The amine from above was dissolved in dry THF (20 mL) and cooled to -20° C. The stirring reaction mixture was placed under argon and a solution of 1-methyl-4-nitroimidazole-2-carbonyl chloride (2.18 g, 11.5 mmol) in dry CH2Cl2 (10 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred overnight then concentrated to dryness and water was added. The suspension was filtered and the solid was washed with carbon tetrachloride and water, then dried in-vacuo (80° C.) to provide N-(N',N'-dimethylamino)-1-methyl-4-[1-methyl-4-nitroimidazole-2-carboxamido]imidazole-2-carboxamide as a pale yellow crystalline solid, 2.18 g (68.8% yield). A sample for analysis was obtained by recrystallization from water: mp 239° C. (dec.). TLC (5% MeOH/CHCl3) Rf 0.66. 1H--NMR (CDCl3); δ2.69 (s, 6H, N(CH3)2), 4.07 (s, 3H, N--CH3), 4.21 (s, 3H, N--CH3), 7.43 (s, 1H, NH). IR (nujol: υ3397 and 1678 cm-1. MS(El) m/z (rel. intensity) 336 (M+, 100), 293 (M+1-N(CH3)2, 85).