Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[C:10]([O:14][C:15]([N:17]1[C@H:22]([CH2:23][NH2:24])[C@@H:21]2[CH2:25][C@H:18]1[CH2:19][CH2:20]2)=[O:16])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>C1COCC1>[C:10]([O:14][C:15]([N:17]1[C@H:22]([CH2:23][NH:24][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[C@@H:21]2[CH2:25][C@H:18]1[CH2:19][CH2:20]2)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CN
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CNC(=O)C(F)(F)F

Procedure:
Ethyl trifluoroacetate (12.2 mmol, 1.30 eq) is added to a solution of (1R,3S,4S)-3-aminomethyl-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (9.42 mmol, 1.00 eq) and DIPEA (14.1 mmol, 1.50 eq) in THF (25 mL). After 50 min the mixture is concentrated in vacuo, diluted with TBME (100 mL) and washed twice with aq. citric acid (5%) and water respectively. The organic layer is dried over MgSO4 and concentrated in vacuo to give a crude product which is used without further purification. LC-MS (basic): tR=0.95 min; [M+H]+=323.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][NH:29]3)=[N:23][C:22]=2[CH:35]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:9])=[N:23][C:22]=2[CH:35]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Reactant: Cc1ccc(-c2cccnc2)c(C(=O)O)c1
Product: Cc1ccc(-c2cccnc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(pyridin-3-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 475 [M+1]+.
Reaction SMILES: C([O-])(O)=O.[Na+].[C:6]([OH:10])(=[O:9])[CH2:7][CH3:8].[C:11](=[O:18])([S:15][CH2:16][CH3:17])[O:12][CH2:13]I>O.C(Cl)Cl>[C:11](=[O:18])([S:15][CH2:16][CH3:17])[O:12][CH2:13][O:9][C:6](=[O:10])[CH2:7][CH3:8]
Reactant: CCC(=O)O
Reactant: CCSC(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCSC(=O)OCOC(=O)CC
Yield: 98.8 %

Procedure:
To a stirred solution of NaHCO3 (45 g, 536 mmol) in H2O (540 ml) is added TBA HSO4 (91.2 g, 268 mmol), propanoic acid (20.1 mL, 268 mmol), and CH2Cl2 (540 ml). Following stirring for 1 h at room temperature a solution of 5b (49.2 g, 200 mmol) in CH2Cl2 (100 mL) is added during 45 min keeping the temperature below 30° C. The stirring is continued for 11/2 h. The organic phase is separated, washed with H2O (200 mL), dried (MgSO4), and evaporated. The residue is stirred in Et2O (800 mL) during the night, filtered, and washed with Et2O (50 mL). The filtrate is evaporated and distilled to yield 38.0 g (98%) of 6cb, bp 71°-73° C./0.3 mbar.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][OH:27])=[C:24]([N+:28]([O-:30])=[O:29])[N:23]=[C:22]2[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl.[OH-].[Na+]>O>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][N:21]2[C:25]([CH2:26][OH:27])=[C:24]([N+:28]([O-:30])=[O:29])[N:23]=[C:22]2[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:18][CH:19]=1)([OH:7])=[O:5]
Reactant: CCCCc1nc([N+](=O)[O-])c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCCCc1nc([N+](=O)[O-])c(CO)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 85.6 %

Procedure:
A solution of 1.98 g of 1[(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-5-hydroxymethyl-4-nitroimidazole, 20 mL of trifluoroacetic acid, and 20 mL of methylene chloride was stirred at 25° for 1 hour. At this point, the solution was poured into water. The resulting mixture was adjusted to pH 3 using 10% sodium hydroxide solution and then extracted with chloroform. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Column chromatography (elution: methanol/chloroform) provided 1.49 g of 1-[(2'-carboxybiphenyl-4-yl)methyl]-2-butyl-5-hydroxymethyl-4-nitroimidazole; m.p. 204°-205.5°. NMR (200 MHz, DMSO-d6): δ 7.71 (d, 1H); 7.56 (t, 1H); 7.43 (t, 1H); 7.32 (m, 3H); 7.15 (d, 2H); 5.63 (br s, 1H); 5.42 (s, 2H); 4.83 (s, 2H); 2.54 (t, 2H); 1.50 (quint., 2H); 1.24 (sext., 2H); 0.76 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:14](I)=[C:13]([O:16][C:17](=[O:19])[CH3:18])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:20])[CH:11]=2)[CH:6]=1.C(N(CC)CC)C.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>CN(C)C=O.C(OCC)(=O)C.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.[Cu](I)I>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:14]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[C:13]([O:16][C:17](=[O:19])[CH3:18])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:20])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OC(C)=O)c1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cc2ccc(F)cc2c(OC(C)=O)c1C#C[Si](C)(C)C
Temperature: 150 °C
Yield: 74.5 %

Procedure:
To a solution of (4-acetoxy-6-fluoro-3-iodo-naphthalen-2-yl)acetic acid methyl ester (300 mg, 0.75 mmol) and triethylamine (3 mL) in N,N-dimethylformamide (3 mL), was added bis(triphenylphosphine)dichloropalladium(II) (53 mg, 0.075 mmol), copper iodide (42 mg, 0.229 mmol) and trimethylsilanylacetylene (108 mg, 1.12 mmol) under an argon atmosphere. After being heated at 150° C. for 6 minutes with microwave irradiation, the resulting mixture was cooled, diluted with ethyl acetate (20 mL), and washed with brine (15 mL×2). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column (elution with 10% ethyl acetate in petroleum ether) to afford (4-acetoxy-6-fluoro-3-trimethylsilanylethynyl-naphthalen-2-yl)-acetic acid methyl ester (208 mg, 75%) as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:36]=[CH:37][CH:38]=1)[O:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH:27]=[C:28]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[N:29]=2)[N:26]=1>O1CCCC1.CN(C)C=O.CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[CH:33]1([C:31]([NH:30][C:28]2[N:29]=[C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]4[CH:18]=[C:17]([NH:16][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=5)=[O:9])[CH:38]=[CH:37][CH:36]=4)=[N:26][N:25]3[CH:27]=2)=[O:32])[CH2:34][CH2:35]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cn1nccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cn1nccc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (106 mg, 0.840 mmol) in tetrahydrofuran (2.0 mL) were added N,N-dimethylformamide (1 drop) and oxalyl chloride (91 μL, 1.01 mmol), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (1 mL) and added to a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol) in N,N-dimethylacetamide (5.0 mL). The mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and extracted three times with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→95/5) and precipitated from ethyl acetate/hexane to give the title compound (241 mg, 89%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[C:5]2I.[NH2:20][C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:24]2[CH:32]=[CH:33][C:34]([CH2:36][OH:37])=[CH:35][C:23]=2[N:22]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[C:5]2[NH:20][C:21]1[N:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:24]2[CH:32]=[CH:33][C:34]([CH2:36][OH:37])=[CH:35][C:23]=2[N:22]=1
Reactant: Nc1nc2cc(CO)ccc2n1-c1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(Br)ccc21
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(Nc2nc3cc(CO)ccc3n2-c2ccccc2)c2cc(Br)ccc21
Yield: 7.3 %

Procedure:
A mixture of 5-bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (906 mg, 0.00200 mol), (2-amino-1-phenyl-1H-benzoimidazol-5-yl)methanol (435 mg, 0.00182 mol), copper(I) iodide (110 mg, 0.00056 mol), trans-N1,N2-dimethylcyclohexane-1,2-diamine (160 mg, 0.0011 mol) and potassium phosphate (772 mg, 0.00364 mol) in tetrahydrofuran (19.4 mL) was stirred under argon sparging until a greenish suspension formed. The mixture was then microwaved at 140° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with 5% citric acid, saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography using 0-100% ethyl acetate-hexanes. The product was taken up in ethyl acetate, washed with 1N HCl to remove residual copper and rechromatograped to give 75 mg of product.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:13]N1C(=O)CCC1=O>C(#N)C>[Cl:13][C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:2]([F:1])[C:3]=1[NH2:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(C(F)(F)F)cc1F
Solvent: CC#N
Product: Nc1c(F)cc(C(F)(F)F)cc1Cl
Yield: 70666.9 %

Procedure:
To a solution of 2-fluoro-4-(trifluoromethyl)aniline (498 g, 2.783 mmol, 1.00 eq.) in acetonitrile (5 L) was added N-chlorosuccinimide (NCS, 408 g, 3.06 mmol, 1.1 eq.). Then the solution was heated under reflux for 3 hours and then concentrated under vacuum, diluted with petroleum ether (PE 1 L) and filtered. The filtrate was concentrated under vacuum to afford a red oil. The oily product was purified by vacuum distillation to give 2-chloro-6-fluoro-4-(trifluoromethyl)aniline as a yellow liquid (420 g, 71%).
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[N:9][C:8]=2[C:12](OCC)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:13][CH2:12][C:8]1[N:9]=[CH:10][NH:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc[nH]c1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nc[nH]c1-c1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of 4.5 g of ethyl 5-phenylimidazole-4-carboxylate [J. Het. Chem. 20, 1417 (1983)]in 50 ml of dry tetrahydrofuran at 5° C. was added in portions 1.1 g of lithium aluminum hydride. The resulting reaction mixture was stirred at room temperature for several hours and was then cooled to 10° C. and quenched with 1N hydrochloric acid until the evolution of hydrogen stopped. The reaction mixture was further diluted with water and extracted several times with ethyl acetate. The extracts were combined, dried and concentrated to give a white solid which has triturated with hexane and filtered, 3.2 g.
Reaction SMILES: C[O-].[Na+].C([O:7][CH2:8][C@H:9]([N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:14]=[CH:13]1)[CH2:10][CH3:11])(=O)C>CO>[N:12]1([C@H:9]([CH2:10][CH3:11])[CH2:8][OH:7])[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:14]=[CH:13]1
Reactant: CC[C@H](COC(C)=O)n1cnc2cnc3ccccc3c21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC[C@H](CO)n1cnc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
Sodium methoxide (163.0 g of 25% in methanol, 1.1 eq.) was added in a single portion to a solution of (2R)-2-(1H-imidazo[4,5-c]quinolin-1-yl)butyl acetate (194.0 g, 1 eq.) in methanol (970 mL). The reaction mixture was stirred at ambient temperature for 3 hours and then concentrated under reduced pressure. The residue was diluted with water (1 L), neutralized (pH 6-7) with acetic acid and then stirred at ambient temperature overnight. The resulting precipitate was isolated by filtration, washed with water (2×200 mL), air dried on the filter and then dried in a vacuum oven overnight at 50° C. to provide 145.5 g of (2R)-2-(1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CC(C)=O>O>[CH2:34]([O:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([C:5]2[C:6]([NH:8][C:9]3[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[CH3:17])=[N:7][C:2]([CH3:1])=[N:3][CH:4]=2)(=[O:20])=[O:19])=[CH:26][CH:25]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(O)cc2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.3 %

Procedure:
A mixture of 4-[2-methyl-4-(2,4,6-trimethylphenylamino)-pyrimidine-5-sulfonyl]-phenol (56 mg, 0.15 mmol), prepared as described in Example 2, potassium carbonate (40 mg, 29 mmol), benzyl bromide (0.034 mL, 0.29 mmol) and acetone (3 mL) was stirred at room temperature under N2 for 48 h. The reaction mixture was diluted with water, and extracted (3×) with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (50:50 hexanes/EtOAc) to provide the target compound (62 mg, 91%) as a white solid: mp 166–168° C.; 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 8.20 (br s, 1H), 7.87 (d, J=8.8 Hz, 2H), 7.36–7.40 (m, 5H), 7.05 (d, J=8.8 Hz, 2H), 6.91 (s, 2H), 5.12 (s, 2H), 2.39 (s, 3H), 2.31 (s, 3H), 2.00 (s, 6H); ESI MS m/z 474 [(M+H)+, calcd for C27H28N3O3S, 474.2].
Reaction SMILES: [Na].[SH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([CH3:17])[N:11]=1>CCO>[NH2:9][C:10]1[N:15]=[C:14]([S:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:13]=[C:12]([CH3:17])[N:11]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: CCOC(=O)CS
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CSc1cc(C)nc(N)n1

Procedure:
Sodium (4.6 g, 0.2 mol) was dissolved in 1 l. abs. EtOH. Ethyl mercaptoacetate (24 g, 0.2 mol) was added and the resultant mixture was stirred 1 hr. at room temperature. The 2-amino-4-chloro-6-methylpyrimidine (0.2 mol) was added and the mixture was heated at reflux for 18 hrs. The reaction mixture was evaporated to a syrupy residue which was portitioned between CHCl3 (1.5 l.) and H2O (100 ml). The CHCl3 phase was dried (MgSO4) and evaporated to give the crude product as an oil, 40.6 g (91%). The straw colored oil crystallized upon standing, m.p. 65°-69°. The analytical sample was obtained by a recrystallization from cyclohexane, 27 g (60%), m.p. 71°-73°.
Reaction SMILES: [BH4-].[Na+].[O:3]([C:10]1[CH:22]=[CH:21][C:13]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.CO>[O:3]([C:10]1[CH:22]=[CH:21][C:13]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[OH:20])=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCCC1Oc1ccc(Oc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1CCCC1Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 3.78 g of sodium borohydride in 10 ml of water is added at room temperature to a solution of 8.04 g of 2-(4-phenoxyphenoxy)-cyclopentan-1-one in 60 ml of methanol. The reaction mixture is stirred for 15 hours at room temperature and then concentrated under reduced pressure. The residue is poured into ice-water and extracted with ether. The organic phase is washed twice with saturated sodium chloride solution, dried over sodium sulphate and concentrated by rotary evaporation. Fractional distillation of the residue yields 2-(4-phenoxyphenoxy)-cyclopentan-1-ol as a colourless oil with a boiling point of 181°-185° C./0.001 torr.
Reaction SMILES: C(O[CH:5]1[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@:6]1([CH3:38])[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[NH2:39][C:40]1[N:45]=[CH:44][N:43]=[C:42]2[NH:46][N:47]=[C:48]([I:49])[C:41]=12.B(F)(F)F.CCOCC>[N+](C)([O-])=O>[NH2:39][C:40]1[N:45]=[CH:44][N:43]=[C:42]2[N:46]([C@@H:5]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:16]([O:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C@@:6]3([CH3:38])[O:7][C:8](=[O:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:47]=[C:48]([I:49])[C:41]=12
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@]1(C)OC(=O)c1ccccc1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: FB(F)F
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1nc(I)c2c(N)ncnc21
Yield: 93.2 %

Procedure:
1-O-Acetyl-2-C-methyl-2,3,5-tri-O-benzoyl-D-ribofuranose (1.0 g, 1.72 mmol) was dissolved in anhydrous nitromethane (10.0 mL) and to this solution compound 1.2 (312 mg, 1.21 mmol) was added. The resulting suspension was brought to reflux and borontrifluoride etherate (0.23 mL, 1.78 mmol) was added. The suspension became a clear solution, which was heated at reflux for 2 hr. The mixture was cooled, the solvents were evaporated and the off-white foamy residue was dissolved in ethyl acetate and then poured with stirring into aq. sat. NaHCO3. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried (Na2SO4), filtered and evaporated to give an off-white solid. This material was purified by flash column chromatography on silica gel using CH2Cl2 to 2-3% MeOH in dichoromethane as eluent to give the desired compound 1.4 (811 mg) as a yellow foam.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]([F:22])([F:21])[C:15]1([C:18](O)=[O:19])[CH2:17][CH2:16]1.[CH2:23]([O:25][C:26]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])[CH3:24]>O1CCCC1>[CH2:23]([O:25][C:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:18]([C:15]2([C:14]([F:22])([F:21])[F:13])[CH2:17][CH2:16]2)=[O:19])[CH2:30][CH2:29]1)=[O:27])[CH3:24]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)C2(C(F)(F)F)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.2 %

Procedure:
1,1′-Carbonyldiimidazole (77.36 g; 467.52 mmol) is added to a solution of 1-(trifluoromethyl)cyclopropanecarboxylic acid (72.04 g; 467.52 mmol) in tetrahydrofuran (600 mL) while keeping the internal temperature below 30° C. Piperidine-4-carboxylic acid ethyl ester (50 g; 311.68 mmol) is added after 10 min and the reaction is stirred under nitrogen atmosphere at room temperature for 16 h. The solvent is removed under controlled vacuum and the residue is partitioned between 2 M aqueous solution of sodium hydroxide (200 mL) and dichloromethane (300 mL). The organic layer is washed with brine (100 mL), dried over magnesium sulphate, filtered and concentrated to obtain 93.45 g of the title compound. MS (m/z) 294 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[N-:11]=[N+:12]=[N-:13].[Na+].C(OCC)(=O)C>CN(C)C=O>[N:11]([CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=[N+:12]=[N-:13]
Reactant: N#Cc1ccccc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1CN=[N+]=[N-]

Procedure:
A solution of 2-bromomethyl-benzonitrile (1.0 g, 5.1 mmol) and sodium azide (0.40 g, 6.1 mmol) in dimethylformamide (10 ml) was stirred at room temperature for 2 h. Ethyl acetate was added and the reaction mixture was washed with water and brine. Drying and solvent evaporation gave 2-azidomethyl-benzonitrile; 1H NMR (CDCl3, 400 MHz) δ 7.71 (d, 1H, J=7.7 Hz), 7.64 (m, 1H), 7.53 (d, 1H, J=7.8 Hz), 7.47 (t, 1H, J=7.6 Hz), 4.62 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:42]([OH:43])[C@@H:41]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:40]([CH2:52][OH:53])[O:39][C@H:10]1[O:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][C@H:18]([C@@H:20]1[C@:37]2([CH3:38])[C@H:23]([C@H:24]3[C@H:34]([CH2:35][CH2:36]2)[C@:32]2([CH3:33])[CH:27]([CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:26][CH2:25]3)[CH2:22][CH2:21]1)[CH3:19])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:54](Cl)(=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:42]([OH:43])[C@@H:41]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@@H:40]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[O:39][C@H:10]1[O:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][C@H:18]([C@@H:20]1[C@:37]2([CH3:38])[C@H:23]([C@H:24]3[C@H:34]([CH2:35][CH2:36]2)[C@:32]2([CH3:33])[CH:27]([CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:26][CH2:25]3)[CH2:22][CH2:21]1)[CH3:19])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C)CO[C@@H]1O[C@H](CO)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C)CO[C@@H]1O[C@H](COC(=O)C(C)(C)C)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Temperature: -2.5 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
Compound 26 (647 mg, 0.885 mmol) was dissolved in pyridine (13 mL). To the solution, pivaloyl chloride (138 μl, 1.15 mmol) was added, and the mixture was stirred at −5 to 0° C. for 0.5 hour. Pivaloyl chloride (138 μl, 1.15 mmol) was further added thereto, and the mixture was stirred at −5 to 0° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, and filtered through Celite, and the filtrate was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine. The ethyl acetate layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:AcOEt=10:1) to obtain Compound 27 (663 mg, 91.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[CH3:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][O:24][C:25](=O)[O:26]N2C(=O)CCC2=O)=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][O:24][C:25]([N:15]2[CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:4]3[C:3]([O:2][CH3:1])=[N:8][C:7]([CH3:9])=[CH:6][N:5]=3)[CH2:13][CH2:14]2)=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(COC(=O)ON2C(=O)CCC2=O)cc1
Reactant: COc1nc(C)cnc1NCC1CCNCC1
Product: COc1nc(C)cnc1NCC1CCN(C(=O)OCc2ccc(C)cc2)CC1

Procedure:
The above compound was prepared in a similar manner as described in EXAMPLE 130 from 4-[(3-methoxy-5-methyl-pyrazin-2-ylamino)-methyl]-piperidine (EXAMPLE 130, STEP 2) using N-(4-methylbenzyloxycarbonyloxy)succinimide (INTERMEDIATE 1A). M.S.(M+1): 385.