Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@H](C(O)=O)CC(C)C.NC(C(O)=O)CCC.[CH3:18][CH2:19][C@H:20]1[O:37][C:35](=[O:36])[CH2:34][C@@H:33]([O:38]C(C)=O)[C@H:32]([CH3:42])[C@@H:31]([O:43][C@@H:44]2[O:49][C@H:48]([CH3:50])[C@@H:47]([O:51][C@@H:52]3[O:57][C@@H:56]([CH3:58])[C@H:55]([O:59]C(CC(C)C)=O)[C@@:54]([OH:67])([CH3:66])[CH2:53]3)[C@H:46]([N:68]([CH3:70])[CH3:69])[C@H:45]2[OH:71])[C@@H:30]([CH2:72][CH:73]=[O:74])[CH2:29][C@@H:28]([CH3:75])[C:26](=[O:27])[CH:25]=[CH:24][C:23]([CH3:76])=[CH:22][C@@H:21]1[CH2:77][O:78][C@@H:79]1[O:84][C@H:83]([CH3:85])[C@@H:82]([OH:86])[C@@H:81]([O:87][CH3:88])[C@H:80]1[O:89][CH3:90]>>[CH3:18][CH2:19][C@H:20]1[O:37][C:35](=[O:36])[CH2:34][C@@H:33]([OH:38])[C@H:32]([CH3:42])[C@@H:31]([O:43][C@@H:44]2[O:49][C@H:48]([CH3:50])[C@@H:47]([O:51][C@@H:52]3[O:57][C@@H:56]([CH3:58])[C@H:55]([OH:59])[C@@:54]([OH:67])([CH3:66])[CH2:53]3)[C@H:46]([N:68]([CH3:70])[CH3:69])[C@H:45]2[OH:71])[C@@H:30]([CH2:72][CH:73]=[O:74])[CH2:29][C@@H:28]([CH3:75])[C:26](=[O:27])[CH:25]=[CH:24][C:23]([CH3:76])=[CH:22][C@@H:21]1[CH2:77][O:78][C@@H:79]1[O:84][C@H:83]([CH3:85])[C@@H:82]([OH:86])[C@@H:81]([O:87][CH3:88])[C@H:80]1[O:89][CH3:90]
Reactant: CC[C@H]1OC(=O)C[C@@H](OC(C)=O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)[C@@H](O[C@H]3C[C@@](C)(O)[C@@H](OC(=O)CC(C)C)[C@H](C)O3)[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)C(=O)C=CC(C)=C[C@@H]1CO[C@@H]1O[C@H](C)[C@@H](O)[C@@H](OC)[C@H]1OC
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CCCC(N)C(=O)O
Agent: CC[C@H]1OC(=O)C[C@@H](O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)[C@@H](O[C@H]3C[C@@](C)(O)[C@@H](O)[C@H](C)O3)[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)C(=O)/C=C/C(C)=C/[C@@H]1CO[C@@H]1O[C@H](C)[C@@H](O)[C@@H](OC)[C@H]1OC
Product: CC[C@H]1OC(=O)C[C@@H](O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)[C@@H](O[C@H]3C[C@@](C)(O)[C@@H](O)[C@H](C)O3)[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)C(=O)C=CC(C)=C[C@@H]1CO[C@@H]1O[C@H](C)[C@@H](O)[C@@H](OC)[C@H]1OC

Procedure:
The conversion reaction was carried out in a manner similar to Example 4 with the same strain, in which L-leucine was used in substitution for DL-norvaline in Example 4 as the isovaleryl donor. About 400 mg of white crystals of 3-acetyl-4"-isovaleryltylosin were obtained from 3 g of tylosin.
Reaction SMILES: OO.FC(F)(F)C(C(F)(F)F)=[O:6].[F:13][C:14]([F:34])([CH:17]([F:33])[O:18][C:19]([F:32])([F:31])[C:20]([F:30])([F:29])[C:21]([F:28])([F:27])[O:22][C:23]([F:26])([F:25])[F:24])[CH2:15][OH:16]>C(Cl)(Cl)Cl>[F:13][C:14]([F:34])([CH:17]([F:33])[O:18][C:19]([F:32])([F:31])[C:20]([F:29])([F:30])[C:21]([F:27])([F:28])[O:22][C:23]([F:24])([F:25])[F:26])[C:15]([OH:6])=[O:16]
Reactant: OCC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: OO
Solvent: ClC(Cl)Cl
Product: O=C(O)C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 2.3 mL (22 mmol) of 30% H2O2 in 20 mL of chloroform, 13.28 g (80 mmol) of hexafluoroacetone (pre-generated from HFA-hydrate) was added followed by 2,2,3-trifluoro-3-(1,1,2,2,3,3-hexafluoro-3-trifluoromethoxy-propoxy)-propan-1-ol (3.64 g, 10 mmol). The mixture was stirred 2 days at room temperature. After separation of phases and evaporation of solvent, the residue was examined by 19F NMR spectroscopy. Yield of the raw product 52%.
Reaction SMILES: [OH-].[Na+].[C:3]1([C:9]2[N:14]3[CH:15]=[C:16]([CH2:18][O:19][C:20]4[CH:41]=[CH:40][C:23]([CH2:24][O:25]/[N:26]=[C:27](/[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)\[CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:22][CH:21]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO.Cl>O1CCCC1>[C:3]1([C:9]2[N:14]3[CH:15]=[C:16]([CH2:18][O:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:24][O:25]/[N:26]=[C:27](/[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)\[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:40][CH:41]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2cn3c(-c4ccccc4)cccc3n2)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2cn3c(-c4ccccc4)cccc3n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of methyl E-4-[4-(5-phenylimidazo[1,2-α]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate (400 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-(5-phenylimidazo[1,2-α]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyric acid (365 mg, yield 94%) as colorless crystals. m.p. 160-161° C.
Reaction SMILES: [CH:1]([C@:4]1([C:24]([OH:26])=O)[CH2:8][CH2:7][C@@H:6]([N:9]([C@H:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[O:22][CH3:23])C(=O)C(F)(F)F)[CH2:5]1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[OH:33][C@H:34]1[C@@H:38]2[NH:39][CH2:40][C@H:35]1[N:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]2.CCN(CC)CC.[OH-].[Na+]>C(Cl)Cl.CN(C=O)C>[OH:33][C@H:34]1[C@@H:38]2[N:39]([C:24]([C@@:4]3([CH:1]([CH3:2])[CH3:3])[CH2:8][CH2:7][CH:6]([NH:9][CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH:17]4[O:22][CH3:23])[CH2:5]3)=[O:26])[CH2:40][C@H:35]1[N:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]2
Reactant: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1CC[C@@](C(=O)O)(C(C)C)C1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2NC[C@@H]1[C@H]2O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1COCCC1NC1CC[C@@](C(=O)N2C[C@@H]3[C@@H](O)[C@H]2CN3C(=O)OC(C)(C)C)(C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 250.2 %

Procedure:
To a solution of the (1S,3R)-1-isopropyl-3-(2,2,2-trifluoro-N-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-yl)acetamido)cyclopentanecarboxylic acid (0.95 g, 2.5 mmol) in CH2Cl2 (5 mL) under N2 at 0° C. is added oxalyl chloride (623 mg, 4.98 mmol) and DMF (3 drops). The mixture is allowed to warm to RT and stir for 2 hr, It was then concentrated. The acid chloride was redissolved in DCM (10 ml), cooled to 0° C., and treated with (1R,4R,7S)-tert-butyl 7-hydroxy-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate (534 mg, 0.249 mmol), followed by Et3N (0.1 ml, 0.75 mmol). The resulting mixture was warmed to RT and stirred for 2 hrs. The solution was then washed with NaHCO3 (1×5 ml), and brine (1×5 ml). The organic layer was then dried over MgSO4, filtered and concentrated, purified by chromatography (100% EtOAc-60% MeOH/EtOAc) to yield crude intermediate which was dried and concentrated. Then it was dissolved in EtOH (2 ml) and treated with NaOH (3 ml, 7.5 mmol) overnight. The reaction mixture was then purified by chromatography (100% EtOAc-100% MeOH) to yield desired product (300 mg, 25%). LC/MS (M+H)=482.3230 exp, 482.3334 obs; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.67 (dd, J=6.95, 3.66 Hz, 3H) 0.80 (dd, J=6.59, 2.93 Hz, 3H) 1.22 (br. s., 1H) 1.35-1.41 (m, 12H) 1.43-1.48 (m, 2H) 1.55-1.68 (m, 2H) 1.85-1.93 (m, 1H) 1.95-2.04 (m, 1H) 2.16-2.28 (m, 1H) 2.66-2.80 (m, 1H) 2.97-3.02 (m, 1H) 3.03-3.10 (m, 2H) 3.17-3.29 (m, 5H) 3.37-3.47 (m, 1H) 3.47-3.58 (m, 1H) 3.61-3.74 (m, 1H) 3.81-3.89 (m, 1H) 3.94-4.04 (m, 2H) 4.24 (br. s., 1H) 5.65-5.77 (m, 1H)
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)[C@@H:12]([CH2:22][O:23]CC2C=CC=CC=2)[O:11][C@H:10]1[N:31]1[C:35]2[N:36]=[CH:37][N:38]=[C:39]([NH2:40])[C:34]=2[CH:33]=[CH:32]1)C1C=CC=CC=1.C(O)(=O)C.COC(O)C.[H][H]>[Pd].O>[C@@H:10]1([N:31]2[C:35]3[N:36]=[CH:37][N:38]=[C:39]([NH2:40])[C:34]=3[CH:33]=[CH:32]2)[O:11][C@H:12]([CH2:22][OH:23])[C@@H:13]([OH:14])[C@@H:9]1[OH:8]
Reactant: [H][H]
Reactant: Nc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd]
Agent: COC(C)O
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncnc2c1ccn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Yield: 80 %

Procedure:
A mixture of 2.5 g of 7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5 ml of acetic acid, 500 mg of 20% of palladium on charcoal, and 95 ml of methoxyethanol is hydrogenated at 50°-55° C. and approximately 3 atmospheres until uptake of hydrogen ceases. The mixture is filtered, evaporated in vacuo, and coevaporated with xylenes to provide a red syrup which is dissolved in water and treated with Amberlite ion exchange resin (20 ml of wet IR-45). The resin is filtered and washed several times with boiling water. The combined filtrates are evaporated in vacuo to provide 992 mg of crude 7-βD-arabinofuranosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine. Recrystallization of this material from water provides 800 mg of product, m.p. 117°-120° C. (after drying at 100° C. for one hour); [α]D25 =+16.2 (1.02% in H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9][CH2:10][CH2:11][C:12]#[N:13])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24]([CH3:25])=[O:37])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9][CH2:10][CH2:11][C:12]#[N:13])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(CCCC#N)c3ccc(Cl)cc3)c[nH]c12
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(CCCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.14 mmol) of the compound from Example 49 were introduced into 9 ml of dichloromethane while cooling in ice, 33.4 mg (0.14 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. 2 ml of methanol were added, and the residue after concentration was taken up in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases were separated, the organic phase was washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 33 mg (63% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: O1CCCC1.[NH:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([NH2:10])=[O:9].[I-:14].CS[C:17]1[S:21][CH:20]=[CH:19][S+:18]=1>CC(C)=O.C(OCC)C>[I-:14].[S:18]1[CH:19]=[CH:20][S:21][C:17]1=[N+:6]1[CH2:13][CH2:12][CH2:11][CH:7]1[C:8](=[O:9])[NH2:10]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CSc1scc[s+]1
Agent: [I-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCOCC
Product: NC(=O)C1CCC[N+]1=c1sccs1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
To 30 ml of tetrahydrofuran, 1.6 g of proline amide was dissolved, and 2.0 g of 2-methylthio-1,3-dithiolium iodide was gradually added under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration and recrystallized from acetone-ethyl ether, whereby 1.3 g (yield: 53%) of 1-(1,3-dithiol-2-ylidene)-2-carbamoylpyrrolidinium iodide (Compound No. 44) was obtained as crystals having a melting point of from 250° to 251° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:15]=O)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:8]=1)([O-:3])=[O:2].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[C:34]([NH2:36])[C:33]([NH2:37])=[CH:32][C:31]=2[F:38])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CO>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:30]2[C:31]([F:38])=[CH:32][C:33]3[N:37]=[C:15]([C:5]4[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]([CH:9]5[CH2:14][CH2:13][CH2:12][CH2:11][O:10]5)[N:6]=4)[NH:36][C:34]=3[CH:35]=2)[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)c(N)cc2F)CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4[N+](=O)[O-])nc3cc2F)CC1
Temperature: 22 °C
Reaction time: 16 h
Yield: 26.6 %

Procedure:
0.9 g of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde is added to a solution of 1.2 g of 4-(4,5-diamino-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester in 30 mL of methanol. The reaction medium is stirred at 22° C. for 16 hours. After evaporation, the reaction crude is purified by flash chromatography, elution being carried out with a mixture of dichloromethane/acetone. 530 mg of 4-{6-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-3H-benzimidazol-5-yl}piperazine-1-carboxylic acid tert-butyl ester are isolated in the form of a red foam. 1H NMR (400 MHz, DMSO-d6, δ in ppm): from 1.35 to 2.25 (m, 6H); 1.43 (s, 9H); 3.03 (m, 4H); 3.52 (m, 4H); 3.72 (m, 1H); 4.00 (m, 1H); 5.65 (dd, J=2.0 and 10.0 Hz, 1H); 7.31 (d, J=8.0 Hz, 1H); 7.54 (d, J=12.0 Hz, 1H); 9.17 (s, 1H). ES mass spectrum: m/z=516 MH+ (base peak).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]([C:7]([CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH2:8])[CH2:5][OH:6].C(N(CC)CC)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:32][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O:6][CH2:5][CH:4]([C:7]([CH2:9][Si:10]([CH3:13])([CH3:11])[CH3:12])=[CH2:8])[CH2:3][CH:2]([CH3:14])[CH3:1])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: C=C(C[Si](C)(C)C)C(CO)CC(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=C(C[Si](C)(C)C)C(COS(=O)(=O)c1ccc(C)cc1)CC(C)C
Temperature: 0 °C
Reaction time: 6 h
Yield: 74.1 %

Procedure:
4-methyl-2-(3-(trimethylsilyl)prop-1-ene-2-yl)pentan-1-ol (59.1 mg, 0.275 mmol) and triethyl amine (835 mg, 8.25 mmol) were dissolved in anhydrous CH2Cl2 (20 mL), and then the solution was cooled to 0° C. p-toluenesulfonyl chloride (57.7 mg, 0.303 mmol) and DMAP (2.00 mg, 0.0138 mmol) were added thereto and the resulting solution was stirred at 0° C. for 6 hr. Water (30 mL) was added thereto to complete the reaction, extraction was performed by using CH2Cl2 (3×20 mL), an organic layer was washed with a brine solution, anhydrous magnesium sulfate was used to perform drying and distillation under reduced pressure, and then column chromatography was used to obtain 75.1 mg (yield 74%) of the title compound which is colorless and in the oil state.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([OH:19])[C@@H:5]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH:7]([CH3:10])[CH2:8]C.CO[CH2:23][CH:24]=[CH2:25]>CN(C)C=O>[CH3:1][O:2][C:3]([CH:4]1[O:19][C:24]([CH3:25])([CH3:23])[N:11]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C@H:5]1[CH2:6][CH:7]([CH3:8])[CH3:10])=[O:20]
Reactant: CCC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)C(=O)OC
Reactant: C=CCOC
Solvent: CN(C)C=O
Product: COC(=O)C1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S)-3-(N-t-butoxycarbonylamino)-5-methyl-2-hydroxyheptanoic acid methyl ester (4.40 g) in N,N-dimethylformamide (16 ml) was added methyl-2-propenyl ether (4.60 ml) and further was added dl-camphor sulfonic acid (186 mg) and the mixture was stirred overnight at room temperature. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1 to 4:1) to give the title compound (3.90 g) having the following physical data.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH3:8][Si:9](Cl)([CH3:11])[CH3:10]>C[Si](N[Si](C)(C)C)(C)C>[Si:9]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:7][Si:9]([CH3:11])([CH3:10])[CH3:8])([CH3:11])([CH3:10])[CH3:8]
Reactant: OCCCCCO
Reactant: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)OCCCCCO[Si](C)(C)C
Temperature: 50 °C

Procedure:
1,5-Pentanediol (65 g, 0.62 mol) was placed in a 500 mL 3-necked RB flask and treated with 0.4 mL trimethylsilyl chloride. A portion of HMDS (ca. 20 mL) was added, and an exothermic reaction took place as the mixture became homogeneous. The remainder of the HMDS (130 mL, 0.71 mol total) was added at a controlled rate (ca. 3-5 mL/min), maintaining the reaction temperature at ca. 50° C. Heating was continued at 100° C. (1 h), and 150° C. (2.5 h). GC analysis (method 1) revealed excess HMDS and one product. Distillation provided 139 g of colorless oil, bp 47-49° C./0.1 mm. 1H NMR (CDCl3): 3.60 (t, J=7 Hz, 4 H), 1.57 (m, 4 H), 1.40 (m, 2 H), 0.12 (s, 18 H), consistent with the assigned structure.
Reaction SMILES: N12CCN(CC1)CC2.[OH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[CH:20]=O)=[N:17][C:16]([O:22][CH3:23])=[CH:15][CH:14]=2.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:36][O:37][C:38](=[O:41])[CH:39]=[CH2:40]>C(OCC)(=O)C>[CH3:36][O:37][C:38]([C:39]1[CH2:40][O:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[CH:20]=1)=[N:17][C:16]([O:22][CH3:23])=[CH:15][CH:14]=3)=[O:41]
Reactant: C=CC(=O)OC
Reactant: COc1ccc2ncc(O)c(C=O)c2n1
Agent: C1CN2CCN1CC2
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C1=Cc2c(cnc3ccc(OC)nc23)OC1
Temperature: 25 °C
Yield: 53 %

Procedure:
1,4-Diazabicyclo[2.2.2]octane (522 mg, 4.65 mmol, 1.0 eq) is added at room temperature to a stirred suspension of 3-hydroxy-6-methoxy-[1,5]naphthyridine-4-carbaldehyde (950 mg, 4.65 mmol, 1.0 eq) in acrylic acid methyl ester (20 mL) and the resulting mixture is heated under reflux for 3 hours. The reaction mixture is then cooled down to room temperature, solvent is removed and the residue is dissolved in 1,2-dichloroethane (20 mL). Triethylamine (19.5 mL, 139.6 mmol, 30.0 eq) is then added at 0° C., followed by methanesulfonyl chloride (3.85 mL, 69.8 mml, 15.0 eq) and the resulting mixture is heated under reflux for 4 hours. Solvent is removed and the residue is extracted with dichloromethane (3×40 mL) and water (40 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 10:1 to 5:1, v/v) to afford 6-methoxy-2H-1-oxa-5,9-diaza-phenanthrene-3-carboxylic acid methyl ester as a light yellow oil (670 mg, 53% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]2[C:12]3[CH2:20][NH:19][CH2:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)[CH3:9])=[CH:4][CH:3]=1.Br[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]2[C:12]3[CH2:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=4)[CH2:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: Clc1ccc(Br)nc1
Reactant: C[C@@H](Nc1ncnc2c1CNCC2)c1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: C[C@@H](Nc1ncnc2c1CN(c1ccc(Cl)cn1)CC2)c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of (R)-N-(1-(4-chlorophenyl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (80.0 mg, 0.277 mmol), 2-bromo-5-chloropyridine (69 mg, 0.36 mmol), dry toluene (5 mL), xantphos (10 mg, 0.02 mmol), sodium tert-butoxide (40 mg, 0.42 mmol), and tris(dibenzylideneacetone)dipalladium(0) (6.3 mg, 0.0069 mmol) under N2 was heated in an oil bath at 100° C. for 1.5 h. The mixture was absorbed on silica gel and purified by column (0-5% MeOH/CH2Cl2) to afford a light tan powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:32]=[C:33](O)[CH:34]=[CH:35][C:36]=1[Cl:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[Cl:37])[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Cl)c(Cl)c3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4- fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3,4-dichlorophenol: ESMS m/e: 542.7 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][NH2:11].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[OH-].[K+].Cl>C(O)C.O>[CH3:16][C:14]1[CH2:13][C:12](=[O:17])[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[N:11]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 280 g of 2,4,6-trichlorophenylhydrazine was added 180 ml of ethyl acetoacetate, and the resulting mixture was stirred at room temperature for 30 minutes. After adding thereto a solution prepared by dissolving 215 g of potassium hydroxide in 7 l of ethanol, the reaction solution was refluxed with heating for 1 hour. The reaction solution was poured into 6 l of water and neutralized with conc. hydrochloric acid. After being cooled to room temperature, a precipitate thus formed was filtered off, washed with water, and then dried under reduced pressure to obtain the titled compound. Yield: 300 g. Melting point: 178° to 180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([NH:23][C@H:24]([C:30]([O:32]CC)=[O:31])[CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1.O1CCCC1.O.[OH-].[Li+]>[Cl-].[Na+].O.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([NH:23][C@H:24]([C:30]([OH:32])=[O:31])[CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:19]([F:21])([F:22])[F:20])=[CH:14][CH:13]=1
Reactant: CCOC(=O)[C@H](CC(C)(C)F)N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2Cl)cc1)C(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2Cl)cc1)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a solution of ethyl N-{(1S)-1-[2′-chloro-4′-(methylsulfonyl)biphenyl-4-yl]-2,2,2-trifluoroethyl}-4-fluoro-L-leucinate in a 3:1:1 mixture (0.1 M) of tetrahydrofuran, water and ethanol was added solid Lithium Hydroxide. The reaction was stirred for 64 h at room temperature and heated for one hour at 38° C. after which TLC analysis indicated disappearance of starting material. The reaction was cooled and treated with aqueous pH 5 NaH2PO4 solution and brine and then 1N aqueous HCL until pH 2. The phases were separated and the organic phase was washed with aqueous pH 5 NaH2PO4 solution and brine.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(NC([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[N:32]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[C:35]([O:42][CH2:43][CH3:44])[CH:34]=3)[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24]2=[O:45])[CH2:19][CH2:18]1)=O)(C)(C)C>>[C:1]1([NH:7][C:8]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[N:32]=[C:31]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[C:35]([O:42][CH2:43][CH3:44])[CH:34]=4)[C@@H:30]4[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]4)[C:24]3=[O:45])[CH2:19][CH2:18]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOc1ccc(C2=NN(C3CCN(C(=O)NC(C)(C)C)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Reactant: O=C=Nc1ccccc1
Product: CCOc1ccc(C2=NN(C3CCN(C(=O)Nc4ccccc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from starting compound A1 and phenylisocyanate as described for compound 6. Crystallisation from ether. M. p. 109-112° C.