Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:30])[CH2:16][N:17]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:19]1[C:18]2[N:17]([CH2:16][CH:15]([OH:30])[CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)Cn2c3ccccc3c3ccccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC(CN1CCNCC1)Cn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 121.5 %

Procedure:
At rt to a solution of Example 2 (3.4 g, 8.30 mmol) in DCM (120 mL) is added TFA (30 mL). The resulting mixture is stirred at rt for 30 min. Concentration in vacuo gives an oily residue. Flash chromatography on a 7×18 cm2 column of SiO2 using DCM:MeOH:TEA (40:5:3) as eluting solvent and removal of the solvent gives the title compound (3.12 g, 92%) as a white foam. Slow addition of HCl (30 mL, 4 eq, 1M in Et2O) into a solution of the above compound in EtOH (40 mL) gives the hydrochloride salt of the title compound as beige crystals in a quantitative yield.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[O:8][CH2:9][CH2:10][O:11][C:4]=2[CH:3]=1.[CH2:12]([CH2:15]OC)OC>>[CH:12]([C:2]1[N:7]=[N:6][C:5]2[O:8][CH2:9][CH2:10][O:11][C:4]=2[CH:3]=1)=[CH2:15]
Reactant: COCCOC
Reactant: Clc1cc2c(nn1)OCCO2
Product: C=Cc1cc2c(nn1)OCCO2
Temperature: 95 °C
Yield: 50 %

Procedure:
A solution of 3-chloro-6,7-dihydro[1,4]dioxino[2,3-c]pyridazine (13.6 g, 0.079 mol) containing ca. 15% of a bromo species in dimethoxyethane (400 ml) was degassed under argon for 10 min then tetrakis(triphenylphosphine)palladium (0) (2 g), potassium carbonate (10.33 g), 2,4,6-trivinylcyclotriboroxane pyridine complex (11.32 g) and water (55 ml) were added. The mixture was heated at 95° C. for 48 hours and cooled and evaporated to dryness. The mixture was treated with aqueous sodium bicarbonate solution and extracted (5×) with DCM. Extracts were dried (sodium sulphate), evaporated and the residue chromatographed on silica gel (500 g), eluting with 0-100% ethyl acetate-hexane, affording the product (6.43 g, 50%); [also some impure fractions (1.8 g)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](N)=[C:10]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.N(O[C:35]([CH3:38])([CH3:37])[CH3:36])=O.[CH3:39][CH2:40][OH:41]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1.[Cl:1][C:2]1[CH:7]=[CH:37][C:35]([C:38]2[C:9]([O:41][CH2:40][CH3:39])=[C:10]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:36][CH:3]=1
Reactant: CC(C)(C)ON=O
Reactant: Nc1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc2c1cnn2-c1ccccc1
Reactant: CCO
Product: CCOc1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc2c1cnn2-c1ccccc1
Product: Clc1ccc(-c2cc3cnn(-c4ccccc4)c3nc2-c2ccc(Cl)cc2Cl)cc1
Temperature: 80 °C

Procedure:
A solution of 5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ylamine (10 mg, 0.022 mol) in EtOH (1 mL) is treated with tert-butyl nitrite (23 mg, 0.22 mol) and heated to 80° C. for 16 hours. After cooling down to room temperature, the mixture is concentrated and purified by preparative thin layer chromatography to provide 5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine (Example 4) and 5-(4-chlorophenyl)-6-(2,4-dichloro-phenyl)-4-ethoxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine is also obtained as side product (Example 5). Example 4: 1H NMR (CDCl3) δ(ppm) 8.35 (d, 2H), 8.29 (s, 1H), 8.14 (s, 1H), 7.48(t, 2H), 7.37(d, 1H), 7.28 (t, 1H), 7.23-7.17(m, 4H), 7.11(d, 2H); HPLC-MS calculated for C24H14C13N3 (M+H+): 450.0. Found: 450.2. Example 5: 1H NMR (CDCl3) δ(ppm) 8.36(s, 1H), 8.30 (d, 2H), 7.48 (t, 2H), 7.32 (d, 1H), 7.29 (d, 1H), 7.18 (d, 2H), 7.05-7.14(m, 4H), 4.68 (q, 2H), 1.42 (t, 3H); HPLC-MS calculated for C26H18C13N3O (M+H+): 494.1, Found: 494.2.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[NH:23][CH2:22][CH2:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][C:18]=3[CH:28]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].[O:29]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[O:29]1[CH:33]=[CH:32][C:31]([CH2:34][N:23]2[C:17]3[CH:16]=[CH:15][C:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH3:3])=[CH:9][CH:10]=4)=[CH:28][C:18]=3[CH:19]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:21][CH2:22]2)=[CH:30]1
Reactant: O=Cc1ccoc1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of methyl 7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (300 mg) and 3-furaldehyde (378 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (416 mg), and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 1-(3-furylmethyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (362 mg) as yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=O.[CH2:12]([C:14]1[S:15][C:16]([CH2:19][CH3:20])=[N:17][N:18]=1)[CH3:13]>C(O)(=O)C.C(OC(=O)C)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:12]([C:14]1[S:15][C:16]([C:19]([CH3:20])=[CH:10][C:3]2[N:2]([CH3:1])[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=2)=[N:17][N:18]=1)[CH3:13]
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Reactant: CCc1nnc(CC)s1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCc1nnc(C(C)=Cc2ncc([N+](=O)[O-])n2C)s1
Yield: 34.6 %

Procedure:
4.65 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde, which has been dissolved in 80 ml of acetic acid and 35 ml of acetic anhydride, is dripped into 17.1 g of 2,5-diethyl-1,3,4thiadiazole, which has been dissolved in a mixture of 60 ml of acetic acid, 25 ml of acetic anhydride and 0.5 g of zinc chloride, over a period of 5 hours at reflux temperature. After being heated for a further 24 hours at reflux temperature the reaction mixture is concentrated by removing the solvent and water is added. The precipitated reaction product is then subjected to sublimation and recrystallized from propanol. 2.9 g of product, corresponding to 35% of the theory, is obtained. The compound melts at 125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)[CH:6]=[N:5]2.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]=[N:5]2
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1cccc(Nc2cnc3cc(Cl)ccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1cccc(Nc2cnc3cc(Cl)ccc3n2)c1

Procedure:
A mixture of 3-[N-(6-chloroquinoxalin-2-yl)amino]phenol (10 mmole), ethyl 2-bromopropionate (10 mmole), anhydrous potassium carbonate (2 g) and methyl ethyl ketone (100 ml) was heated under reflux for a period of 12 hours. The reaction mixture was filtered and the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography over alumina (eluent dichloromethane) to give ethyl 2-{3-[N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionate as an oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH:22]([OH:23])[CH2:21][CH2:20][C@@:19]2([CH3:24])[CH:6]1[CH2:7][CH2:8][C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C@@H:13]2[OH:25])(=[O:3])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[C:1]([O:4][C@@H:5]1[C:22](=[O:23])[CH2:21][CH2:20][C@@:19]2([CH3:24])[CH:6]1[CH2:7][CH2:8][C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C:13]2=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C(O)CC[C@@]2(C)C1CC[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(=O)O[C@@H]1C(=O)CC[C@@]2(C)C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of the 3α:3β mixture of 4α-acetoxyandrostan-3,17β-diol (380 mg), TPAP (38 mg), NMO (383 mg) under N2 in DCM (15 ml) was stirred in the presence of 4 Å molecular sieves (540 mg) for 1 h. The mixture was filtered and the filtrate was purified by flash chromatography (SiO2, n-hexane/EtOAc 7/3) to give the title compound (353 mg, 93%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)[N:3]=1>C1CCCCC=1.C1COCC1.[Pd]>[NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[N:3]=1
Reactant: Cc1ccc(C(=O)n2nc(Nc3ccc(OCc4ccccc4)cc3)nc2N)cc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)n2nc(Nc3ccc(O)cc3)nc2N)cc1
Temperature: 70 °C
Reaction time: 48 h
Yield: 35.3 %

Procedure:
A mixture of 5-amino-3-[4-(benzyloxy)phenylamino]-1-(4-methylphenyl)carbonyl-1H-1,2,4-triazole (Ia-3) (3.95 g, 9.89 mmol) and 10% Pd/C (0.80 g) in cyclohexene (64 mL) and THF (128 mL) was stirred and heated at 70° C. After 2 d, additional 10% Pd/C (0.80 g) was added and heating and stirring at 70° C. was continued for an additional 3 d. After cooling to ambient temperature, the mixture was filtered through diatomaceous earth and concentrated to give a yellow-brown residue. Purification by flash chromatography (95:5 methylene chloride/methanol) followed by trituration with methylene chloride afforded 5-amino-3-[4-(hydroxy)phenylamino]-1-(4-methylphenyl)carbonyl-1H-1,2,4-triazole (Ia-4) (1.08 g, 35%) as a pale yellow solid: Rf 0.36 (95:5 methylene chloride/methanol); mp 221-223° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.88 (s, 1H), 8.13 (d, J=8.2 Hz, 2H), 7.74 (br s, 2H), 7.38-7.32 (m, 4H), 6.64 (d, J=8.8 Hz, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.1, 158.4, 157.3, 151.0, 142.9, 132.9, 130.6, 129.8, 128.4, 118.1, 115.1, 21.1; IR (ATR) 1697 cm−1; ESI MS m/z 310 [C16H16N6O2+H]+; HPLC (Method A) >99% (AUC), tR=11.22 min. Anal. Calcd for C16H16N6O2.0.5H2O: C, 60.47; H, 4.92; N, 22.04. Found: C, 60.27; H, 4.70; N, 21.51.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([N:13]([CH3:48])[C:14]([N:16]([CH3:47])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]3[O:33][C:32]([CH:34]4[CH2:39][CH2:38][N:37]([C:40](OC(C)(C)C)=[O:41])[CH2:36][CH2:35]4)=[N:31][N:30]=3)[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[CH3:52]C(O)C>>[C:40]([N:37]1[CH2:38][CH2:39][CH:34]([C:32]2[O:33][C:29]([N:19]3[CH2:20][C@@H:21]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[C@H:17]([N:16]([CH3:47])[C:14]([N:13]([C:5]4[CH:4]=[C:3]([C:2]([F:49])([F:1])[F:50])[CH:8]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:6]=4)[CH3:48])=[O:15])[CH2:18]3)=[N:30][N:31]=2)[CH2:35][CH2:36]1)(=[O:41])[CH3:52]
Reactant: CN(C(=O)N(C)[C@@H]1CN(c2nnc(C3CCN(C(=O)OC(C)(C)C)CC3)o2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)O
Agent: Cl
Product: CC(=O)N1CCC(c2nnc(N3C[C@@H](N(C)C(=O)N(C)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@H](c4ccc(F)cc4)C3)o2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43 %

Procedure:
A mixture of the compound (0.10 g) obtained in step 1 and 2N hydrogen chloride/2-propanol was stirred at room temperature for 3 days. The mixture was concentrated under reduced pressure, and to the residue were added acetyl chloride (0.016 mL), triethylamine (0.071 mL) and acetonitrile (4.0 mL), and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 50→100% ethyl acetate/hexane) to give the title compound (0.041 g, 43%) as a pale-brown powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[C:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)(=[O:24])[CH3:23]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:3][CH2:2][O:1][C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:22](=[O:24])[CH3:23])=[CH:27][CH:28]=2)=[CH:6][C:7]=1[C:13]([F:15])([F:16])[F:14])#[N:10]
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: CC(=O)Nc1ccc(O)cc1
Product: CC(=O)Nc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-acetamidophenol: MS (ES) m/z 446 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.CO>O>[N:1]1[CH:2]=[CH:3][C:4]([S:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(Sc2ccncc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Sc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.6 %

Procedure:
A mixture of ethyl 4-(4-pyridylthio)benzoate (400 mg, 1.54 mmol) and 5 N aqueous sodium hydroxide (2 mL) in 1:1 tetrahydrofuran/methanol (2 mL) was stirred at room temperature for 18 h. The mixture was diluted with water and washed with diethyl ether. The aqueous layer was acidified to pH 6 with concentrated hydrochloric acid. The resulting precipitate was collected via vacuum filtration to provide 280 mg (78%) of the title compound as a pale yellow solid.
Reaction SMILES: Cl.[CH2:2]([S:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[S:18][C:17]([NH:19][C:20](=[O:35])[N:21]([CH:28]3[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]3)[CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:16][CH:15]=2)[CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH3:3].[CH:36]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([C:41]([N:25]2[CH2:26][CH2:27][CH:22]([N:21]([CH:28]3[CH2:29][CH2:30][CH:31]([CH3:34])[CH2:32][CH2:33]3)[C:20]([NH:19][C:17]3[S:18][C:14]([CH2:13][N:10]4[CH2:11][CH2:12][N:7]([S:4]([CH2:2][CH3:3])(=[O:5])=[O:6])[CH2:8][CH2:9]4)=[CH:15][N:16]=3)=[O:35])[CH2:23][CH2:24]2)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCNCC3)C3CCC(C)CC3)s2)CC1
Agent: Cl
Product: CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCC(C)CC3)C3CCN(C(=O)C4CCCC4)CC3)s2)CC1
Yield: 40 %

Procedure:
Prepared as described in general procedure (N) using 3-[5-(4-ethanesulfonyl-piperazin-1-ylmethyl)-thiazol-2-yl]-1-(4-methyl-cyclohexyl)-1-piperidin-4-yl-urea hydrochloride (48 mg, 0.078 mmol), TEA (24 μL, 0.17 mmol) and cyclopentane carbonylchloride (11 μL, 0.086 mmol) and to afford 19 mg (40%) of the desired product after purification.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:22])[C:16](=[O:21])C(O)(C)C)[N:13]([C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:24])[C:12]1=[O:30])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I(O)(=O)(=O)=[O:32]>CO>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:12](=[O:30])[N:13]([C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:24])[C@@H:14]1[C@@H:15]([CH3:22])[C:16]([OH:32])=[O:21])[CH3:10])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=O)C(C)(C)O
Solvent: CO
Product: CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-(ethoxalyl)-4-[(1R)-3-hydroxy-1,3-dimethyl-2-oxobutyl]-2-azetidinone (50 mg) in methanol (2 ml) was added 0.54M aqueous periodic acid solution (1.0 ml). After stirring at room temperature for 5 hours, the solvent was removed in vacuo and the residue was extracted with dichloromethane. The extract was dried over magnesium sulfate and evaporated to afford (2R)-2-[(2S,3S)-3-{(1R)-1-(t-butyldimethylsilyloxy)ethyl}-1-(ethoxalyl)-4-oxoazetidin-2-yl]propionic acid (93 mg). To a solution of the compound obtained above in diethyl ether (2 ml) was added a solution of diazomethane in diethyl ether at room temperature. The solvent was removed in vacuo and the residue was chromatographed on silica gel (1 g) eluting with a mixture of ethyl acetate and hexane (1:5, V/V) to give methyl (2R)-2-[(2S,3S)-3-{(1R)-1-(t-butyldimethylsilyloxy)ethyl}-1-(ethoxalyl)-4-oxoazetidin-2-yl]propionate (24 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:23][NH:24][O:25][CH3:26]>>[CH3:26][O:25][N:24]([CH3:23])[C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CNOC
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Product: COc1cc(C(=O)N(C)OC)cc(OC)c1OC

Procedure:
3,4,5-Trimethoxybenzoic acid was allowed to react with oxalyl chloride, and the resulting acid chloride was allowed to react with N,O-dimethylhydroxyamine hydrochloride to obtain N,3,4,5-tetramethoxy-N-methylbenzamide. The resulting compound was allowed to react with 4-phenylbutylmagnesium chloride to obtain 5-phenyl-1-(3,4,5-trimethoxyphenyl)pentan-1-one. The resulting compound was allowed to react with lithium diisopropylamine and methyl2-[4-(bromomethyl)phenoxy]benzoate in the presence of N,N,N′,N″,N″-pentamethyldiethylenetriamine to obtain methyl2-{4-[5-phenyl-2-(3,4,5-trimethoxybenzoyl)pentyl]phenoxy}benzoate. The resulting compound was hydrolyzed with sodium hydroxide to give the title compound having the following physical properties.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=O)(C)(C)C.C[N:49]1[CH2:54][CH2:53]OCC1.C(OC([NH:62][CH2:63][CH2:64][CH2:65]Br)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[NH2:62][CH2:63][CH2:64][CH2:65][N:8]([CH2:6][CH2:53][CH2:54][NH2:49])[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)CCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CN1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)CCN(CCCN)CCCN
Reaction time: 2 h

Procedure:
200 mg (0.3 mmol, MW 665.12) of N-tert-butoxycarbonyl-N′,N′-dioctadecylethylenediamine are dissolved in 2 ml of a mixture of trifluoroacetic acid and methylene chloride (1:3 v/v). After two hours, the mixture is subject to rotary evaporation and dried for 2 hours under a high vacuum. The residue is then taken up in 20 ml of chloroform, and 1 ml (920 mg, 4.5 mmol, MW 101.15, d=0.92) of 4-methylmorpholine is added. 640 mg (2.68 mmol, MW 238.13) of N-(tert-butoxycarbonyl)-3-bromopropylamine are then added. After boiling for 48 hours under reflux, the whole is concentrated by rotation and the BOC-protected precursor product is purified by flash chromatography. The product is then dissolved in 2 ml of a mixture of trifluoroacetic acid and methylene chloride (1:3 v/v), concentrated by rotary evaporation and lyophilised.
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH2:19][NH:20]C(=O)C(F)(F)F)[C:3]([C:5]1[N:6]=[C:7]([CH3:17])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:4].C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:20][CH2:19][CH2:18][N:2]([CH3:1])[C:3]([C:5]1[N:6]=[C:7]([CH3:17])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:4]
Reactant: Cc1nc(C(=O)N(C)CCNC(=O)C(F)(F)F)c(-c2ccc(F)cc2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1nc(C(=O)N(C)CCN)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
A solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid methyl-[2-(2,2,2-trifluoro-ethanoylamino)-ethyl]-amide, D4 (443 mg, 1.14 mmol) im methanol/water (30 ml/10 ml) was treated with solid K2CO3 (787 mg, 5.70 mmol) and stirred at room temperature, under argon for 16 h. The methanol was removed in vacuo. The residue was diluted with water and extracted with ethyl acetate (3×). The combined organics were dried (MgSO4) and the solvent removed in vacuo to afford the title compound as a yellow gum (240 mg, 72%).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([O:12][CH2:13][C:14]([OH:16])=O)[C:8]=2[Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])(O)=O.[O:22]([CH2:26][CH2:27][NH2:28])[N+:23]([O-:25])=[O:24]>C(O)C>[O:22]([CH2:26][CH2:27][NH:28][C:14](=[O:16])[CH2:13][O:12][C:9]1[C:8]([Br:17])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1)[N+:23]([O-:25])=[O:24]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)COc1noc(-c2ccccc2)c1Br
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: O=C(COc1noc(-c2ccccc2)c1Br)NCCO[N+](=O)[O-]
Yield: 64.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.53 g of 5-phenyl-4-bromo-3-isoxazolyloxyacetic acid and 0.30 g of nitroxyethylamine nitrate, 0.44 g of the title compound was obtained as colorless needles (solvent for recrystallization; ethanol).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:34](O)(=[O:36])[CH3:35]>>[C:34]([N:17]1[CH2:18][CH2:19][C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[C@H:15]([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:16]1)(=[O:36])[CH3:35]
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.8 mg) obtained in Example 26 and acetic acid (6.9 μl) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.