Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:30])[C:22]=3[C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]([F:42])([F:41])[CH:34]1[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH3:14][C:11]1([CH3:15])[O:12][CH2:13][C:8]([NH:7][C:6](=[O:31])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:30][CH:37]4[CH2:38][CH2:39][CH:34]([C:33]([F:42])([F:41])[F:32])[CH2:35][CH2:36]4)[C:22]=3[C:26]([F:27])([F:28])[F:29])[CH:17]=2)[CH2:9][O:10]1
Reactant: OC1CCC(C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3c(C(F)(F)F)c(O)ccc3c2)COC(C)(C)OC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc3c(C(F)(F)F)c(OC4CCC(C(F)(F)F)CC4)ccc3c2)COC(C)(C)OC1
Temperature: 0 °C
Yield: 64.1 %

Procedure:
[5-(6-Hydroxy-5-trifluoromethyl-naphthalen-2-yl)-2,2-dimethyl-1,3-dioxinan-5-yl]-carbamic acid tert-butyl ester (1 g, 0.003 mol), 4-Trifluoromethyl-cyclohexanol (0.50 g, 0.0029 mol), and triphenylphosphine (0.84 g, 0.0032 mol) were combined in dry toluene (15 mL, 0.14 mol) and stirred under nitrogen. The solution cooled to 0° C. on an ice bath and diisopropyl azodicarboxylate (0.65 g, 0.0032 mol) was added slowly (dropwise) over 30 min. Once all DIAD was added the mixture was stirred on an icebath for 30 minutes. The ice bath was then removed and the mixture was allowed to warm to room temperature while stirring under nitrogen for 16 hours. The mixture was then washed with 1.0 N HCl, and washed with Sat. Na2CO3, and brine. The organic layer was dried over MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude reaction was then dissolved in methylene chloride, absorbed onto 10 g silica and purified (dry load) via column chromatography 0-50% EtoAC/Hexanes using a 125 g column to give 1.1 g the desired product as a white solid. Material was carried forward without additional purification. ESI-MS: 592 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:15]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:15])=[O:6])[CH:8]=[CH:9][N:10]=1
Reactant: CO
Reactant: O=C(O)c1ccnc(Cl)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccnc(Cl)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
2-Chloro-isonicotinic acid (5.10 g, 32.38 mmol) was dissolved in methanol (150 mL). Thionyl chloride (12 mL) was added. This suspension was stirred 5 h at 70° C. and concentrated in vacuo. The residue was dissolved in dichloromethane (250 mL) washed with a solution of 10% aqueous K2CO3 (2×150 mL) dried with MgSO4, filtered and evaporated. Methyl 2-chloropyridine-4-carboxylate SLA 07150 was obtained as a yellow solid (5.06 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:29])=[C:4]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][C:14](=[O:16])[CH3:15])=[O:8].[C:30]([O:33][CH2:34][C:35](Cl)=[O:36])(=[O:32])[CH3:31].C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[C:30]([O:33][CH2:34][C:35]([NH:1][C:2]1[C:3]([I:29])=[C:4]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][C:14](=[O:16])[CH3:15])=[O:8])=[O:36])(=[O:32])[CH3:31]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(=O)Nc1c(I)c(COC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Reaction time: 8 h
Yield: 99.4 %

Procedure:
5-Amino-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide (3.0 g, 4.03 mmol) was dissolved in dry N,N-dimethylacetamide (8 ml) at ambient temperature. With efficient stirring acetoxyacetyl chloride (4.39 ml, 40.3 mmol) was added dropwise, and the mixture was stirred overnight. The mixture was then added slowly with stirring into a saturated solution of sodium hydrogen carbonate (80 ml). The precipitate formed was filtered off and dissolved in chloroform (80 ml). The organic solution was washed with an aqueous saturated solution of NaHCO3 (25 ml), and then evaporated to dryness. The solid residue was dissolved in acetone and filtered through a pad of alumina with acetone as eluent. Evaporation of the solvent gave 3.38 g (100%) of a white crystalline product.
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([NH2:31])=[CH:29][CH:30]=4)=[CH:20][CH:19]=3)=[CH:13][CH:14]=2)=[CH:40][CH:41]=1
Reactant: CCCCCCC(Cc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1)Cc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC(Cc1ccc(Cc2ccc(N)cc2)cc1)Cc1ccc(Cc2ccc(N)cc2)cc1
Yield: 96.9 %

Procedure:
In a 1-liter three-necked flask having a fit equipped with a stirring device and a nitrogen substituting device, 40.9 g of 1,3-bis(4-(4-nitrobenzyl)phenyl)-2-n-hexyl propane, 5 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) and 300 milliliters of tetrahydrofuran were introduced, and contacted with hydrogen gas at a normal pressure with stirring. After hydrogen absorption was stopped, the catalyst was filtered off and the solution was concentrated. Residues were dissolved in chloroform, and then subjected to a separating operation by a column chromatography with silica gel. By removing off the solvent again, 35.3 g of 1,3-bis(4-(4-aminobenzyl)phenyl)-2-n-hexyl propane was obtained as yellow oil.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6]1)=O.C([NH2:19])=O.C[O-].[Na+].[Na]>CN(C=O)C.CO.C(O)(C)C>[CH2:10]([N:7]1[CH2:8][CH2:9][CH:5]([C:3]([NH2:19])=[O:2])[CH2:6]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC=O
Reactant: COC(=O)C1CCN(Cc2ccccc2)C1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)O
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(Cc2ccccc2)C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a mixture of 4.4 g of 1-benzyl-pyrrolidine-3-carboxylic acid methyl ester (M. J. Kornet et al., J. Org. Chem., 33:3637–3639(1968)) and 3 g of formamide in 10 mL of anhydrous DMF heated to 100° C. was added a solution of sodium methoxide, from 0.33 g of sodium dissolved in methanol, dropwise over 20 min. After stirring for 1 h at 100° C., the mixture was allowed to cool to rt and added to 100 mL of isopropanol. The mixture was concentrated to dryness. The resulting residue was triturated with 200 mL of chloroform, filtered and concentrated to dryness under reduced pressure. The resulting oil was fairly homogeneous by TLC (development with 90:10 chloroform saturated with ammonia: methanol):
Reaction SMILES: [CH3:1][N:2]([CH3:13])/[C:3](/SC)=[N:4]/[C:5](=O)[CH:6]=[C:7]([CH3:9])[CH3:8].[CH3:14][NH:15][NH2:16]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:13])[C:3]1[N:4]=[C:5]([CH:6]=[C:7]([CH3:9])[CH3:8])[N:15]([CH3:14])[N:16]=1
Reactant: CNN
Reactant: CS/C(=N\C(=O)C=C(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)=Cc1nc(N(C)C)nn1C
Temperature: 100 °C
Yield: 38.1 %

Procedure:
A mixture of (Z)-methyl N,N-dimethyl-N′-(3-methylbut-2-enoyl)carbamimidothioate (2.41 g, 12.0 mmol, Eq: 1.00) and methylhydrazine (5.54 g, 6.34 ml, 120 mmol, Eq: 10) was heated to 100° C. for 30 minutes. The mixture was dissolved in ethyl acetate and washed with water 3 times and once with brine. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated affording dimethyl-[1-methyl-5-(2-methyl-propenyl)-1H-[1,2,4]triazol-3-yl]-amine (824 mg/38.0%) as a yellow liquid. A mixture of N,N,1-trimethyl-5-(2-methylprop-1-enyl)-1H-1,2,4-triazol-3-amine (824 mg, 4.57 mmol, Eq: 1.00), osmium tetroxide 4% aq. (872 mg, 872 μl, 137 μmol, Eq: 0.03), sodium periodate (3.91 g, 18.3 mmol, Eq: 4) and benzyltriethylammonium chloride (416 mg, 1.83 mmol, Eq: 0.4) in dioxane (42 ml) and water (13 ml) was stirred for 2 hours at 60° C. The mixture was diluted with ethyl acetate and washed with 2× water and brine. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated affording 1.0 g dark brown oil. The crude material was applied on silicagel and purified by flash chromatography over a 50 g silicagel column using ethyl acetate/methanol 0-10% as eluent affording 5-dimethylamino-2-methyl-2H-[1,2,4]triazole-3-carbaldehyde (127 mg/60.0%) as a brown oil. MS: m/e=155.3 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].Cl.[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][N:37]([C:42]2[CH:55]=[CH:54][C:45]3[N:46]([CH2:50][C:51](O)=[O:52])[C:47](=[O:49])[O:48][C:44]=3[CH:43]=2)[S:38]([CH3:41])(=[O:40])=[O:39])[CH2:31][CH2:30]1.C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:51](=[O:52])[CH2:50][N:46]1[C:45]2[CH:54]=[CH:55][C:42]([N:37]([CH2:36][CH2:35][N:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:43][C:44]=2[O:48][C:47]1=[O:49]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(c1)oc(=O)n2CC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(c1)oc(=O)n2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reaction time: 8 h
Yield: 37.8 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (281 mg, 0.669 mmol), 2-(6-(N-(2-morpholinoethyl)-methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid hydrochloride (350 mg, 0.803 mmol), EDC (192 mg, 1.004 mmol) and DMAP (204 mg, 1.673 mmol) were dissolved in dry DCM (8 ml), and the mixture was reacted at room temperature for 5 hours. Additional EDC (128 mg, 0.669 mmol) and DMAP (82 mg, 0.669 mmol) were added, and the reaction was stirred at the same temperature overnight. Thus, the mixture was treated with 1N HCl (30 ml) and extracted with DCM (2×100 ml). The organic phase was washed with brine and dried over Na2SO4; the solvent was removed under reduced pressure and the resulting crude was purified by flash chromatography (DCM/MeOH 98/2 to 90/10) yielding (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(6-(N-(2-morpholinoethyl)methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetoxy)ethyl)pyridine 1-oxide (203 mg, 0.253 mmol, 37.8% yield, MS/ESI+ 801.15 [MH]+, [αD]=−20.63, c=0.505, DCM). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (s, 2H), 7.52 (d, 1H), 7.27 (dd, 1H), 7.22 (d, 1H), 7.20 (d, 1H), 7.11 (d, 1H), 6.97 (dd, 1H), 7.08 (t, 1H), 6.04 (dd, 1H), 4.86 (d, 1H), 4.72 (d, 1H), 3.94 (d, 2H), 3.74 (t, 2H), 3.46-3.57 (m, 4H), 3.38 (dd, 1H), 3.22 (dd, 1H), 3.09 (s, 3H), 2.22-2.44 (m, 6H), 1.16-1.31 (m, 1H), 0.50-0.66 (m, 2H), 0.28-0.46 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][CH:12](C(OC)=O)[C:11](=[O:18])[CH2:10][S:9]2)=[CH:4][CH:3]=1>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[S:9][CH2:10][C:11](=[O:18])[CH2:12][S:13]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1SC(c2ccc(C)cc2)SCC1=O
Agent: O=S(=O)(O)O
Product: Cc1ccc(C2SCC(=O)CS2)cc1

Procedure:
131 g of methyl 2-(4-methylphenyl)-1,3-dithia-cyclohexan-5-one-4-carboxylate (0.464 mol) were heated under reflux with 350 ml of 2N sulfuric acid for 6 hours, with intensive stirring. After cooling, the mixture was decanted and the residue was taken up in ethyl acetate. The organic phase was washed with bicarbonate solution and water, dried and concentrated. For further purification, the solid residue was suspended in diisopropyl ether and filtered off with suction. This gave 62.7 g of yellow crystals (60.2% of theory), melting point: 112-113° C.
Reaction SMILES: [C:1]1([CH2:7]C(N)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCC=O)C=CC=CC=1.C1([CH2:27][CH:28]([NH:39][C:40](=[O:48])[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:29][C:30](=[O:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)C=CC=CC=1>>[C:1]1([CH2:7][CH2:27][CH:28]([NH:39][C:40](=[O:48])[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:29][C:30](=[O:38])[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)Cc1ccccc1
Reactant: O=C(Cc1ccccc1)NC(Cc1ccccc1)NC(=O)Cc1ccccc1
Agent: O=CCCc1ccccc1
Product: O=C(Cc1ccccc1)NC(CCc1ccccc1)NC(=O)Cc1ccccc1
Yield: 92 %

Procedure:
Compound 45 was prepared from 2-phenylacetamide and 3-phenylpropanal using the procedure for compound 44. Yield: 92%. 1HNMR (400 MHz, DMSO-d6) δ 8.45 (d, J=7.6 Hz, 2H), 7.10-7.31 (m, 15H), 5.26 (t, J=7.6 Hz, 1H), 3.38-3.46 (m, 4H), 2.47-2.53 (m, 2H), 1.88-1.94 (m, 2H). LCMS (ESI): m/z 387.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:18]([C:20]([C:22]1[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=1)=[O:21])[NH2:19].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:19][NH:18][C:20]([C:22]3[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=3)=[O:21])[CH3:17])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc(C(=O)NN)s1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(Cl)c(Cl)c3)c2O)s1
Yield: 86.5 %

Procedure:
From 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (57.4 mg, 0.2 mmol), methyl 5-hydrazinocarbonyl-2-thiophenecarboxylate (40.0 mg, 0.2 mmol) and tosylic acid monohydrate (11.4 mg, 0.06 mmol), 81.2 mg of the desired product was obtained in the same manner as in Synthetic Example 65 as a pale yellow solid (yield 87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[N:37]2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J34) (313 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K23) (287 mg, 1.0 mmol) according to the general procedure M. Obtained as a pale brown foam (220 mg, 42%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=O)=[O:22])[C:16]=1[CH3:34].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[F:64][C:65]1[CH:70]=[CH:69][C:68]([NH2:71])=[C:67]([NH2:72])[CH:66]=1>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:71][C:68]2[CH:69]=[CH:70][C:65]([F:64])=[CH:66][C:67]=2[NH2:72])=[O:33])=[O:22])[C:16]=1[CH3:34]
Reactant: Nc1ccc(F)cc1N
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCCCC(=O)Nc1ccc(F)cc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.8 %

Procedure:
8-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-octanoic acid (469 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-fluoro-o-phenylenediamine (151 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (386 mg, 67% yield) as a red solid. LC-MS (m/z) 578 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[CH:27]=[C:21]2[N:22]([CH3:26])[CH2:23][CH2:24][CH2:25][N:20]2[C:19](=[O:28])[N:18]=1>>[CH3:26][N:22]1[CH2:23][CH2:24][CH2:25][N:20]2[C:19](=[O:28])[N:18]=[C:17]([O:15][CH2:14][C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[CH:27]=[C:21]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccccc2)cc1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccccc3)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-phenoxyphenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:26][C:27](=[O:37])[NH:28][O:29]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N+:19]=3[O-:25])=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([CH2:6][C@H:7]([CH2:26][C:27]([NH:28][OH:29])=[O:37])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N+:19]=3[O-:25])=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccc(F)c[n+]1[O-])NOCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccc(F)c[n+]1[O-])NO
Reaction time: 1 h
Yield: 50 %

Procedure:
(5S)-1-((2R)-2-(Cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-(5-fluoro-1-oxido-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (90 mg, 0.18 mmol) was dissolved in methanol (8 mL), and Pearlman's catalyst (24 mg, 0.03 mmol) was added to the solution. The mixture was stirred under 1 atm of H2 (balloon) for 1 hour. After 1 hour, the reaction mixture was filtered, concentrated, and purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (5S)-1-[(2R)-2-(cyclopentylmethyl)-4-(hydroxyamino)-4-oxobutanoyl]-N-(5-fluoro-1-oxido-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (38 mg, 0.09 mmol, 50% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.79-0.94 (m, 1H) 1.04-1.24 (m, 3H) 1.41-1.68 (m, 7H) 1.72-2.32 (m, 18H) 2.39-2.52 (m, 2H) 2.58-2.74 (m, 2H) 3.21-3.31 (m, 1H) 3.39-3.50 (m, 1H) 3.69-3.81 (m, 1H) 5.08-5.22 (m, 1H) 7.03-7.07 (m, 1H) 7.17-7.24 (m, 2H) 8.23-8.29 (m, 1H) 8.42-8.49 (m, 1H) 10.92-11.05 (m, 1H). MS: 422 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(O)C.[Na]>O>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2
Reactant: Nc1cccc2cccnc12
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c1NCCC2
Yield: 52.4 %

Procedure:
To a solution of 20.00 g of 8-aminoquinoline in boiling absolute ethanol (400 ml) was added 44.74 g of sodium pellets over 20 mins, with stirring, until the sodium is dissolved. The reaction mixture was poured into water (50 ml) and concentrated. The residue was diluted with sodium bicarbonate solution and the mixture was extracted with dichloromethane. The extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was distilled under vacuum to give 10.77 g (52.3%) of product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1CO
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (50 g, 218.1 mmol) in dry THF (300 mL) was cooled to −78° C. followed by adding BH3-THF solution (261.7 mL, 260.0 mmol) dropwise over 1 h. The resulting mixture was warmed to RT and stirred for 48 h. The reaction was quenched with HOAc/H2O (1:1 ratio, 100 mL). The resulting mixture was partitioned between EtOAc and sat. NaHCO3. The organic layer was washed with more sat. NaHCO3, H2O, brine, and dried over MgSO4. Concentration in vacuo gave a white solid. MS m/z: 216.2 (M+H). Calc'd. for C11H21NO3-215.15.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:10]2[CH2:11][CH:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)([CH2:13]3)[CH2:9]2)=[O:26])=[CH:23][CH:22]=1
Reactant: Clc1ccc(C23CNCC2C3)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(c1ccc(F)cc1)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
Following the procedure of Example 8, 19.35 g. of 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane, 10.59 g. of sodium carbonate and 15.8 g. of p-fluorobenzoyl chloride are reacted. Ether extraction of the reaction product gives a white solid, mp 130°-132° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]([F:35])([F:34])[C@H:26]([OH:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CC1C=CN=C(N)C=1C.C(N(CC)CC)C>C(Cl)Cl>[F:24][C:25]([F:34])([F:35])[C@H:26]([O:33][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)=[O:22])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: O=C(Cl)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: CCCCCC[C@@H](O)C(F)(F)F
Agent: Cc1ccnc(N)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC[C@@H](OC(=O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1)C(F)(F)F
Temperature: 0 °C

Procedure:
To a solution of 4-benzyloxybiphenyl-4'-carboxylic acid chloride (1.23 g) in methylene chloride (10 ml) was added by little and little under ice-cooling a solution of (R)-(+)-1,1,1-trifluoro-2-octanol (0.96 g) ([α]D22.5 =+20.1, optical purity 96.3%ee), dimethyl-aminopyridine (0.55 g) and triethylamine (0.48 g) in methylene chloride (20 ml). The mixture was left to stand over-night at room temperature in order to complete the reaction before the mixture obtained was poured in ice-water.