Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH2:11][C:12]#[N:13].[NH2:14][C:15]1[C:20]([CH:21]=O)=[CH:19][N:18]=[C:17]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:16]=1.O>C(OCCO)C>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:12]([NH2:13])=[N:14][C:15]2[N:16]=[C:17]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:18]=[CH:19][C:20]=2[CH:21]=1
Reactant: N#CCc1c(Cl)cccc1Cl
Reactant: Nc1nc(Nc2ccccc2)ncc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCCO
Product: Nc1nc2nc(Nc3ccccc3)ncc2cc1-c1c(Cl)cccc1Cl
Yield: 68.4 %

Procedure:
To a solution of 0.022 g 60% sodium hydride suspension in 2.00 mL of 2-ethoxyethanol was added 0.46 g of 2,6-dichlorophenylacetonitrile and 0.50 g of 4-amino-2-phenylamino-pyrimidine-5-carboxaldehyde from Example 72. The reaction was refluxed for 4 hours, cooled, poured into water, and extracted several times with dichloromethane. The dichloromethane washes were combined, washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The residue was washed with diethyl ether to give 0.61 g of the title compound, CIMS (1% NH3 in CH4): 410=M+ +C2H5, 382=M+ +H, 381=M+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[N:24]=[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:22]=1[CH3:38].Cl.O1CCOCC1.CN1C(=O)CCC1>>[N:4]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]=[C:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[C:22]=3[CH3:38])=[CH:11][C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 160 °C

Procedure:
Prepared according to Procedure K, method 2 using 2,5-dimorpholinopyridin-3-amine (143 mg, 0.543 mmol; described herein), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (148 mg, 0.54 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (140 μL, 0.54 mmol), and NMP (780 μL, 8.1 mmol). The reaction was heated in a microwave at 160° C. for three h. Purification afforded N-(2,5-di-4-morpholinyl-3-pyridinyl)-7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.75 (1H, dd, J=4.3, 0.8 Hz), 7.93 (3H, d, J=5.5 Hz), 7.86 (1H, br. s.), 7.60-7.69 (1H, m), 7.38-7.46 (1H, m), 7.29-7.36 (2H, m), 6.31 (1H, br. s.), 3.91 (4H, br. s.), 3.68-3.81 (4H, m), 3.25 (4H, br. s.), 2.95 (4H, br. s.), 2.38 (3H, s). Mass Spectrum (ESI) m/e=501.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][CH:4]=1.[NH2:12][C@@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CC(N(C)C)=O>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([NH:12][C@@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=[CH:5][CH:4]=1
Reactant: CC(C)[C@@H](N)C(=O)O
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O
Temperature: 90 °C
Yield: 46 %

Procedure:
4-Trifluoromethyliodobenzene (0.27 g, 1.0 mmol), D-valine (0.12 g, 1.0 mmol), potassium carbonate (0.21 g, 1.5 mmol), copper(I) iodide (19 mg, 0.10 mmol) and dimethylacetamide (1 mL) were charged in a threaded test tube, and the mixture was stirred with heating at 90° C. for 2 days. After work-up according to a conventional method, the object product was eluted by silica gel column chromatography (20% to 40% mixed solvent of ethyl acetate/hexane) to give the title compound (0.12 g, 0.46 mmol, 46%).
Reaction SMILES: [CH3:1][Mg]I.[CH3:4][O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([C:9]3=[O:16])[CH2:7]1)[CH2:13]2>CCOCC.C1COCC1>[CH3:4][O:5][C:6]12[CH2:7][CH:8]3[CH2:14][CH:12]([CH2:11][CH:10]([C:9]3([CH3:1])[OH:16])[CH2:15]1)[CH2:13]2
Reactant: COC12CC3CC(C1)C(=O)C(C3)C2
Reactant: C[Mg]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC12CC3CC(C1)C(C)(O)C(C3)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Freshly prepared methyl magnesium iodide in ether (1M, 32 mL), was added through a canula to 5-methoxyadamantan-2-one (3.0 g, 16 mmol) in THF (32 mL) at 0° C. After stirring the mixture at 0° C. for 0.5 h, the reaction mixture was quenched by adding saturated aq. NH4Cl solution. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain 5-methoxy-2-methyladamantan-2-ol as 1:1 anomeric mixture (3.0 g yield, 96%). m/z (M+23), 219; 1H NMR (CDCl3) 300 MHz δ 3.24 (s, 1½H), 3.23 ((s, 1½H), 2.68-2.62 (m, 1H), 2.40-1.55 (m, 10H), 1.53-1.35 (m, 2H), 1.38 (s, 3H).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C=CC(S(O)(=O)=O)=C(N)C=2)=[CH:4][C:3]=1C(O)=O.N1C(Cl)=NC(Cl)=NC=1Cl>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc(Sc2cc(C(=O)O)c(N)c3c2C(=O)c2ccccc2C3=O)ccc1S(=O)(=O)O
Agent: Clc1nc(Cl)nc(Cl)n1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
Example 13 was repeated, provided that the compounds described in 1st, 2nd and 3rd columns of the following table were used in place of the 1-amino-2-carboxy-4-(3'-amino-4'-sulfophenylthio)anthraquinone, cyanuric chloride and 1-aminobenzene-3-8-sulfatoethylsulfone, respectively, thereby obtaining a corresponding anthraquinone compound. A color shade obtained by dyeing cotton with the anthraquinone compound is as shown in a 4th column of the table.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[CH2:22]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:23][CH2:24][CH2:25][CH3:26].C(NCCCC)CCC>>[CH2:28]([N:27]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCNCCCCC
Reactant: Cc1cccn2cc(-c3ccc(OCCCCl)cc3)nc12
Solvent: CCCCNCCCC
Product: CCCCCN(CCCCC)CCCOc1ccc(-c2cn3cccc(C)c3n2)cc1

Procedure:
This compound was prepared according to the procedure described in Example 1 above using 2-(4-chloropropoxyphenyl)-8-methylimidazo[1,2-a]pyridine and dipentylamine instead of 2-(4-chloropropoxyphenyl)-imidazo[1,2-a]pyridine and dibutylamine respectively. Analysis Calc'd for C27H39N3O3HCl; C, 8.03; H, 60.05; N, 7.78. Found: C, 8.35; H, 60.16; N, 7.39.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[C:39]([N:43]=[C:44]=[O:45])([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:11]([CH2:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][NH:2][C:44]([NH:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:45])[CH:5]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: CC(C)(C)N=C=O
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (55 mg, 0.11 mmol) in dry DCM (0.5 mL) was added triethylamine (0.015 mL, 0.11 mmol), followed by tert-butyl isocyanate (0.013 mL, 0.11 mmol). The reaction mixture was stirred at room temperature for 1.5 h. LCMS showed mainly required product with 6% SM. The reaction mixture was diluted with DCM and methanol and then concentrated in vacuo. The resultant residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was evaporated in vacuo to give the title compound (52 mg, 84%). LCMS (System A) RT=1.15 min, ES+ve m/z 562/564 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]([CH2:30][CH2:31][CH3:32])[CH:9]2[CH2:18][C:17]3[CH:16]=[C:15]([O:19][S:20]([C:23]4[C:24]([CH3:29])=[N:25][O:26][C:27]=4[CH3:28])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=3[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.C(OC([N:40]1[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>ClCCl>[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][N:8]([CH2:30][CH2:31][CH3:32])[CH:9]3[CH2:18][C:17]4[CH:16]=[C:15]([O:19][S:20]([C:23]5[C:24]([CH3:29])=[N:25][O:26][C:27]=5[CH3:28])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=4[CH2:11][CH2:10]3)[CH2:3][CH2:2]2)=[O:47])[CH2:42][CH2:41]1
Reactant: CCCN(CC1CCNCC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CC1CCN(C(=O)C2CCNCC2)CC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.7 %

Procedure:
Under an inert atmosphere 3,5-dimethyl-isoxazole-4-sulfonic acid 7-(piperidin-4-ylmethyl-propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl ester (400 mg, 0.87 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (199 mg, 0.87 mmol, 1 eq.), EDCl (166 mg, 0.87 mmol, 1 eq.), triethylamine (0.25 mL, 1.79 mmol, 2 eq.), and dichloromethane (35 mL) were combined. The mixture was stirred at room temperature for 48 h and then concentrated in vacuo. The residue was taken up in EtOAc (50 mL) and washed with water (30 mL), 1 N NaOH (30 mL), brine (30 mL), and then dried (MgSO4). The solution was filtered and concentrated to afford a yellow oil. The oil was flash chromatographed on silica gel eluting with 20% acetone in hexanes to afford the protected amine as a foam (447 mg), which was deprotected with trifluoroacetic acid, as described herein, to afford 3,5-dimethyl-isoxazole-4-sulfonic acid 7-{[1-(piperidine-4-carbonyl)-piperidin-4-ylmethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl ester (320 mg), 114M+H]+=609.
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH2:3][CH2:2]1.[C:11](OC(=O)C)(=[O:13])[CH3:12].S(=O)(=O)(O)O.O>O(CC)CC>[C:11]([O:10][C:5]1[C:4]2[CH2:3][CH2:2][CH2:1][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:13])[CH3:12]
Reactant: Oc1cccc2c1CCC2
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: CC(=O)Oc1cccc2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 115 %

Procedure:
A mixture of 2,3-dihydro-1H-inden-4-ol (0.37 mol) and acetic anhydride (0.37 mol) in sulfuric acid (300 mol) was stirred for 1 hour at room temperature. The reaction mixture was poured out into a mixture of water and 1,1'-oxybisethane. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 75 g (>100% crude residue) of 2,3-dihydro-1H-inden-4-ol acetate (ester) (interm. 1-a).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1Cl.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O>[Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1
Reactant: CN1CCNCC1
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Solvent: O
Product: CN1CCN(c2cnn(C)c(=O)c2Cl)CC1

Procedure:
A mixture of 4,5-dichloro-2-methylpyridazin-3(2H)-one [S.-F. Chen and R. P. Panzica, J. Org. Chem., 46, 2467-2473 (1981)] (8.95 g, 50 mmol) and 1-methylpiperazine (12.5 g, 125 mmol) in water (150 ml) was refluxed for 30 h. After cooling, about two thirds of the solvent was removed under reduced pressure and the mixture was adjusted to pH 7-8 by addition of aqueous NaHCO3. It was then extracted with dichloromethane (4×40 ml) and the combined extracts were washed with water, dried (Na2SO4) and evaporated. The crude product was purified by recrystallization from ethanol (95%).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][C:6]1=[O:17].[CH3:26][O:27][C:28](=[O:45])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[CH3:26][O:27][C:28](=[O:45])[CH2:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=2[CH2:4][N:5]2[C@@H:9]([CH3:10])[C@@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:17])[CH:33]=[CH:32][CH:31]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Br
Reactant: COC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)Cc1cccc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (4S,5R)-3-(2-bromo-5-trifluoromethyl-benzyl)-4-methyl-5-phenyl-oxazolidin-2-one and [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([CH2:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.[O:27]1[CH2:32][CH2:31][CH:30]([CH:33]=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]([C:6]2[C:7]([CH2:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[CH2:2][CH2:3]1
Reactant: CCc1nn2c(-c3c(C)cc(C)cc3OC)cccc2c1NCC1CC1
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1nn2c(-c3c(C)cc(C)cc3OC)cccc2c1N(CC1CCOCC1)CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
After dissolving N-cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine (255 mg) in tetrahydrofuran (2 mL), tetrahydro-2H-4-pyrancarbaldehyde (173 mg) [CAS No. 50675-18-8] and sodium triacetoxyborohydride (241 mg) were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (134 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a yellow oil.
Reaction SMILES: C1C[O:4]CC1.[CH2:6]1[CH2:11][CH2:10][CH:9]([N:12]=[C:13]=[N:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:8][CH2:7]1.C(N)CCCCCCCCCCC>N1C=CC=CC=1>[C:13]([NH:12][CH:9]1[CH2:8][CH2:7][CH2:6][CH2:11][CH2:10]1)([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:4]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C1CCOC1
Agent: CCCCCCCCCCCCN
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
If the desacylsaponins are soluble in anhydrous pyridine, alone or with anhydrous THF, the reaction can be carried out with DCC. 100 mg of (4) (60 μmoles) are dissolved in pyridine and/or THF, using no less than 1 ml but no more than 5 ml. 1 ml of a 0.3M dodecylamine solution (300 μmoles) in pyridine and/or THF is thereafter added to the reaction mixture, followed by 300 μmoles of dry DCC. The mixture is allowed to react with mixing overnight at 0° C. to 10° C. During the reaction, insoluble dicyclohexylurea is formed; this is removed by centrifugation. The supernatant containing the conjugated desacylsaponins (5) is diluted with 10 volumes of EtOAc to precipitate (5). The EtOAc containing the free alkyl amine, residual DCC, and the pyridine and/or THF is discarded. Precipitate is washed with EtOAc, dissolved in water and re-extracted with EtOAc before removing the EtOAc and lyophilizing.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[O:38][N:37]=[C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[CH:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:42][C:39]5([C:36]6[CH:35]=[C:34]([CH3:33])[O:38][N:37]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: Cc1cc(C2(N)CC2)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cc(C)on5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(5-methylisoxazol-3-yl)cyclopropanamine (0.074 g, 0.5 mmol, 1.1 eq), HOBT (0.094 g, 0.69 mmol, 1.5 eq), EDC.HCl (0.0.13 g, 0.69 mmol, 1.5 eq), in DCM at ambient temperature and under a nitrogen atmosphere was added diisopropylethylamine (0.19 ml, 1.3 mmol, 3.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by Preparative TLC (Eluent Hexane:Ethyl acetate 1:1, 300 ml). Yield: 0.1 g (39.22%). 1H NMR (400 MHz, CD3OD): δ 1.39-1.48 (m, 4H), 2.36 (s, 3H), 2.380-2.382 (d, 3H, J=0.8 Hz), 2.96 (s, 3H,), 4.05, (s, 3H), 6.05 (d, 1H, J=0.8 Hz), 7.12 (s, 1H), 7.26-7.34 (m, 3H), 7.58-7.59 (d, 1H, J=1.2 Hz), 7.62-7.64 (d, 1H, J=8.8 Hz), 7.81 (s, 1H), 7.96-7.98 (m, 2H). LCMS: (ES+) m/z=554.2 (M+H)+
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20](O)=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br.[S:26]1[C:30]2[CH2:31][CH:32]([NH2:35])[CH2:33][CH2:34][C:29]=2[N:28]=[C:27]1[NH2:36]>>[NH2:36][C:27]1[S:26][C:30]2[CH2:31][CH:32]([NH:35][C:20](=[O:21])[CH2:19][N:14]3[C:15]([CH3:18])=[CH:16][CH:17]=[C:12]([NH:11][S:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)(=[O:10])=[O:9])[C:13]3=[O:23])[CH2:33][CH2:34][C:29]=2[N:28]=1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Reactant: Nc1nc2c(s1)CC(N)CC2
Agent: Br
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)NC1CCc2nc(N)sc2C1

Procedure:
The title compound was prepared from 2-[3-[(benzylsulfonyl)amino]-6 -methyl-2-oxo-1(2H)-pyridinyl]acetic acid and 4,5,6,7-tetrahydro-1,3-benzothiazol-2,6-diamine dihydrobromide using the procedure of EXAMPLE 1 (STEP 6), and was obtained as an off-white solid compound.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([CH2:63][CH2:64][CH2:65][C@H:66]([NH:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:67](OCC#N)=[O:68])=[N+:61]=[N-:62]>O.O1CCCC1>[N:60]([CH2:63][CH2:64][CH2:65][C@@H:66]([NH:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:67]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:68])=[N+:61]=[N-:62]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN=[N+]=[N-])C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCN=[N+]=[N-])C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (77 mg, 0.121 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 5-azido-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk70) (144 mg, 0.484 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (18 mL), and the mixture was stirred at room temperature for 0.5 hour. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-azido-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk71) (24.5 mg, 23%).
Reaction SMILES: [CH2:1]([C:3]1([CH3:15])[CH2:12][C:11](=O)[C:10]2[C:5](=[CH:6][C:7]([OH:14])=[CH:8][CH:9]=2)[O:4]1)[CH3:2].C1(C=CC=C(O)C=1)O.B(F)(F)F.CCOCC.C1C=CC2OCCC(=O)C=2C=1.[F:44][C:45]([F:55])([F:54])[C:46]1[CH:47]=[C:48]([Mg]Br)[CH:49]=[CH:50][CH:51]=1>>[CH2:1]([C:3]1([CH3:15])[CH:12]=[C:11]([C:50]2[CH:49]=[CH:48][CH:47]=[C:46]([C:45]([F:55])([F:54])[F:44])[CH:51]=2)[C:10]2[C:5](=[CH:6][C:7]([OH:14])=[CH:8][CH:9]=2)[O:4]1)[CH3:2]
Reactant: CCC1(C)CC(=O)c2ccc(O)cc2O1
Reactant: FC(F)(F)c1cccc([Mg]Br)c1
Agent: FB(F)F
Agent: O=C1CCOc2ccccc21
Agent: Oc1cccc(O)c1
Solvent: CCOCC
Product: CCC1(C)C=C(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1

Procedure:
2-Ethyl-7-hydroxy-2-methyl-4-chromanone, m.p. 109°-110.5° C., was prepared by condensing resorcinol with 3-methyl-2-pentanoic acid in the presence of boron trifluoride diethyl etherate. Reaction of the chromanone with 3-trifluoromethylphenyl magnesium bromide as described in Preparation 5 gave the title chromene as a golden yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[N+:13]([O-])([OH:15])=[O:14].O>C(Cl)Cl>[CH3:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][C:5]([N+:13]([O-:15])=[O:14])=[C:4]([OH:12])[CH:3]=1
Reactant: Cc1cc(O)ccc1S(C)(=O)=O
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)c([N+](=O)[O-])cc1S(C)(=O)=O
Yield: 19.5 %

Procedure:
3-Methyl-4-(methylsulfonyl)phenol (D85, 503 mg, 2.29 mmol) was dissolved in DCM (5 mL) and 70% nitric acid (0.16 mL, 3.58 mmol) was added dropwise to the reaction. The mixture was stirred o/n. A further 2 mL of 70% nitric acid was then added. The reaction was stirred for 4 h, then H2O (20 mL) was added and the 2 phases were separated. The aqueous layer was extracted with DCM and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a yellow solid, which was purified via flash column chromatography (silica, iso-hexane to 50% EtOAc/50% iso-hexane) to give a yellow solid. This solid was triturated with Et2O (2×) to give 5-methyl-4-(methylsulfonyl)-2-nitrophenol (D86, 103 mg, 19%) as a yellow solid.