Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](B(O)O)[CH3:11]>>[CH2:10]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:11]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCB(O)O
Product: CCc1ccc(C=O)cc1
Yield: 51.3 %

Procedure:
The compound was synthesized as in Example 3.1 using 4-bromobenzaldehyde (250 mg, 1.35 mmol) in place of 5-bromo-2-formylfuran and ethylboronic acid (165 mg, 2.23 mmol) in place of hexylboronic acid to give 4-ethylbenzaldehyde (93 mg, 51%). Used without further characterization.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[N+:32]([C:35]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:36]=1[S:44](Cl)(=[O:46])=[O:45])([O-:34])=[O:33].C([O-])(O)=O.[Na+]>C(Cl)Cl>[N+:32]([C:35]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:36]=1[S:44]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=2)[CH2:18][CH2:19]1)(=[O:46])=[O:45])([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
To a 20 mL resealable vial was added 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.27 g, 0.67 mmol, Example 91, Step 1), DCM (6 mL), triethylamine (0.47 mL, 3.4 mmol) and finally 2,4-dinitrobenzenesulfonyl chloride (0.22 g, 0.81 mmol). The mixture was stirred at room temperature for 15 min. To the reaction mixture was added saturated aqueous NaHCO3. This was stirred for 5 min and then the solution was transferred onto a phase separation cartridge (Radleys Discovery Technologies) with the organic phase being collected and passed through a plug of Na2SO4. The collected solution was concentrated and purified by silica gel chromatography (0 to 70% EtOAc/hexane) afforded 2-(4-(4-((2,4-dinitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.31 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]O.C1CCN2C(=NCCC2)CC1>COCCOC>[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][O:8][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: CN(C)CCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CN(C)CCOc1nc(N)nc(-c2ccco2)c1[N+](=O)[O-]

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, 2-dimethylaminoethanol and DBU in DME. ES-MS m/e (%): 294 (M+H+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[O:8][C:9]([CH:15]([Cl:20])[C:16]([F:19])([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[O:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[O:8][C:9]([CH:15]([Cl:20])[C:16]([F:19])([F:17])[F:18])([C:11]([F:12])([F:13])[F:14])[O:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2

Procedure:
72 g of 5-nitro-2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole from Example 16a were dissolved in 500 ml of tetrahydrofuran, and hydrogenated using 5 g of palladium on carbon (5%) for 5 hours at room temperature with 15 to 20 bar of hydrogen. The mixture was then filtered and the solvent stripped off in vacuo. The yield was 60 g (93% of theory), the boiling point was 80° to 82° C. at 0.1 mbar. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -66.5 and -79.4 ppm; 1H-NMR: 4.68 ppm.
Reaction SMILES: [OH-].[Na+].[C:3]1([C:12]([O:14]CC)=[O:13])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4]1>C(O)C>[CH2:10]([O:9][C:7]([C:3]1([C:12]([OH:14])=[O:13])[CH2:4][CH2:5][CH2:6]1)=[O:8])[CH3:11]
Reactant: CCOC(=O)C1(C(=O)OCC)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Sodium hydroxide (1N, 22.5 mmol) was added dropwise (1 drop for every 20 seconds) to a stirred solution of diethyl 1,1-cyclobutanedicarboxylate (4.5 g, 22.5 mmol) in ethanol (20 ml). The resulting mixture was stirred at room temperature for 6 hours, then concentrated by evaporation to a volume of about 10 ml. This residue was shaked with diethyl ether and the aqueous layer was separated. This aqueous was acidified with 12N hydrochloric acid while the temperature was kept below 10° C. The resulting mixture was extracted with diethyl ether (3×50 ml). The combined extracts were dried over magnesium sulfate, filtered and evaporated to yield the desired product as a colorless oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[CH2:31][C@H:30]([O:32][CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:29][CH2:28][C@@H:27]1[CH:42]=[O:43])=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:44][C:45]1[CH:50]=[C:49]([CH2:51][CH2:52][N+:53]([O-:55])=[O:54])[CH:48]=[C:47]([F:56])[CH:46]=1>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][C@H:30]([O:32][CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:29][CH2:28][C@@H:27]1[CH:42]([OH:43])[CH:52]([N+:53]([O-:55])=[O:54])[CH2:51][C:49]1[CH:50]=[C:45]([F:44])[CH:46]=[C:47]([F:56])[CH:48]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=[N+]([O-])CCc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCOCc2ccccc2)CC[C@@H]1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OCOCc2ccccc2)CC[C@@H]1C(O)C(Cc1cc(F)cc(F)c1)[N+](=O)[O-]
Reaction time: 8 h

Procedure:
Add tetrabutylammonium fluoride (12.0 mL, 11.9 mmol, 1.0 M in tetrahydro-furan) to (2R, 5R)-5-Benzyloxymethoxy-2-formyl-piperidine-1-carboxylic acid 1-tert-butyl ester (8.0 g, 23.90 mmol) and 1,3-difluoro-5-(2-nitro-ethyl)-benzene (4.92 g, 26.30 mmol) in 150 mL tetrahydrofuran at room temperature, stir overnight and concentrate. Subject to silica gel chromatography, eluting with 100% hexane to 90:10 hexane: ethyl acetate) to provide the desired compound as a mixture of 3 isomers (8.0 g, 62% overall yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:12].[H-].[Na+].[CH3:22]I>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:22])[C:11]([C:13]1[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[O:12]
Reactant: CI
Reactant: COc1ccc(CC(=O)c2cnc(C)cn2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C(=O)c2cnc(C)cn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A solution of 2-(2-chloro-4-methoxy-phenyl)-1-(5-methyl-pyrazin-2-yl)-ethanone (370 mg, 1.3 mmol) in DMF (5 mL) was added slowly over 30 min to a suspension of NaH (50% in mineral oil, 96 mg, 1.9 mmol) in DMF (2 mL). After 30 min, methyl iodide (199 mg, 1.4 mmol) was added slowly, and the mixture was stirred for 2 d at r.t. The reaction mixture was taken up in ethyl acetate, and washed (water, brine). The organic layer was separated, dried (Na2SO4), and the solvent was evaporated to give a residue, which was purified by column chromatography (silica gel, heptane:ethyl acetate=100:0-80:20) to give the title compound (290 mg, 75%). 1H NMR (300 MHz, CDCl3) □ 9.08 (1H, s), 8.45 (1H, s), 7.11 (1H, d), 6.92 (1H, d), 6.73 (1H, dd), 5.53 (1H, q), 3.75 (3H, s), 2.61 (3H, s), 1.49 (3H, d); MS (m/e)=291.0 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:11]([O-])([OH:13])=[O:12].OS(O)(=O)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Chlorobenzoic acid (2 g, 12.7 mmol) was added with stirring at 25° C. to a nitrating mixture (20 mL) prepared from 1:1 HNO3 (70%) and H2SO4 (98%). It was stirred for 1 h. and poured into ice water. The title compound obtained was filtered and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([CH:14]([CH3:16])[CH3:15])=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[NH:23]1[C:31]2[C:26](=[CH:27][C:28](B(O)O)=[CH:29][CH:30]=2)[CH:25]=[CH:24]1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:23]1[C:31]2[C:26](=[CH:27][C:28]([C:2]3[CH:3]=[C:4]([C:9]4[O:10][C:11]([CH:14]([CH3:16])[CH3:15])=[N:12][N:13]=4)[C:5]([NH2:8])=[N:6][CH:7]=3)=[CH:29][CH:30]=2)[CH:25]=[CH:24]1
Reactant: CC(C)c1nnc(-c2cc(Br)cnc2N)o1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nnc(-c2cc(-c3ccc4[nH]ccc4c3)cnc2N)o1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-3-(5-isopropyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ylamine (250 mg, 0.883 mmol) in dioxane (15 mL) and water (7 mL) were added K2CO3 (365 mg, 2.649 mmol), indole-5-boronic acid (156 mg, 0.971 mmol) in a sealed tube. The reaction mixture was degassed by N2 for 20 min, then Pd(PPh3)4 (102 mg, 0.088 mmol) was added and stirred for 18 h at 100° C. Water (20 mL) was added and extracted with ethyl acetate (3×20 mL) and the organic layer was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. Crude product was purified by column chromatography using 100-200 mesh silica gel compound eluted with 40% ethyl acetate in petroleum ether to afford the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][C:29]=1[N+:30]([O-])=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:30][C:29]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:18][C:17]=1[CH2:16][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10]
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(N)c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 3-[[bis-(t-butoxycarbonyl)]amino]methyl-4-nitrobenzoate (4.2 g, 9.3 mmol) in ethanol (150 mL) was hydrogenated at 40 psi in the presence of 10% Pd on C (0.40 g). After 30 minutes, catalyst was filtered and solvent removed to give the title compound in essentially quantitative yield: MS (ES) m/e 423 (M+H)+ ; 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 4.92 (br s, 2H), 4.68 (s, 2H), 1.62 (s, 9H), 1.49 (s, 18H).
Reaction SMILES: [Si]([O:8][C@H:9]([C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([NH:55][CH:56]=[O:57])[CH:49]=1)[CH2:10][NH:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([NH:20][C:21]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([O:31][C:32](=[O:46])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:27][CH2:26]2)=[O:22])=[C:15]([CH3:47])[CH:14]=1)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C>ClCCl>[CH:56]([NH:55][C:50]1[CH:49]=[C:48]([C@@H:9]([OH:8])[CH2:10][NH:11][CH2:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([NH:20][C:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32](=[O:46])[NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:27][CH2:26]3)=[O:22])=[C:15]([CH3:47])[CH:14]=2)[CH:53]=[CH:52][C:51]=1[OH:54])=[O:57]
Reactant: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(NC=O)c1
Agent: F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CNC[C@H](O)c1ccc(O)c(NC=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(tert-butyldimethylsilanyloxy)-2-(3-formylamino-4-hydroxyphenyl)ethylamino]methyl}-2,5-dimethylphenylcarbamoyl)-ethyl]piperidin-4-yl ester (238 mg, 0.30 mmol) in dichloromethane (3.0 mL) was added triethylamine trihydrofluoride (147 μL, 0.90 mmol). This mixture was stirred at room temperature overnight and then the mixture was concentrated under reduced pressure. The residue was purified by prep-RP-HPLC (gradient: 2 to 50% acetonitrile in water with 0.05% TFA). The appropriate fractions were collected and combined and lyophilized to give biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester as the ditrifluoroacetate salt (50 mg, 97% purity). LPLC (2-90) Rt=2.76; [M+H+] found 680.8.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C@@H:3]([C:9]([O:11]C(C)(C)C)=[O:10])[NH:4][S:5]([CH3:8])(=[O:7])=[O:6]>Cl.O1CCOCC1>[CH3:1][C:2]([CH3:17])([CH3:16])[C@@H:3]([C:9]([OH:11])=[O:10])[NH:4][S:5]([CH3:8])(=[O:7])=[O:6]
Reactant: CC(C)(C)OC(=O)[C@@H](NS(C)(=O)=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)[C@H](NS(C)(=O)=O)C(=O)O
Yield: 106.4 %

Procedure:
A solution of Example 152A (59 mg, 0.22 mmol) in 4N HCl in dioxane (1 mL) at 25° C. for 4 h, and the solvents were evaporated to give the crude title compound (49 mg, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1OC)([O-:3])=[O:2].[CH:19]([NH2:23])([CH2:21][CH3:22])[CH3:20]>>[CH:19]([NH:23][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])([CH2:21][CH3:22])[CH3:20]
Reactant: CCC(C)N
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
More specifically, the process for producing N-sec-butyl-4-tert-butyl-2,6-dinitroaniline comprises reacting 4-tert-butylphenol with dimethyl sulfate to produce 4-tert-butylanisole. The 4-tert-butylanisole is then reacted with a nitrating agent including a mixture of nitric acid, sulfuric acid and oleum to produce 2,6-dinitro-4-tert-butylanisole. The 2,6-dinitro-4-tert-butylanisole is then reacted with sec-butylamine to produce N-sec-butyl-4-tert-butyl-2,6-dinitroaniline.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH:9]=[CH:8][C:7]=1[C:18](=[O:20])[CH3:19])([OH:3])=[O:2].[CH2:21]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[OH-].[K+]>C(O)C>[C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]=[C:15]([CH3:16])[CH3:17])[CH:9]=[CH:8][C:7]=1[C:18](=[O:20])[CH:19]=[CH:32][C:31]1[CH:34]=[CH:35][C:28]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:29][CH:30]=1)([OH:3])=[O:2]
Reactant: CC(=O)c1ccc(OCC=C(C)C)cc1OCC(=O)O
Reactant: CCCCCCCc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCc1ccc(C=CC(=O)c2ccc(OCC=C(C)C)cc2OCC(=O)O)cc1
Reaction time: 5 h

Procedure:
To a solution of 3.48 9 of 2'-carboxymethoxy-4'-(3-methyl-2-butenyloxy)acetophenone and 2.80 g of 4-n-heptylbenzaldehyde in 120 ml of ethanol was added 3.5 g of potassium hydroxide, and the mixture was stirred for 5 hours. After neutralization with dilute sulfuric acid, the resulting precipitate was collected by filtration, washed with water, dried and recrystallized from ethanol to give 4.10 g of 2'-carboxymethoxy-4-n-heptyl-4'-(3-methyl-2-butenyloxy)chalcone as pale yellow needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].Br[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][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)Cc1ccc(N)cc1F
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)OCC)c(F)c1

Procedure:
A solution of 8.2 g. of 2-fluoro-4-aminophenylacetic acid, 150 ml. of absolute ethanol, and 3 ml. of boron trifluoride etherate is heated to reflux for 15 hours. The solution is concentrated by distillation and then evaporated to dryness in vacuo. The residue is dissolved in ethyl ether, washed with aqueous sodium bicarbonate dried and evaporated to yield ethyl 2-fluoro-4-aminophenylacetate. A mixture of 5.0 g. of this amine, 9.4 g. of 1-bromohexadecane, 4.2 g. of anhydrous potassium carbonate and 40 ml. of hexamethylphosphoramide is heated at 80° C. for 7 hours. The mixture is then cooled, diluted with water, and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from a mixture of chloroform and hexane, yielding ethyl 2-fluoro-4-(hexadecylamino)phenylacetate.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH:16]=[C:15]([CH3:25])[CH:14]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[O:28][CH3:29]>C1COCC1.CO.[Pt](=O)=O>[F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH2:16][CH:15]([CH3:25])[CH2:14]3)=[CH:11][CH:12]=2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: COc1cc(Oc2ccc(C3=CC(C)=CN4CCS(=O)(=O)N=C34)cc2)ccc1F
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(Oc2ccc(C3CC(C)CN4CCS(=O)(=O)N=C34)cc2)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.5 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-[4-(4-fluoro-3-methoxyphenoxy)phenyl]-7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (400 mg) in THF (dry) (15 ml) and MeOH (15 mL). The mixture was stirred at room temperature under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc). Platinum(IV) oxide (30 mg) was added and the mixture was stirred at room temperature under hydrogen overnight. AcOH (10 mL) and platinum(IV) oxide (30 mg) were added and the mixture was stirred at room temperature under hydrogen for 1 day and at 50° C. for 1 day. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (30.3 mg) as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([I:14])=[CH:12][N:13]=[C:7]2[CH:6]=1)=O.O.[NH2:16][NH2:17]>CO>[I:14][C:11]1[N:8]2[CH:9]=[CH:10][C:5]([C:3]([NH:16][NH2:17])=[O:2])=[CH:6][C:7]2=[N:13][CH:12]=1
Reactant: NN
Reactant: COC(=O)c1ccn2c(I)cnc2c1
Solvent: CO
Solvent: O
Product: NNC(=O)c1ccn2c(I)cnc2c1
Yield: 90.3 %

Procedure:
To a suspension of Methyl-3-Iodo-imidazo[1,2-a]pyridine-7-carboxylate (0.4 g, 1.32 mmol) in MeOH (6 ml) was added hydrazine hydrate (0.25 ml, 5.28 mmol). The mixture was refluxed for 4 h then further hydrazine hydrate (0.25 ml, 5.28 mmol) was added, the mixture heated o/n, allowed to cool, solid was filtered off and washed with MeOH and dried to afford 0.36 g of product. MS: [M+H]+ 303.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:39])[C:8]2[CH:14]=[C:13]([CH:15]=[CH:16][C:17]3[CH:38]=[CH:37][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].[H][H]>FC(F)(F)C(O)=O.[Pd]>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:39])[C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:37][CH:38]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C=Cc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Yield: 56 %

Procedure:
A solution of diethyl N-(4-[2-(2-acetamido-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethenyl]benzoyl)-L-glutamate in 30 mL of trifluoroacetic acid was hydrogenated at 55 psi of hydrogen in the presence of 1.0 g of 5% Pd/C at room temperature for 14 hours. The catalyst was removed by filtration, the filtrate evaporated under reduced pressure, and the residual solid partitioned between 100 mL of chloroform and 50 ml of 2N aqueous sodium carbonate. The organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent removed by evaporation to give a gum which was chromatographed on silica gel. Elution with chloroform:methanol (97:3) gave 0.25 g (56%) of diethyl N-(4-[2-(2-acetamido-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate; mp 215°-217° C.; NMR (CDCl3) delta 1.25, 1.35 (2t, 6H, J=6 Hz), 2.1-2.5 (m, 4H), 2.55 (s, 3H), 3.1 (s, 4H), 4.15, 4.25 (2q, 4H, J=6 Hz), 4.6-4.96 (m, 1H), 7.05 (s, 1H), 7.25, 7.75 (AB q, 4H, J= 9 Hz), 8.35 (d, 1H, J=3 Hz), 8.77 (d, 1H, J=3 Hz); IR (Nujol) 3200, 3150, 1725, 1675, 1630, 1605 cm-1. Anal.: Calc'd for C27H31N5O7 : C, 60.32; H, 5.81; N, 13.03. Found: C, 59.98; H, 6.03; N, 12.92).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH:6]=[O:7].[N+:17]([CH3:20])([O-:19])=[O:18]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH2:20][N+:17]([O-:19])=[O:18])[CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)ccc1-c1ccccn1
Solvent: C1CCOC1
Product: COc1cc(C(O)C[N+](=O)[O-])ccc1-c1ccccn1

Procedure:
A THF solution of 3-methoxy-4-pyridin-2-ylbenzaldehyde (0.3 g, 1.4 mmol), nitromethane (0.23 mL, 4.2 mmol) and TEA (0.2 mL, 1.4 mmol) was stirred at 55° C. over night, concentrated and purified on silica gel (2:1 hexane-ethyl acetate) to afford a yellow foam.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:6][CH2:7][NH2:8].C(O[CH:16](OCC)[CH2:17][O:18][C:19]1[CH:23]=[N:22][S:21][N:20]=1)C.O>Cl.C(O)CCC>[ClH:1].[S:21]1[N:22]=[CH:23][C:19]([O:18][CH2:17][CH:16]2[C:9]3[C:5](=[CH:4][C:3]([OH:2])=[C:11]([OH:12])[CH:10]=3)[CH2:6][CH2:7][NH:8]2)=[N:20]1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(COc1cnsn1)OCC
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: Oc1cc2c(cc1O)C(COc1cnsn1)NCC2
Yield: 74.1 %

Procedure:
A mixture of 3,4-dihydroxyphenethylamine hydrochloride (1.62 g), (1,2,5-thiadiazol-3-yl)oxyacetaldehyde diethyl acetal (2.6 g), n-butanol (50 ml), water (25 ml) and 10% hydrochloric acid (3 drops) was refluxed for 15 hours. After the reaction, n-butanol was distilled off from the reaction mixture under reduced pressure. The residue was dissolved in water, and the solution was washed twice with chloroform and once with ether and then the aqueous layer was concentrated to give colourless crystals of 1-(1,2,5-thiadiazol-3-yl)oxymethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2 g). The product was recrystallized from aqueous methanol to give colourless crystals like cotton, mp 252° C. (dec.).