Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]1([C:31]2[C:32]([O:41][CH:42]3[CH2:47][CH2:46][C:45]([F:49])([F:48])[CH2:44][CH2:43]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36](O)=[O:37])[CH2:30][CH2:29]1.CS(N)(=O)=O.[CH:55]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56]1>>[CH:28]1([C:31]2[C:32]([O:41][CH:42]3[CH2:47][CH2:46][C:45]([F:49])([F:48])[CH2:44][CH2:43]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([NH:61][S:58]([CH:55]2[CH2:57][CH2:56]2)(=[O:60])=[O:59])=[O:37])[CH2:30][CH2:29]1
Reactant: O=C(O)c1cc(C2CC2)c(OC2CCC(F)(F)CC2)cc1F
Reactant: NS(=O)(=O)C1CC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoic acid and to replace methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained as a colorless solid (0.093 g, 48%): 1H NMR (300 MHz, DMSO-d6) δ 11.79 (br s, 1H), 7.13-7.06 (m, 2H), 4.78 (br s, 1H), 3.08-2.99 (m, 1H), 2.08-1.86 (m, 9H), 1.09-1.06 (m, 4H), 0.88-0.82 (m, 2H), 0.66-0.60 (m, 2H); 19F NMR (282 MHz, DMSO-d6) δ −92.1 (d, J=231 Hz, 1F), −98.5 (d, J=231 Hz, 1F), −112.5 (s, 1F); MS (ES−) m/z 416.10 (M−1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][N:15]([CH3:17])[CH3:16])=[N:7][C:6]=2[N:20]=1.[C:29]([N:33]=[C:34]=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][C:34]([NH:1][C:2]1[C:3]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][N:15]([CH3:17])[CH3:16])=[N:7][C:6]=2[N:20]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CN(C)CC(C)(C)CNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Product: CN(C)CC(C)(C)CNc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)NC(C)(C)C)nc2n1

Procedure:
Following the procedure of Example 21, 1.0 g of 7-amino-6-(2,6-dichlorophenyl)-2-(3-dimethylamino-2,2-dimethyl-propylamino)-pyrido[2,3-d]pyrimidine from Example 29 was reacted with 0.26 g of t-butyl isocyanate to give the title compound; mp 161-170° C.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:19]([N:18]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCCCCNCCCCC
Product: CCCCCCC/C=C/C(=O)N(CCCCC)CCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and diamylamine as starting materials to give the aimed compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:21]1[C:22]2[C:27]([N:28]=[C:29]3[C:34]=1[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:26][CH:25]=[CH:24][CH:23]=2>>[C:17]([O:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][C:6]=2[C:21]2[C:22]3[C:27]([N:28]=[C:29]4[C:34]=2[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9][CH2:10]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCCN1CCN(c2ccc(N)cc2)CC1
Reactant: Clc1c2c(nc3ccccc13)CCCC2
Product: CC(=O)OCCN1CCN(c2ccc(N)cc2-c2c3c(nc4ccccc24)CCCC3)CC1
Yield: 47 %

Procedure:
0.14 ml (2.0 mmol) of 2-bromoethanol and 0.17 ml (2.4 mmol) of acetyl chloride were dissolved in 2 ml of dichloromethane. 0.28 ml (2.0 mmol) of triethylamine was added, and the reaction mixture was stirred at room temperature. After 1 h 50 ml of dichloromethane was added to the reaction mixture, which was then washed with a sodium bicarbonate (sat.) solution, a 10% citric acid solution and water. The organic phase was dried over sodium sulfate and evaporated to obtain 0.241 g (72%) of 2-bromoethylacetate. Following the procedure outlined in Step 1 of Example 1, but substituting 2-bromoethylacetate for methyl iodide, afforded 2-[4-(4-nitrophenyl)piperazin-1-yl]ethylacetate (64%), which was reduced according to the procedure of Step 2 in Example 1 to give the corresponding amine 2-[4-(4-aminophenyl)piperazin-1-yl]ethylacetate in quantitative yield. 2-[4-(4-aminophenyl)piperazin-1-yl]ethylacetate was reacted with 9-chloro-1,2,3,4-tetrahydroacridine (according to the procedure of Step 4 in Example 1) to obtain 2-{4-[4-amino-(1,2,3,4-tetrahydroacridin-9-yl)phenyl]piperazin-1-yl}ethyl acetate with 47% yield. Treating the ester with 4 equivalents of lithium hydroxide in a dioxane/water solution overnight, afforded the title compound with 60% yield (overall yield 20%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[C:18]([O:22][C:23](=[O:48])[CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH:34][S:35]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])=[CH:33][C:28]=2[N:27]=[C:26]1[CH2:45][CH2:46][CH3:47])([CH3:21])([CH3:20])[CH3:19]>CC#N.CCOC(C)=O.O>[C:18]([O:22][C:23](=[O:48])[CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][C:32]([N:34]([CH2:2][CH2:3][O:4][C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=3)[S:35]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)(=[O:36])=[O:37])=[CH:33][C:28]=2[N:27]=[C:26]1[CH2:45][CH2:46][CH3:47])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: Clc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc2cc(N(CCOc3ccc(Cl)cc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Chlorophenyl 2-bromoethyl ether (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH2:11][OH:12])[CH:5]=1.[NH3:14]>CO>[OH:12][CH2:11][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([CH3:10])[N:7]=1)[C:3]([NH2:14])=[O:2]
Reactant: COC(=O)c1cc(C)nc(CO)c1
Reactant: N
Solvent: CO
Product: Cc1cc(C(N)=O)cc(CO)n1
Temperature: 25 °C

Procedure:
A solution of 2-hydroxymethyl-6-methyl-isonicotinic acid methyl ester (400 mg, 2.21 mmol) in 7 N NH3 in methanol (25 mL) is stirred in a sealed vessel at 70° C. for 24 h. The mixture is cooled to rt, the solvent is removed in vacuo and the residue is dried under HV to give crude 2-hydroxymethyl-6-methyl-isonicotinamide (400 mg) as a pale yellow solid; LC-MS: tR=0.21 min, [M+1]+=167.01; 1H NMR (D6-DMSO): δ 2.50 (s, 3H), 4.56 (d, J=5.5 Hz, 2H), 5.44 (t, J=5.8 Hz, 1H), 7.49 (s, 1H), 7.58 (s br, 1H), 7.67 (s, 1H), 8.16 (s br, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[S:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([NH:7][CH:11]2[CH2:12][CH2:13][S:8][CH2:9][CH2:10]2)=[N:5][N:6]=1
Reactant: O=C1CCSCC1
Reactant: Cc1nnc(N)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nnc(NC2CCSCC2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.5 %

Procedure:
To a solution (50 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (2.5 g) and tetrahydro-4H-thiopyran-4-one (3.6 g) in acetic acid was added sodium cyanoborohydride (8.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (2.4 g, 48%).
Reaction SMILES: OC1C=CC(C(C2C=CC=CC=2)=O)=CC=1.BrCCCCl.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:45]=[CH:44][C:35]([C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:37])=[CH:34][CH:33]=1.C(C1C=CC(OCCCOC2C=CC(C(=O)C3C=CC=CC=3)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH:79]([CH2:83][CH2:84][OH:85])[CH2:80][CH2:81][OH:82].[I-].[Na+]>CC(C)CC(=O)C>[OH:82][CH2:81][CH2:80][N:79]([CH2:83][CH2:84][OH:85])[CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:45]=[CH:44][C:35]([C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: O=C(c1ccccc1)c1ccc(OCCCCl)cc1
Reactant: OCCNCCO
Agent: ClCCCBr
Agent: O=C([O-])[O-]
Agent: O=C(c1ccccc1)c1ccc(O)cc1
Solvent: CC(=O)CC(C)C
Product: O=C(c1ccccc1)c1ccc(OCCCN(CCO)CCO)cc1
Temperature: 120 °C
Yield: 89 %

Procedure:
A 500 mL three-neck flask was charged with 4-hydroxybenzophenone (80.00 g; 0.4036 mol), 1-bromo-3-chloropropane (76.25 g; 0.4843 mol) and 4-methyl-2-pentanone (330 mL). Anhydrous potassium carbonate (61.36 g; 0.4440 mol) was added and the reaction mixture was stirred at reflux (120° C.) for 4 h. HPLC analysis shows that the reaction mixture contains 90.0% 4-(3-chloropropoxy)benzophenone; 7.0% 1,3-bis(4-benzoylphenoxy)propane and 0.8% 4-hydroxybenzophenone. The reaction mixture was filtered hot and the inorganic solids were washed with 4-methyl-2-pentanone (100 mL). The filtrate was charged into a mixture of diethanolamine (148.5 g; 1.412 mol), sodium iodide (6.05 g; 0.0404 mol) and 4-methyl-2-pentanone (150 mL). The reaction mixture heated to reflux (122° C.) for 24 h. The reaction mixture was cooled to room temperature and extracted with water (500 mL). The organic phase was extracted with 1 M HCl (500 mL) at 70° C. to prevent crystallisation of the 1,3-bis(4-benzoylphenoxy)propane byproduct. The aqueous phase was separated, cooled to room temperature and taken to pH 12 with 50% aqueous NaOH. The resulting emulsion was extracted with 4-methyl-2-pentanone (3×200 mL). The organic phase was separated, dried (MgSO4), filtered and the solvent removed in vacuo. This provides 4-{3-[bis(2-hydroxyethyl)amino]propoxy}benzophenone (123.2 g; 89% yield over 3 steps).
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:38]=[CH:39][CH:40]=1)[CH2:15][C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1>>[N:4]1[N:3]([CH2:7][C:8]([N:19]2[CH2:20][C@H:16]([CH2:15][C:14]3[CH:38]=[CH:39][CH:40]=[C:12]([F:11])[CH:13]=3)[CH2:17][C@H:18]2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: O=C(O)Cn1nccn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(F)c2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(F)c2)CN1C(=O)Cn1nccn1
Yield: 39 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride and (2S,4R)-4-(3-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 49, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(3-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (74 mg, 39%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.96 (s, 1H), 7.79 (s, 2H), 7.57-7.51 (m, 2H), 7.38-7.29 (m, 1H), 7.22-6.90 (m, 10H), 5.56-5.41 (m, 2H), 4.52-4.54 (m, 1H), 3.84-3.77 (m, 1H), 2.79-2.63 (m, 3H), 2.01-1.87 (m, 2H). MS (EI) for C28H25F2N5O3. found 517.9 (MH+).
Reaction SMILES: [C:1]([C:4]1([CH2:14][S:15][C:16]([CH3:19])(C)C)[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=[O:2].S.C(OC(=O)C)(=[O:23])C>FC(F)(F)C(O)=O.C(OCC)C>[C:1]([C:4]1([CH2:14][S:15][C:16](=[O:23])[CH3:19])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=[O:2]
Reactant: CC(C)(C)SCC1(C(=O)O)CCc2ccccc2C1
Reactant: CC(=O)OC(C)=O
Agent: S
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCC1(C(=O)O)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (5.36 g, 20.0 mmol) in trifluoroacetic acid (40 mL) and add mercuric acetate (6.36 g, 20.0 mmol). Stir at ambient temperature under an atmosphere of argon for 4.5 hours, then treat with gaseous hydrogen sulfide. Remove the resulting black solid by filtration and dilute the filtrate to 100 mL with methylene chloride. Wash with water, then with brine and dry (MgSO4). Evaporate the solvent in vacuo to a residue. Mix the residue with sulfuric acid (0.3 mL of 10% solution in acetic acid) and add acetic anhydride (2.04 g, 20.0 mmol). Stir the mixture for 2 hours under an atmosphere of argon at ambient temperature, then dilute with 100 mL ethyl ether. Wash with water, brine then dry (MgSO4). Concentrate the filtrate in vacuo to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:18])=[N:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([C:29]([CH3:33])([CH3:32])[CH2:30][Cl:31])=[O:28].C(Cl)Cl>C(C(C)=O)C>[CH3:1][N:2]1[C:6]([O:7][CH2:26][C:27](=[O:28])[C:29]([CH3:33])([CH3:32])[CH2:30][Cl:31])=[C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:18])=[N:3]1
Reactant: CC(C)(CCl)C(=O)CBr
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: Cc1nn(C)c(OCC(=O)C(C)(C)CCl)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 47.8 %

Procedure:
Into a four necked flask was charged 1.0 g of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxypyrazole, and the contents were dissolved in 20 ml of methyl ethyl ketone. 0.54 g of anhydrous potassium carbonate was added thereto, and 0.75 g of 1,1-dimethyl-2-chloroethyl bromomethyl ketone was further dropwise added while stirring whereby the mixture was reacted for 2 hours under the reflux condition (80° C.). After completion of the reaction, the reaction product was collected by filtration, and the solvent (methyl ethyl ketone) was distilled off to obtain a crude product. The crude product was passed through a silica gel column (eluent: methylene chloride), and the eluent was distilled off to obtain 0.7 g of the titled compound having a melting point of 58° to 60° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:17])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[CH:7]2.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH3:17])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[CH:7]2)=[O:22])[CH3:19]
Reactant: Cc1cc(N)c2[nH]c(-c3ccccn3)cc2c1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1cc(C)cc2cc(-c3ccccn3)[nH]c12

Procedure:
7-Amino-5-methyl-2-(pyridin-2-yl)-1H-indole prepared in Step A of Example 1 and ethylisocyanate were reacted according to the same procedure as Example 22 to give the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=2)[CH:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1[CH2:53][CH2:52]OCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:16]3[CH:12]=[N:11][C:10]4[C:52]([CH:53]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:12]2[N:11]=[C:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=2)[CH:9]=1
Reactant: COC(=O)Cc1ccc(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)cc1
Reactant: C1COCCO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)cc1
Temperature: 90 °C

Procedure:
Under Ar, methyl 2-(4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)methyl)phenyl)acetate (180 mg, 0.26 mmol) was mixed with Pd(dppf)Cl2 (21 mg, 0.26 mmol, K3PO4 (106 mg, 0.5 mmol), 3-quinoline bornic acid (55 mg, 0.31 mmol) and dioxane (10 mL with 1 ml water). The resulting mixture was heated at 90° C. and stirred over night. After cooled to room temperature, the mixture was diluted with EtOAc (60 mL) and filtered through celite. After concentration, the crude was purified with column (silica gel, 0˜30% EtOAc/Hexane) gave the product methyl 2-(4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)phenyl)acetate (150 mg). HPLC-MS tR=2.50 min (UV254 nm); mass calculated for formula C37H49N5O4Si2 683.3, observed LCMS m/z 684.4 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[N:31]=[C:17]2[N:18]=[C:19]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[N:20]=[C:21]([NH2:22])[N:16]2[N:15]=1.CCN(CC)CC>CC#N>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[N:31]=[C:17]2[N:18]=[C:19]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][N:27]([CH2:2][C:3]4[CH:7]=[C:6]([CH3:8])[O:5][N:4]=4)[CH2:26]3)[N:20]=[C:21]([NH2:22])[N:16]2[N:15]=1
Reactant: Cc1cc(CCl)no1
Reactant: Nc1nc(NCC2CCCNC2)nc2nc(-c3ccco3)nn12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(CN2CCCC(CNc3nc(N)n4nc(-c5ccco5)nc4n3)C2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chloromethyl-5-methyl-isoxazole (1.5 eq.) was directly added to a solution of 2-furan-2-yl-N5-piperidin-3-ylmethyl-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine (0.14 mmol) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.90 (br s, 2H), 7.80 (d, J=1.0 Hz, 1H), 7.05 (d, J=3.6 Hz, 1H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 6.30 (s, 1H), 3.65 (m, 2H), 3.20-2.75 (m, 11 H), 2.35 (s, 3H) ppm. MS: m/z: 410 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH:23][C:31](=[O:32])[CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc([N+](=O)[O-])c1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)Cc2ccccc2)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and 2-phenylacetyl chloride, gave 5-formyl-6-methoxy-3′-nitro-N-(2-phenylacetyl)-biphenyl-3-sulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].C1C(=O)N([I:17])C(=O)C1>CO>[Cl:1][C:2]1[CH:7]=[C:6]([I:17])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1c(Cl)cccc1Cl
Solvent: CO
Product: Oc1c(Cl)cc(I)cc1Cl
Yield: 59.2 %

Procedure:
A solution of 2,6-dichlorophenol (10 g, 61.35 mmol, 1.00 equiv) and NIS (27.6 g, 245.33 mmol, 2.00 equiv) in methanol (100 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was redissolved in 50 mL of ethyl acetate and washed with 3×30 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with petroleum ether (100%) to give 10.5 g (59%) of 2,6-dichloro-4-iodophenol as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 9.83 (s, 1H), 7.27 (s, 2H) ppm.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:14]=[C:15]([Cl:19])[CH:16]=[N:17][CH:18]=1)[CH3:2].[I:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.N1C=CC=CC=1.C>C(Cl)Cl.C(OCC)(=O)C.CO>[CH2:1]([NH:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([NH:11][S:28]([C:25]2[CH:26]=[CH:27][C:22]([I:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:14]=[C:15]([Cl:19])[CH:16]=[N:17][CH:18]=1)[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CCNC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CCNC(=O)c1cc(NS(=O)(=O)c2ccc(I)cc2)ccc1Oc1cncc(Cl)c1
Yield: 73.2 %

Procedure:
To a suspension of N-ethyl 5-amino-2-(3-chloro-5-pyridyloxy)benzamide from Example 17.3 (0.9 g) in methylene chloride (10 mL) was added 4-iodobenzenesulfonyl chloride (1.03 g), followed by pyridine (275 μL). The reaction progress was monitored by TLC, and upon completion the solvent was removed under vacuum. The resulting residue was partitioned between methylene chloride and water. The organic layer was drawn off and concentrated to form pink crystals. The crystals were dissolved in ethyl acetate (200 mL) and methanol (10 mL), and decolorized with activated charcoal. After filtration, the solution was concentrated to an oil and the residue was triturated with ether to provide 1.26 g of the title compound as colorless crystals. mp 154-156° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]2[C@H:12]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=1)(=O)C>CO.OS(O)(=O)=O>[F:22][C:21]([F:23])([F:24])[C:20]([NH:19][C@H:12]1[C:13]2[C:8](=[CH:7][C:6]([CH2:5][OH:4])=[C:15]([N+:16]([O-:18])=[O:17])[CH:14]=2)[CH2:9][CH2:10][CH2:11]1)=[O:25]
Reactant: CC(=O)OCc1cc2c(cc1[N+](=O)[O-])[C@H](NC(=O)C(F)(F)F)CCC2
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=C(N[C@@H]1CCCc2cc(CO)c([N+](=O)[O-])cc21)C(F)(F)F
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-(3-nitro-5-(2,2,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl)methyl acetate (17 mg) in 10 mL of MeOH was added one drop of 96% H2SO4 and the resulting mixture was stirred at 50° C. for 3 h. After cooling to RT, the reaction was quenched with Sat. NaHCO3 (0.5 mL). The MeOH was evaporated and the residue was directly loaded on column chomatography (SiO2, DCM to DCM/EtOAc=2:1 to 1:1) to give (R)-2,2,2-trifluoro-N-(6-(hydroxymethyl)-7-nitro-1,2,3,4-tetrahydro-naphthalen-1-yl)acetamide as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7](OCC)(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10].C1C(CCCCC(N)=O)SSC1>C(O)C>[CH3:11][C:9]([CH2:8][C:7]([O:1][CH2:2][CH:3]([OH:4])[CH2:5][OH:6])=[O:12])=[O:10]
Reactant: CCOC(=O)CC(C)=O
Reactant: OCC(O)CO
Agent: NC(=O)CCCCC1CCSS1
Solvent: CCO
Product: CC(=O)CC(=O)OCC(O)CO

Procedure:
In accordance with at least one other embodiment of the present technology, glycerol can be treated with ethyl acetoacetate in presence of a lipase at from about 55° C. to about 70° C., alternatively from about 20 to about 75, for approximately 14 to 48 hours, alternatively 20 to 36 hours. The lipase can be, for example, Novozyme® 435, Lipozyme® RM IM, or Lipozyme® TL IM, all available from Novozymes A/S, Franklinton, N.C. The reaction can be performed in an inert (e.g., nitrogen) atmosphere. During the reaction, ethyl alcohol by-product can be removed, for example, via distillation. At the end of the reaction, the remaining ethyl acetoacetate can be removed through distillation (e.g., at 60° C., 1 mmHg). The structure of the triglyceride of acetoacetin produced can be confirmed through, for example, NMR analysis and/or GC.