Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH2:16][OH:17])[CH2:8][C:7]2[C:9]([CH3:15])=[CH:10][C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.[CH3:18]I.[Cl-].[NH4+]>C(OCC)(=O)C.C1COCC1>[CH3:18][O:17][CH2:16][C:4]1([CH3:3])[CH2:8][C:7]2[C:9]([CH3:15])=[CH:10][C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1
Reactant: Cc1cc(C)c2c(c1C)OC(C)(CO)C2
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCC1(C)Cc2c(C)cc(C)c(C)c2O1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 65.5 %

Procedure:
60% sodium hydride (60 mg, 1.46 mmol) was added to a solution of THF (3 mL) containing (2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl)methanol (200 mg, 0.970 mmol) synthesized in Reference Example 122 under ice-cooling condition, and the mixture was stirred at 0° C. for 20 minutes. After that, methyl iodide (413 mg, 2.19 mmol) was added thereto, and the mixture was warmed to room temperature, followed by stirring for 15 hours. The reaction solution was poured into a saturated ammonium chloride aqueous solution, and extraction was performed using ethyl acetate. The extract was washed with saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 98:2-92:8) to give 140 mg of the title compound (yield: 66%).
Reaction SMILES: [CH3:1][N:2]([CH3:38])[C:3]([O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]([C:22]([NH:24][C:25]3[CH:26]=[C:27](/[CH:31]=[CH:32]/[C:33]([O:35]CC)=[O:34])[CH:28]=[CH:29][CH:30]=3)=[O:23])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=1)=[O:4].O[Li].O>C1COCC1.O>[CH3:38][N:2]([CH3:1])[C:3]([O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]([C:22]([NH:24][C:25]3[CH:26]=[C:27](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])[CH:28]=[CH:29][CH:30]=3)=[O:23])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: CCOC(=O)/C=C/c1cccc(NC(=O)c2cc(-c3cccc(OC(=O)N(C)C)c3)cc3ccccc23)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)Oc1cccc(-c2cc(C(=O)Nc3cccc(/C=C/C(=O)O)c3)c3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
Compound 26 (0.23 mmol,) was dissolved in THF/H2O (1:1, 20 mL) mixture. LiOH.H2O (0.35 mmol,) was added to the reaction mixture and stirred at room temperature for 3 h. The reaction mixture was concentrated under vacuum to dryness. The resulting residue was adjusted to pH 5 with dilute HCl and extracted with ethyl acetate (3×10 mL), washed with water and brine. The organic layer was dried over Na2SO4, filtered, and the solvent was removed in vacuo. The resulting solid was purified using reverse phase column chromatography to afford pure 27 as a white solid.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10](Cl)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[C:13]1([C:19]2([CH2:22][OH:23])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[S:1]1[C:5]2[C:6]([C:10]([O:23][CH2:22][C:19]3([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][CH2:21]3)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: OCC1(c2ccccc2)CC1
Reactant: O=C(Cl)c1cccc2nnsc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCC1(c2ccccc2)CC1)c1cccc2nnsc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.7 g of benzo-1,2,3-thiadiazole-7-carboxylic acid chloride in 33 ml of dichloromethane is added dropwise at a maximum of 15° C., with cooling, to a solution of 5.0 g of 1-phenylcyclopropanemethanol, 6.1 ml of triethylamine and 200 mg of 4-dimethylaminopyridine in 50 ml of dichloromethane. The mixture is stirred overnight at room temperature until the reaction is complete, dichloromethane and ice-water are added, the aqueous phase is extracted with dichloromethane, and the organic phase is washed with water and NaCl solution, dried over Na2SO4 and concentrated by evaporation. The residue is purified on silica gel (hexane-ethyl acetate 1:1) and the product obtained is recrystallised from diethyl ether/hexane. 7.5 g of crystals having a melting point of 55°-57° C. are obtained.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.[F:23][C:24]([F:34])([F:33])[C:25]1[C:29]([CH2:30][CH2:31][OH:32])=[CH:28][NH:27][N:26]=1.[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[OH:32][CH2:31][CH2:30][C:29]1[C:25]([C:24]([F:34])([F:33])[F:23])=[N:26][N:27]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]3)[CH:28]=1
Reactant: OCCc1c[nH]nc1C(F)(F)F
Reactant: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(CO)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(Cn3cc(CCO)c(C(F)(F)F)n3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
(R)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (45 mg, 0.17 mmol) was dissolved in DCM (5 mL) and thionyl chloride (99 mg, 0.83 mmol) was added. The reaction mixture was stirred at room temperature for 1 h before being concentrated to dryness. The whole was dissolved in DMF (2 mL) and added to a solution of 2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)ethanol (30 mg, 0.17 mmol) in DMF (2 mL) which had been treated with sodium hydride (8 mg, 0.33 mmol) for 15 min. The reaction mixture was heated to 65° C. for 3 h before being quenched with water (2 mL) and the organics extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Purification by preparative basic HPLC gave (R)—N-(5-((4-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (13.6 mg, 0.032 mmol, 18.9%). MS (ESI): m/z [M+H]+ 432.5
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:16])[NH:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C=O)C>[F:8][C:6]1[CH:5]=[C:4]([C:9]2([CH3:16])[NH:13][C:12](=[O:14])[N:11]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[C:10]2=[O:15])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC1(c2cc(F)cc(F)c2)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)NC(C)(c3cc(F)cc(F)c3)C2=O)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (±)-5-(3,5-difluorophenyl)-5-methylimidazolidine-2,4-dione from Step A (6.53 g, 28.9 mmol) in DMF (60 mL) was added potassium carbonate (4.39 g, 31.8 mmol) and 4-methoxybenzyl chloride (3.92 mL, 28.9 mmol). The reaction was stirred at ambient temperature for 16 h and at 50° C. for 1 h and then quenched with H2O (100 mL). The resulting precipitate was filtered and rinsed with water to provide the title compound. MS: m/z=347 (M+1).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[OH:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29].Cl>N1C=CC=CC=1>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[O:27][C:28](=[O:30])[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1sc2cc3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1C1CCCC1
Yield: 99.7 %

Procedure:
To 2-cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (2.8 g, 7.5 mmol) in anhydrous pyridine (20 mL) at room temperature under nitrogen was added dropwise acetic anhydride (0.92 mL, 9.8 mmol). The reaction mixture was placed in the refrigerator. After 41 h the reaction was diluted and acidified with 10% aqueous hydrochloric acid to a pH of 1. The mixture was extracted with diethyl ether (500 mL), and the diethyl ether layer was washed with 5% aqueous hydrochloric acid (100 mL), twice with water (100 mL), brine (100 mL), and then dried (MgSO4). Concentration under reduced pressure gave the tide compound as a white solid (3.1 g, 98%): (DMSO-d6): δ 8.48 (s, 1H), 7.97 (d, 1H), 7.47-7.43 (m, 1H), 7.38-7.36 (m, 2H), 7.28 (s, 1H), 7.19 (d, 2H), 3.14 (quintet, 1H), 2.40 (s, 3H), 2.37 (s, 3H), 1.99-1.91 (m, 2H), 1.69-1.40 (m, 6H), 1.56 (s, 3H); MS(EI): [M+] 414; Anal. Calc. for C27H26O2S: C, 78.23, H, 6.32, N, 0.00. Found: C, 77.68, H, 6.39, N, 0.04.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH2:17][S:18][CH3:19])[NH2:15].[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[C:30]1[O:34][C:33](=[O:35])[C:32]2([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[N:31]=1>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH2:17][S:18][CH3:19])[NH:15][C:33]([C:32]1([NH:31][C:30]([C:22]2[S:21][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH:23]=2)=[O:34])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)=[O:35]
Reactant: O=C1OC(c2cc3ccccc3s2)=NC12CCCCC2
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)C1(NC(=O)c2cc3ccccc3s2)CCCCC1
Reaction time: 8 h
Yield: 86.4 %

Procedure:
679 mg (5.3 mmol) of diisopropylethylamine was added to a suspension of 419 mg (2 mmol) of L-methionine methyl ester hydrochloride and 500 mg (1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 10 ml of toluene, and the mixture was heated under reflux overnight. After the solvent was distilled off under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with a 10% aqueous potassium hydrogensulfate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, diethyl ether was added, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 678 mg (86%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[N:20]=1.[OH-].[Na+].O.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[N:20]=1
Reactant: COC(=O)CCn1ccc(-c2cc3c(ccc4nnc(C)n43)n2Cc2cccc(Cl)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nnc2ccc3c(cc(-c4ccn(CCC(=O)O)n4)n3Cc3cccc(Cl)c3)n12
Reaction time: 0.42 h

Procedure:
6-(3-Chlorobenzyl)-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (25 mg, 0.069 mmol, from Example 103, Step 5) in acetonitrile (0.90 mL) was treated with methyl acrylate (19 μL, 0.21 mmol, Aldrich) and 1,8-diazabicyclo[5.4.0]undec-7-ene (10. μL, 0.069 mmol, Aldrich) and stirred for 70 minutes. Purification via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) followed by evaporation of eluent afforded methyl 3-(3-(6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl)propanoate. The ester intermediate was dissolved in THF (0.45 mL) and was treated with 1.0 M NaOH in water (0.45 mL, 0.45 mmol). After 25 minutes, the reaction was acidified to pH 3-4 by the addition of 1 N HCl. Water was added (3 mL), and the precipitated product was isolated by filtration and air dried. Yield: (21 mg, 70%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[CH3:20]O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Reactant: CO
Product: COC(=O)CCCCCCCCCCCCCCCO

Procedure:
Synthesis was carried out in the same manner as described in Preparation Example 20 from 16-hydroxyhexadecanoic acid and methanol to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[N:3]=1.[CH2:20]([O:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34](OCC)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1)[CH3:21]>O1CCCCC1.O1CCCC1>[CH2:20]([O:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34]([NH:11][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[C:2]([CH3:1])=[N:3][N:4]4[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1)[CH3:21]
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Reactant: CCOCOc1ccn2c(C(=O)OCC)cnc2c1
Solvent: C1CCOC1
Solvent: C1CCOCC1
Product: CCOCOc1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 0 °C
Yield: 59.5 %

Procedure:
3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (22 mg, 0.09 mmol) was dissolved in tetrahydropyran (DriSolve; 0.5 mL) and degassed before back-filling with nitrogen gas. The solution was then cooled in an ice water bath for 15 minutes before drop-wise addition of lithium bis(trimethylsilyl)amide (0.09 mL, 1 M in tetrahydrofuran). The reaction stirred for 10 minutes before drop-wise addition into a solution of ethyl 7-(ethoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylate (11 mg, 0.04 mmol) in tetrahydrofuran (DriSolve; 0.2 mL) cooled in an ice-water bath. The reaction was then stirred while being cooled in the ice-water bath for 1.5 hours. The reaction was quenched with water and concentrated. The resulting crude material was purified by reverse phase chromatography, eluting with a gradient from 10% to 70% ACN/water over 25 column volumes, to give 7-(ethoxymethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (11.2 mg).
Reaction SMILES: N[C@H](C(O)=O)CC(=O)O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+].[O:39]=[CH:40][C@@H:41]([C@H:43]([C@@H:45]([C@@H:47]([CH2:49][OH:50])[OH:48])[OH:46])[OH:44])[OH:42].[OH:51][CH2:52][C:53]([C@H:55]([C@@H:57]([C@@H:59]([CH2:61]O)[OH:60])[OH:58])[OH:56])=[O:54]>>[CH2:49]([OH:50])[C@H:47]1[O:48][C@H:40]([O:39][CH2:61][C@H:59]2[O:60][C:53]([OH:54])([CH2:52][OH:51])[C@@H:55]([OH:56])[C@@H:57]2[OH:58])[C@H:41]([OH:42])[C@@H:43]([OH:44])[C@@H:45]1[OH:46]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: N[C@@H](CC(=O)O)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: OC[C@H]1O[C@H](OC[C@H]2OC(O)(CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
6100 units of glucoamylase of Asp. niger origin were added to 5 ml of a reaction mixture of a citric acid-sodium citrate buffer (pH 4.5) containing 10% glucose and 30% fructose, and a reaction was carried out at 65° C. overnight. The yield of isomaltulose formed during the reaction was 46% in relation to the glucose added. Note, the isomaltulose was determined according to the following procedure: The reaction mixture was filtrated by a ultrafiltration membrane to eliminate proteins, and the filtrate was diluted 6 to 10 fold. One μl of the diluted sample was spotted on a thin layer Kiesel Gel 60F254 plate (Merck), and the plate was subjected to two-dimensional thin layer chromatography using, as a developing solution, a mixture of methyl ethyl ketone, 2-propanol, acetonitrile, 0.5 M boric acid, and 0.25 M isopropylamine dissolved in acetic acid (2:3:1:1), and a mixture of methyl ethyl ketone, dipropyl ether, 2-propanol, pyridine, water and pheny boric acid (2:1:3:1:2.4). The plate was then treated with a mixture of 2% diphenylamine and 2% aniline dissolved in acetone, and phosphoric acid (1:1:8.5) to detect the isomaltulose by color development. Further, the reaction mixture was analyzed by high performance liquid chromatography using Shodex DC 613 column or Shodex SZ 5532 column (Showa Denko, Japan)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[CH:9][CH:8]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[O:39]1[CH:43]=[CH:42][CH:41]=[C:40]1B(O)O>C1COCC1>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:13](=[C:14]2[CH2:15][C:16]([CH3:22])([CH3:23])[CH2:17][C:18]([CH3:20])([CH3:21])[CH2:19]2)[C:10]2[CH:9]=[CH:8][C:7]([C:40]3[O:39][CH:43]=[CH:42][CH:41]=3)=[CH:12][CH:11]=2)=[CH:29][CH:28]=1
Reactant: OB(O)c1ccco1
Reactant: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(-c3ccco3)cc2)CC(C)(C)C1
Temperature: 120 °C
Yield: 80.7 %

Procedure:
The Suzuki procedure described for 28 was utilized using triflate 25 (150 mg, 0.319 mmol), PdCl2 (Ph3P)2 (23 mg, 0.032 mmol), 2 N aqueous Na2CO3 (1.6 mL, 3.2 mmol), 2-furanylboronic acid (179 mg, 1.6 mmol), and THF (2 mL). The mixture was heated at 120° C. for 15 min using microwave conditions. Standard work-up followed by purification gave 100 mg (81%) of the title product 30 as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.58 (d, J=8.4 Hz, 2H), 7.44 (s, 1H), 7.18-7.12 (m, 4H), 6.96 (t, J=8.8 (Hz, 2H), 6.60 (d, J=3.2 Hz, 1H), 7.45 (br s, 1H), 2.0 (s, 2H), 1.96 (s, 2H), 1.30 (s, 2H), 0.93 (s, 12H). LCMS (APCI): m/z 389 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:16](=O)[CH3:17])[CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7](=O)[CH3:8])C.O.[NH2:21][NH2:22]>C(O)C>[CH3:1][O:3][C:4]([C:5]1[CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH3:8])=[N:21][NH:22][C:16]=1[CH3:17])=[O:19]
Reactant: NN
Reactant: CCOC(=O)C(C(C)=O)C(C(C)=O)c1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)C1=C(C)NN=C(C)C1c1ccccc1

Procedure:
19 g (75 mmols) of 2-acetyl-4-oxo-3-phenyl-pentanoic acid ethyl ester were heated to the boil together with 3.75 g (75 mmols) of hydrazine hydrate in 100 ml of ethanol under nitrogen for 10 hours. The solvent was then distilled off in vacuo and the residue was recrystallised from isopropanol.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([C:8]1[O:12][N:11]=[C:10]([N:13]=[C:14]=[O:15])[CH:9]=1)([CH3:7])([CH3:6])[CH3:5]>C1C=CC=CC=1>[CH3:1][N:2]([CH3:3])[C:14]([NH:13][C:10]1[CH:9]=[C:8]([C:4]([CH3:7])([CH3:5])[CH3:6])[O:12][N:11]=1)=[O:15]
Reactant: CNC
Reactant: CC(C)(C)c1cc(N=C=O)no1
Solvent: c1ccccc1
Product: CN(C)C(=O)Nc1cc(C(C)(C)C)on1

Procedure:
1,1-Dimethyl-3-(5-tert.-butyl-3-isoxazolyl)urea is prepared by condensing dimethylamine with 5-tert.-butyl-3-isoxazolyl isocyanate in benzene. After removal of the reaction solvent and purification by chromatography or crystallization, there is obtained 1,1-dimethyl-3-(5-tert.-butyl-3-isoxazolyl)urea. M.P. 119.5°-120.5° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([CH2:12]P(=O)(OC)OC)([OH:11])=[O:10].[CH3:19][O:20][C:21](=[O:51])[CH2:22][O:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][CH2:28][CH:29]2[C:34](N(CC1C=CC=CC=1)CC1C=CC=CC=1)=O.Cl>O1CCCC1>[C:9](/[CH:12]=[CH:34]/[CH:29]1[C:30]2[C:25](=[C:24]([O:23][CH2:22][C:21]([O:20][CH3:19])=[O:51])[CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:27][CH2:28]1)([OH:11])=[O:10]
Reactant: COP(=O)(CC(=O)O)OC
Reactant: COC(=O)COc1cccc2c1CCCC2C(=O)N(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)COc1cccc2c1CCCC2/C=C/C(=O)O
Reaction time: 0.17 h
Yield: 118.5 %

Procedure:
To a solution of isopropylamine (1.87 ml) in dry tetrahydrofuran (50 ml) was added dropwise 1.15M n-butyllithium in hexane solution (10.6 ml) at -78° C. The mixture was stirred for 20 min at -78° C. to give lithium diisopropylamide. To the obtained lithium diisopropylamide solution was added a solution of dimethyl carboxymethylphosphonate (1.02 g) in dry tetrahydrofuran (3 ml) at -78° C. After stirred for 10 min, to the mixture was added the aldehyde compound (prepared in reference example 1, 1.38 g) at room temperature. The mixture was stirred for 1 h at room temperature. After acidified by adding 1N hydrochloric acid until pH 3, the mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and evaporated. The residue was crystallized from ethyl acetate-hexane (3:7) to give the title compound (1.07 g) as white powder having the following physical data.
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:49])C=1.C(OCC)(=O)C.CO>C(Cl)(Cl)Cl>[CH2:1]([N+:4]([O-:49])([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:2]=[CH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCN(CCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=CC[N+]([O-])(CCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Into a cooled solution of 5.0 g (9 mmol) of N-allyl-N,N-dioctadecylamine in 50 ml of chloroform at 0° C. under a nitrogen atmosphere is added dropwise with stirring a solution of 2.82 g (9 mmol) of 55% active m-chloroperbenzoic acid in 25 ml of chloroform. After the addition is complete (approximately 10 minutes), the resultant solution is allowed to warm to ambient temperature (about 22°-24° C.). The reaction is complete after about 2 hours when TLC analysis (silica gel, 19:1 v/v ethyl acetate:methanol) indicates the starting material has completely reacted. The reaction mixture is passed through a short column of basic alumina using chloroform as an eluent to give 5.2 g (quantitative yield) of the title compound as a white solid melting at 59°-64° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.[CH:32]1[C:41]2[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[C:36]=2[CH:35]=[CH:34][N:33]=1>O>[CH:32]1[C:41]2[C:36](=[C:37]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=3)[CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][N:33]=1
Reactant: OB(O)c1cccc2cnccc12
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(COc2ccc(-c3cccc4cnccc34)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.5 mL of a sonicated and degassed solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1; 740 mg, 2 mmol), potassium carbonate (830 mg, 6 mmol), bis(tri-cyclohexylphosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 70 mg, 0.1 mmol), dioxane (41 mL) and water (4.1 mL) was added to a reaction vial containing 5-isoquinolineboronic acid (available from Frontier Scientific, Inc., Logan, Utah; 104 mg, 0.6 mmol). The solution was sonicated and degassed. The mixture was heated in a microwave oven at 170 degrees for 25 min. The reaction mixture was filtered through silica, and washed with dioxane (1 mL) and dimethylacetamide (1 mL). 2 M potassium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight, and then 1 M HCl (0.8 mL) was added. The solvents were removed in the Genevac and then 50% aqueous methanol (2 mL) was added. The vial was centrifuged and the solvent removed. This process was repeated and then the same was dried overnight in the oven to give 3-(4-isoquinolin-5-yl-phenoxymethyl)-benzoic acid. Mass spectrum MH+=356.