Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@@H:8]1[O:34][C@H:33]([C:35]([O:37][CH3:38])=[O:36])[C@@H:25]([O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C@H:17]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:9]1[O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])(=O)C(C)(C)C.[I-:39].[K+].B(F)(F)F.CCOCC.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C>[I:39][C@H:8]1[O:34][C@H:33]([C:35]([O:37][CH3:38])=[O:36])[C@@H:25]([O:26][C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[CH3:31])[C@H:17]([O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])[C@H:9]1[O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)[C@H]1O[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: [I-]
Agent: FB(F)F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)[C@H]1O[C@H](I)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C

Procedure:
Methyl 1,2,3,4-tetra-O-pivaloyl-β-D-glucopyranuronate (2.72 g, 5 mmol) in acetonitrile (10 cm3) was heated and stirred at gentle reflux under argon with potassium iodide (1.66 g, 10 mmol) and boron trifluoride diethyl etherate (2.50cm3). After 1 h the dark mixture was cooled, then 10% aq. sodium thiosulfate (25 cm3) and saturated aqueous sodium bicarbonate (NaHCO3) (25 cm3) were added and the product was extracted using ethyl acetate (50 cm3+20 cm3). The combined organic phases were washed with further NaHCO3, water and brine, then dried over anhydrous Na2SO4 and evaporated to an orange gum (2.8 g). Triuration with ethanol gave a crystalline product; evaporation of the mother liquors, followed by chromatography on silica gel, eluting with 10% ethyl acetate in hexane, afforded further product of equal purity; combined yield, 1.89 g (66%), m.p. 98-100° C.; δH (220 MHz, CDC13) 1.10-1.30 (27H, 3s), 3.73 (3H, s), 4.26 (1H, dd), 4.35 (1H, d), 5.22, 5.61 (2H, 2t) and 7.04 (1H, d).
Reaction SMILES: [C:1]([NH:9][C:10](=[S:24])[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:25]1[CH2:31][C:29](=[O:30])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:26]1=[S:27].[Cl-].[NH4+].N>C(O)C>[C:1]([NH:9][C:10](=[S:24])[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[C:31]2[S:25][C:26](=[S:27])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:29]2=[O:30])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)c1csc(NC(=S)NC(=O)c2ccccc2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=S)NC(=O)c2ccccc2)n1

Procedure:
The reaction described in Example 1 was repeated, but using 1.5 g of ethyl 2-(3-benzoylthioureido)thiazol-4-ylglyoxylate, 0.79 g of rhodanine-3-acetic acid, 0.1 g of ammonium chloride, 0.4 ml of 28% v/v aqueous ammonia, and 20 ml of ethanol, giving the title compound as a yellow powder.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][S:5][CH:4]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([NH:2][C:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][S:5][CH:4]=1)(=[O:21])[CH3:20]
Reactant: COC(=O)c1cscc1N
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cscc1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A mixture of methyl 3-aminothiophene-4-carboxylate hydrochloride (3.1 g, 16 mmol) and triethylamine (6.7 mL, 48 mmol), in methylene chloride (75 mL) was stirred 30 minutes and then chilled over wet ice. Acetyl chloride (1.4 mL, 19.2 mmol) was added and the reaction was warmed to ambient temperature and stirred 1 hour. The reaction was quenched with water and diluted with methylene chloride. The phases were separated and the aqueous layer was extracted with methylene chloride. The combined organic layer was washed with water, dried over magnesium sulfate, and concentrated to afford 2.85 g (91%) of methyl 3-acetamidothiophene-4-carboxylate as a brown oil which solidified on standing. The product was suitable for use without purification.
Reaction SMILES: [C:1]1([C:7]([N:9]=[C:10]=[S:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=1[CH3:34].C1(C)C=CC=CC=1>C(O)C>[C:7]([NH:9][C:10]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[N:20]=[CH:19][CH:18]=2)=[C:28]([CH3:34])[CH:29]=1)=[S:11])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (61 mg, yield 80%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:34])[CH:14]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[NH:15][C:16](=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([C:24]#[N:25])[CH3:23])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:14]2[N:15]=[C:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH3:23])[C:24]#[N:25])[O:34][C:13]=2[C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)=[CH:32][CH:31]=1
Reactant: CC(C#N)CCCCCC(=O)NC(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C#N)CCCCCc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)o1
Temperature: 90 °C
Yield: 91.8 %

Procedure:
8 g of phosphorus oxychloride are added with stirring to a solution of 7.5 g (RS)-1,2-bis(4-chlorophenyl)-2-(7-cyanooctanamido)ethanone in 35 cm3 of toluene, and the mixture is heated to 90° C. for 6 hours. After treatment, the product obtained is chromatographed on a column 2.8 cm in diameter containing 110 g of silica gel (50 to 200μ). The column is eluted with 0.6 liter of diisopropyl ether, collecting 50 cm3 fractions. The fractions emerging at between 0.15 liter and 0.6 liter are concentrated under reduced pressure (0.2 kPa). 6.6 g (91%) of (RS)-7-[4,5-bis(4-chlorophenyl)-2-oxazolyl]-2-methylheptanenitrile are obtained in the form of a yellowish oil, which is used directly in the subsequent reaction.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:19]=[C:9]2[N:10]=[C:11](S(C)(=O)=O)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([Cl:35])[C:26]=1[C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28]>CC#N>[NH2:14][C:13]1[N:8]2[N:7]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:19]=[C:9]2[N:10]=[C:11]([N:32]2[CH2:33][CH2:34][N:29]([C:27]([C:26]3[C:25]([Cl:35])=[CH:24][N:23]=[CH:22][C:21]=3[Cl:20])=[O:28])[CH2:30][CH2:31]2)[N:12]=1
Reactant: O=C(c1c(Cl)cncc1Cl)N1CCNCC1
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Solvent: CC#N
Product: Nc1nc(N2CCN(C(=O)c3c(Cl)cncc3Cl)CC2)nc2nc(-c3ccco3)nn12
Temperature: 25 °C

Procedure:
2-Furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.15 mmol; see Example 1(a) above) was suspended in 4 mL of CH3CN along with 3 eq. of (3,5-Dichloro-pyridin-4-yl)-piperazin-1-yl-methanone. The reaction mixture was stirred under reflux for 3 hours. It was then cooled to room temperature and concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 8.9 (s, 2H), 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 2.2-3.2 (m, 8H). MS: m/z: 461 [M+H]+.
Reaction SMILES: [C:1](OC(=O)NC(C1C=C(F)C=C(F)C=1)(C)C=O)(C)(C)C.[ClH:21].[NH2:22][C:23]1([C:28]([O:30][CH3:31])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.NC1(C(O)=O)CCCCC1>>[ClH:21].[NH2:22][C:23]1([C:28]([O:30][CH3:31])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:1]1
Reactant: CC(C)(C)OC(=O)NC(C)(C=O)c1cc(F)cc(F)c1
Reactant: COC(=O)C1(N)CCCC1
Agent: Cl
Agent: NC1(C(=O)O)CCCCC1
Product: COC(=O)C1(N)CCCCC1

Procedure:
Essentially following the procedures described in Intermediate 1 for methyl 1-aminocyclopentanecarboxylate hydrochloride, but using 1-aminocyclohexanecarboxylic acid in place of 1-aminocyclopentanecarboxylic acid, the title compound was obtained. MS: m/z=158 (M+1).
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4]>FC(F)(F)C([O-])=O.[Ru+3].FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O>[CH2:1]([O:5][CH:1]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:2][CH2:3][CH3:4])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC=O
Agent: [Ru+3]
Agent: O=C([O-])C(F)(F)F
Product: CCCCOC(CCC)OCCCC

Procedure:
Example 3 is repeated, while replacing ruthenium chloride with ruthenium trifluoroacetate, the other conditions of the example being unchanged. 13.8 m.moles butanal and 32 m.moles 1,1-dibutoxybutane have been formed.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]23[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]2)[C:11](=[O:17])[O:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:19][CH2:20]O>O>[C:1]1([CH2:7][CH2:8][C:9]2[CH2:16][CH2:15][CH:12]([C:11]([O:10][CH2:19][CH3:20])=[O:17])[CH2:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: O=C1OC2(CCc3ccccc3)CCC1CC2
Agent: Cl
Solvent: O
Product: CCOC(=O)C1CC=C(CCc2ccccc2)CC1

Procedure:
Slowly add 2-phenylethyl bromide (2.6 g) to a slurry of Mg (0.37 g) in THF (50 mL) and heat at reflux for 4 h. Cool the solution to ambient temperature and add to a solution of ethyl 4-oxo-cyclo-hexanecarboxylate (2.4 g) in THF (50 mL). After 2 h, pour the reaction mixture into a half-saturated solution of NH4Cl and extract with EtOAc. Partially purify the product on a silica gel column, eluting with EtOAc. Dissolve the product in toluene (100 mL), treat with p-TsOH and heat at reflux overnight with azeotropic removal of water. Cool the reaction mixture, wash with saturated NaHCO3 solution and concentrate. Purify the crude product on a silica gel column, eluting with CH2Cl2 to obtain ethyl 4-(2-phenylethyl)-cyclohex-3-enecarboxylate (0.45 g) and 1-(2-phenyl-ethyl)-2-oxabicyclo[2.2.2]octan-3-one (0.71 g). Dissolve 1-(2-phenyl-ethyl)-2-oxabicyclo[2.2.2]octan-3-one in EtOH, treat with conc.HCl (catalytic) and heat at reflux overnight. Dilute the reaction mixture with water and extract with EtOAc. Concentrate the organic layer to obtain additional ethyl 4-(2-phenylethyl)-cyclohex-3-enecarboxylate (0.88 g).
Reaction SMILES: [C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:33](O)(=O)CCC/C=C\CC=CCC=CCC=CCC=CCC.Cl.COC(=O)[C@H]([C@@H](C)O)N>>[C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[C@@H:24]([CH3:33])[O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20]
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O
Reactant: CCC=CCC=CCC=CCC=CC/C=C\CCCC(=O)O
Agent: COC(=O)[C@@H](N)[C@@H](C)O
Agent: Cl
Product: CCC=CCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@H](C(=O)O)[C@@H](C)OP(=O)(O)O

Procedure:
This compound was prepared as described above for (6), using 0.5 mmol (151 mg) of cis-5,8,11,14,17-eicosapentaenoic acid and 1 mmol (170 mg) of L-threonine methyl ester hydrochloride; yield 99 mg, (41%); Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1.2-1.4 (d, 3H, CH3CHOP); 1.5-1.6 (t, 2H, CH2); 2.0-2.2 (m, 6H, CH2CO and 2CH2CH═CH); 2.7-2.9 (br s, 8H, 4HC═CH—CH2—CH═CH); 4.1-4.3 (m, 2H, 2CH); 5.2-5.4 (br s, 10H, 5HC═CH); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: [Cl:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[CH:3]=1.[CH3:11]COCC.[H-].[Na+].S(OC)(OC)(=O)=O>O>[CH3:11][N:6]1[C:2]([Cl:1])=[CH:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5]1
Reactant: COC(=O)c1c[nH]c(Cl)c1
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COC(=O)c1cc(Cl)n(C)c1
Reaction time: 1 h

Procedure:
Methyl 5-chloropyrrole-3-carboxylate (800 mg., 5 mmoles) was dissolved in 75 ml. of ether. Sodium hydride (57% dispersion in oil, 430 mg., 10 mmoles) was added and the mixture stirred under nitrogen for 1 hour. Dimethyl sulfate (1 ml., 10.7 mmoles) was added and stirring continued for 2 hours. Excess sodium hydride was decomposed by cautious addition of 20 ml. of water. The ether phase was washed with 20 ml. of water and evaporated to yield methyl 1-methyl-5-chloropyrrole-3-carboxylate (oil); the entire batch being used directly in the next step.
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH3:23])[C:12]([CH2:20][CH2:21][CH3:22])=[C:13]([C:17](=[O:19])[CH:18]=2)[C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]([CH3:23])[C:12]([CH2:20][CH2:21][CH3:22])=[C:13]([C:17](=[O:19])[CH:18]=2)[C:14]([O-:16])=[O:15])=[CH:8][CH:9]=1.[Na+:2]
Reactant: CCCc1c(C(=O)O)c(=O)cc(-c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(C(=O)[O-])c(=O)cc(-c2ccc(Cl)cc2)n1C
Reaction time: 1 h
Yield: 88 %

Procedure:
0.42 g (0.0052 mol) of 50% aqueous sodium hydroxide is added to a suspension of 1.6 g (0.0052 mol) 6-(4-chlorophenyl)-1-methyl-2-n-propyl-4-oxonicotinic acid in 25 ml of methanol. The solution formed is allowed to stand at room temperature for 1 hr. and is concentrated in vacuo. The concentrate is dried to afford 1.5 g (88% yield) of product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]>[Pd]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CCCCCCCCC=Cc1cccs1
Agent: [Pd]
Product: O=C(O)CCCCCCCCCCc1cccs1
Yield: 90.7 %

Procedure:
This compound was synthesized from 11-(2-thienyl)-10-undecenoic acid (800 mg, 3 mmol) by a hydrogenation reaction using Pd/C (80 mg). Crystallization (petroleum ether) afforded the product (0.73 g, 91%) as white crystals (mp 41-42° C.): IR: 3450-2500, 1715 cm-1 ; 1H-NMR: 1.30 (m, 12H), 1.63 (m, 4H), 2.32 (t, 2H), 2.80 (t, 2H), 6.78 (d, 1H), 6.90 (t, 1H), 7.10 (d, 1H), 9.80 (bs, 1H). Anal. Calcd. for C15H24O2S: C, 67.12, H, 9.01%; Found: C, 67.55, H, 8.89%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[C:21](OC)(=O)[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:23]>>[OH:23][CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21]1[NH:20][C:18](=[O:19])[C:3]2[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:2]=2[N:1]=1
Reactant: COC(=O)C(O)c1ccccc1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Product: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(C(O)c3ccccc3)nc21

Procedure:
Analogously to the procedure of Example 5, the title compound is prepared from 1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 1.89 g (11.4 mmol) of methyl mandelate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[F:20].[I:21]I.OS([O-])=O.[Na+]>S([O-])([O-])(=O)=O.[Ag+2].CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[C:16]([I:21])[C:15]([O:18][CH3:19])=[CH:14][C:13]=1[F:20]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2F)c(Cl)c1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Agent: O=S([O-])O
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(I)c(OC)cc2F)c(Cl)c1

Procedure:
Methyl 2-chloro-2′-fluoro-4′-methoxybiphenyl-4-carboxylate (550 mg, 1.87 mmol), methanol (8 mL), iodine (474 mg, 1.87 mmol), and silver sulfate (583 mg, 1.87 mmol) were stirred at room temperature for 2 hours to complete the reaction. The crude reaction mixture was worked up with NaHSO3 (aq). Volatiles were removed under reduced pressure. The pot residue was worked up with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated to afford a light brown solid. This solid was purified on SiO2 (Biotage HorizonFlash system, 40+M cartridge, 0-20% EtOAc/hexanes, v/v) to afford the title compounds as a light yellow solid. LCMS calc.=419.94; found=420.86 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10](OC(=O)C)(=[O:14])[C:11]([CH3:13])=[CH2:12]>>[C:10]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: NCCCCCC(=O)O
Reactant: C=C(C)C(=O)OC(C)=O
Product: C=C(C)C(=O)NCCCCCC(=O)O
Reaction time: 12 h
Yield: 86.9 %

Procedure:
To a solution of 6-aminocaproic acid (6.55 g), 50 mmol) in 150 ml of glacial acetic acid methacrylic anhydride (8.7 ml, 55 mmol) were added at room temperature, and resulting mixture was stirred for 12 hours. All volatiles were removed under reduced pressure. Crude material was submitted to column chromatography on silica gel, which was performed in chloroform with applying gradient of methanol (0-7.5%) and gave 8.65 g (87%) of N-methacryloyl-6-aminocaproic acid as white solid. MALDI MS: found 200.06 (M+H)+, C10H17NO3; calc. 199.07.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:39]=[C:38]([N:40]4[CH2:45][CH2:44][N:43]([CH2:46][C:47]5[CH2:52][C:51](=O)[CH2:50][CH2:49][C:48]=5[C:54]5[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=5)[CH2:42][CH2:41]4)[CH:37]=[CH:36][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1>ClCCl.CO>[Cl:60][C:57]1[CH:58]=[CH:59][C:54]([C:48]2[CH2:49][CH2:50][CH:51]([N:61]3[CH2:66][CH2:65][O:64][CH2:63][CH2:62]3)[CH2:52][C:47]=2[CH2:46][N:43]2[CH2:42][CH2:41][N:40]([C:38]3[CH:37]=[CH:36][C:12]([C:13]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=4)(=[O:18])=[O:17])=[O:14])=[C:11]([O:10][C:6]4[CH:7]=[C:8]5[C:9](=[CH:4][CH:5]=4)[NH:1][CH:2]=[CH:3]5)[CH:39]=3)[CH2:45][CH2:44]2)=[CH:55][CH:56]=1
Reactant: C1COCCN1
Reactant: O=C1CCC(c2ccc(Cl)cc2)=C(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]ccc5c4)c3)CC2)C1
Solvent: CO
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(N4CCOCC4)C3)CC2)cc1Oc1ccc2[nH]ccc2c1
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 249F (120 mg) in dichloromethane (2 mL) and methanol (0.5 mL) was added morpholine (37 mg) and 2-picoline borane complex (15.04 mg). The mixture was stirred overnight. The mixture was then diluted with dichloromethane (200 mL) and washed with aqueous NaHCO3, water, and brine, and dried over Na2SO4. The residue, after evaporation of solvent, was dissolved in dichloromethane and chromatographed with 0-10% 7N NH3 in 5% methanol in dichloromethane to give the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11.15 (s, 1H), 8.58 (m, 2H), 7.79 (dd, 1H), 7.53 (m, 1H), 7.35 (m, 4H), 7.17 (m, 1H), 7.07 (m, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.39 (s, 1H), 6.13 (d, 1H), 3.84 (m, 2H), 3.58 (m, 5H), 3.01 (m, 5H), 2.63 (m, 6H), 2.10 (m, 14H), 1.61 (m, 3H), 1.26 (m, 3H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[N:18]=[C:17]([N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:16]=[C:15]2[N:34]([CH2:42][C:43]3[C:48]([CH3:49])=[C:47]([O:50][CH3:51])[C:46]([CH3:52])=[CH:45][N:44]=3)[N:35]=[C:36]([CH2:37][CH:38]([C:40]#[N:41])[OH:39])[C:14]=12.ClCCl.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:39][CH:38]([C:40]#[N:41])[CH2:37][C:36]2[C:14]3[C:15](=[N:16][C:17]([N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[N:18][C:13]=3[Cl:12])[N:34]([CH2:42][C:43]3[C:48]([CH3:49])=[C:47]([O:50][CH3:51])[C:46]([CH3:52])=[CH:45][N:44]=3)[N:35]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1c(C)cnc(Cn2nc(CC(O)C#N)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1c(C)cnc(Cn2nc(CC(C#N)OS(=O)(=O)c3ccc(C)cc3)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
p-Toluenesulfonyl chloride (511 mg) was added to a mixture composed of the above crude di-tert-butyl {4-chloro-3-(2-cyano-2-hydroxyethyl)-1-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate (788 mg) and dehydrated dichloromethane (12 mL), followed by dropwise addition of triethylamine (0.56 mL). Then, 4-dimethylaminopyridine (16 mg) was added and the mixture was stirred at room temperature for three hours. The reaction mixture was diluted with chloroform and washed with water. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (450 mg, 45%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:4]([CH:5]=[O:6])[C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([O:11][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: BrCCc1ccccc1
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Cl)cc(Cl)c1OCCc1ccccc1
Reaction time: 120 h
Yield: 70 %

Procedure:
To 3,5-dichlorosalicylaldehyde (229 mg, 1.2 mmol) in DMF (5 ml) was added K2CO3 (1.06 g, 7.7 mmol) followed by (2-bromoethyl)benzene (0.14 ml, 1.0 mmol). The mixture was stirred under argon for five days then diluted with H2O (30 ml), extracted with Et2O (3×50 ml), dried (MgSO4), filtered, and concentrated in vacuo to give the title compound as a white powder (207 mg, 0.7 mmol, 70%); δH (CDCl3) 3.17 (2H, t), 4.31 (2H, t), 7.19-7.36 (5H, m), 7.60 (1H, d), 7.67 (1H, d), 9.95 (1H, s).