Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [B:1]([O-:7])([O-:6])[O:2][CH:3]([CH3:5])[CH3:4].O[C:9]([C:12](O)([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[CH:3]([O:2][B:1]1[O:7][C:12]([CH3:14])([CH3:13])[C:9]([CH3:11])([CH3:10])[O:6]1)([CH3:5])[CH3:4]
Reactant: CC(C)OB([O-])[O-]
Reactant: CC(C)(O)C(C)(C)O
Product: CC(C)OB1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A 5 L 4-neck flask equipped with a reflux condenser, mechanical stirrer, N2 inlet, and thermowell was flushed well with N2 and charged with isopropyl borate (2.673 L, 11.5 mol, 1.15 equiv) and pinacol (1.179 kg, 10 mol). The resulting mixture was heated at reflux)(80-85° for overnight. The mixture was then cooled to room temperature, transferred to a 5 L 4-neck flask equipped with a 24 inch Vigreux column, magnetic stirrer, and thermowell. The mixture was distilled at atmospheric pressure under nitrogen. After the low boiling fraction (bp 90-180°) which contained predominately 2-propanol and isopropyl borate (GC analysis) was removed, the completed distillation afforded 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (10, 1.628 kg, 1.86 Kg theoretical, 87.5%) as a colorless liquid (bp 180-185° C. with GC purity >97.5%). This material was stored in Sure/Seal bottles to minimize hydrolysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][N:18]([CH3:31])[CH2:19][CH2:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22].C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([CH2:20][CH2:19][N:18]([CH3:31])[CH3:17])(=[O:23])=[O:22])=[CH:29][CH:28]=1
Reactant: CN(C)CCS(=O)(=O)c1ccc(N)cc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCS(=O)(=O)c1ccc(N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1
Yield: 37.7 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.17 g, 0.61 mmol) and 4-(2-dimethylamino-ethanesulfonyl)-phenylamine (0.14 g, 0.61 mmol) were stirred in N,N-dimethylformamide (3 mL) and triethylamine (0.16 mL) at 60-70° C. The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol, and then dried under vacuum to give (4Z)-6-bromo-4-{[(4-{[2-(dimethylamino)ethyl]sulfonyl}-phenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (0.11 g, 36%) as a golden powder.
Reaction SMILES: [CH2:1]1[CH2:21][N:20]2[C:4]3[C:5]([CH2:17][CH2:18][CH2:19]2)=[C:6]2[O:13][C:11](=[O:12])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][C:7]2=[CH:8][C:3]=3[CH2:2]1.C[O:23][C:24](=[O:31])[CH2:25][CH2:26][CH:27](N)[CH2:28][CH3:29].C[N:33](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH2:1]1[CH2:21][N:20]2[C:4]3[C:5]([CH2:17][CH2:18][CH2:19]2)=[C:6]2[O:13][C:11](=[O:12])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][C:7]2=[CH:8][C:3]=3[CH2:2]1.[NH2:33][CH:25]([CH2:26][CH2:27][CH2:28][CH3:29])[C:24]([OH:23])=[O:31]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCC(N)CCC(=O)OC
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cc2cc3c4c(c2oc1=O)CCCN4CCC3
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC(N)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Coumarin 343 (5 mmol, Aldrich No. 393029) and each 5.5 mmol of 4-aminohexanoic acid methyl ester and HBTU (O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate) as well as 11 mmol triethylamine were dissolved in 100 ml DMF and stirred for 1.5 h at room temperature. The solvent is removed by evaporation on a rotary evaporator and the residuum is dissolved in trichloromethane. Residual HBTU is removed by extraction with water with 0.5 mol/l hydrochloric acid. The organic solvent is separated and evaporated to dryness in a rotary evaporator. The crude product (2.37 g) is purified by flash chromatography (silica gel 60, Merck, No: 11452134001) with a mobile phase consisting of trichloromethane:ethyl acetate 2:1 (v/v) (yield: 1.03 g).
Reaction SMILES: [C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:7]=1[CH2:26][C:27]([CH3:32])([CH3:31])[C:28](O)=[O:29])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:36])=O.CN(C=O)C>C(Cl)Cl>[C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:7]=1[CH2:26][C:27]([CH3:31])([CH3:32])[C:28]([Cl:36])=[O:29])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)c1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)Cl)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-isopropyl-1H-indol-2-yl]-2,2-dimethyl-propionic acid (prepared according to the procedures described in U.S. Pat. No. 5,081,138 issued Jan. 14, 1992; 0.25 g, 0.53 mmol) suspended in CH2Cl2 (5 mL) was added oxalyl chloride (48 uL, 0.56 mmol) and catalytic DMF. The reaction was stirred at room temperature for 3 hours, and then concentrated to give I-1, which was used without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([Cl:12])=[O:11])=[N:2]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]#[C:29][CH2:30][NH2:31])[CH2:23][CH2:22]1.C(N(CC)CC)C>ClCCl.O>[ClH:12].[ClH:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:27][C:28]#[C:29][CH2:30][NH:31][C:10]([C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][N:2]=2)=[O:11])[CH2:25][CH2:26]1
Reactant: O=C(Cl)c1nsc2ccccc12
Reactant: COc1ccccc1N1CCN(CC#CCN)CC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CC#CCNC(=O)c2nsc3ccccc23)CC1
Product: Cl
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A mixture of 1,2-benzisothiazole-3-carboxylic acid chloride (2.0 g) and 1-(2-methoxyphenyl)-4-(4-amino-2-butynyl)piperazine (2.63 g) in dichloromethane (100 ml), was stirred while triethylamine (2.83 ml) was added dropwise. Stirring was continued overnight. After 24 hr, the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica using ethyl acetate as the eluent. The appropriate fractions were collected and concentrated. The residue was taken up in ether/dichloromethane. Ethereal hydrogen chloride was added. The precipitate was recrystallized from methanol/dichloromethane/ether to provide 2.27 g (45.7%) of product, mp 162°-164° C.
Reaction SMILES: [C:1]1([OH:9])[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[C:2]=1[OH:8].[C:10](=O)(O)[O-].[K+].CI>CC(C)=O>[CH3:10][O:8][C:2]1[C:3]([OH:7])=[CH:4][CH:5]=[CH:6][C:1]=1[OH:9]
Reactant: Oc1cccc(O)c1O
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(O)cccc1O
Temperature: 25 °C
Yield: 27 %

Procedure:
To a stirring solution of benzene-1,2,3-triol (2 g, 15.87 mmol) in acetone was added potassium bicarbonate (1.9 g, 19.04 mmol) and methyl iodide (3.3 g, 23.8 mmol) and the resultant reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was diluted with ether, solid separated out was filtered and the filtrate was concentrated under reduced pressure to afford the crude product. The crude product was purified by flash column chromatography (silica gel, 0-15% ethyl acetate in pet ether) to afford 2-Methoxybenzene-1,3-diol as a solid (600 mg, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:11][N:12]([CH:15]3[CH2:17][CH2:16]3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([CH3:33])[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:24][C:25]2[CH:26]=[C:27]([CH3:33])[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=2)[C:9]2[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:11][N:12]([CH:15]3[CH2:17][CH2:16]3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)c1nn(C2CC2)c(C)c1C(O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1nn(C2CC2)c(C)c1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-5-methyl-1H-pyrazole-3-carboxylate (Step 17.5) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.59 min (HPLC 1); tR: 1.05 min (LC-MS 2); ESI-MS: 455 [M+H]+ (LC-MS 2); Rf=0.45 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]([C:13]2[CH2:20][S:19][CH:18]3[N:15]([C:16](=[O:30])[CH:17]3[NH:21][C:22](=[O:29])[CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[C:14]=2[C:31]([O:33]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:32])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)=O>[NH:1]([C:8]1[S:9][C:10]([C:13]2[CH2:20][S:19][CH:18]3[N:15]([C:16](=[O:30])[CH:17]3[NH:21][C:22](=[O:29])[CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[C:14]=2[C:31]([OH:33])=[O:32])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4ccccc4)s3)CSC12
Solvent: O=CO
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(c3cnc(Nc4ccccc4)s3)CSC12
Yield: 59.3 %

Procedure:
3-(2-Anilino-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]-oct-2-ene (0.9 g) is treated with formic acid (9 cc) in accordance with the working method described in Example 1, and 3-(2-anilino-thiazol-5-yl)-2-carboxy-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.4 g) is obtained in the form of a yellow solid.
Reaction SMILES: O[C:2]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[NH:13]C(OC(C)(C)C)=O)([CH3:7])[CH2:3][CH:4]([CH3:6])[CH3:5].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH2:13][C:12]1[CH:11]=[CH:10][S:9][C:8]=1[CH:2]([CH3:7])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)CC(C)(O)c1sccc1NC(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC(C)c1sccc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.5 %

Procedure:
After dissolving 1.2 g of 2-(1-hydroxy-1,3-dimethylbutyl)-3-t-butoxycarbonylaminothiophene in 10 ml of methylene chloride, 0.44 g of triethylsilane and 4.3 g of trifluoroacetic acid were added. The mixture was stirred at room temperature for 20 hours, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.43 g of the desired product as a crystal. 1H-NMR(270 MHz, CDCl3, δppm, J:Hz):0.89(3H,d,J=6.6), 0.90(3H,d,J=6.6), 1.23(3H,d,J=6.6),1.35-1.65(3H,m), 2.95(1H, sextet, J=6.6), 3.35(2H,brs), 6.55(1H,d,J=5.1), 6.95(1H,d,J=5.1)
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[CH:18]=[CH:17][C:16](N)=[CH:15][CH:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[C:20](Cl)(=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C([N:36](CC)CC)C>O1CCCC1>[C@@H:1]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:36][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: Nc1ccc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)Nc1ccccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 80 %

Procedure:
The p-aminophenol-β-D-glucopyranoside (250 mg) thus obtained was dissolved in tetrahydrofuran (20 ml), and lauroyl chloride (300 mg) and triethylamine (1.0 g) were added. The reaction mixture was refluxed for 5 hours. The reaction solution was filtered to remove solids, and the filtrate was evaporated under vacuum to give a dry solid. The residue was purified by silica gel chromatography using a tetrahydrofuran/chloroform mixed solvent (1/1, volume ratio) as an eluant, and dodecanoylaminophenol-β-D-glucopyranoside was thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[N:4]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]#[N:39])[CH:29]=1)[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=1[O:25][CH3:26].C([O-])([O-])=[O:42].[K+].[K+].OO.O>CS(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:40])[N:4]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([NH2:39])=[O:42])[CH:29]=1)[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=1[O:25][CH3:26]
Reactant: COC(=O)N(Cc1cc(C#N)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)N(Cc1cc(C(N)=O)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of methyl[3-cyano-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (35.0 mg, 0.06 mmol) (Example 36) in DMSO (248 μL) was cooled to 0° C. Next, K2CO3 (17.4 mg, 0.05 mmol) was added followed by 30% H2O2 (42.2 μL), and the reaction was slowly warmed to room temperature. After stirring at room temperature for 15 minutes, the mixture was diluted with EtOAc (50 mL) and poured into H2O (15 mL). The organic extract was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 5% to 80% EtOAc/hexanes afforded methyl[3-(aminocarbonyl)-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.45 (20% EtOAc/hexanes). LCMS=583.3 (M+1)+. 1H NMR. (C6D6, 500 MHz, 70° C.) δ 7.75 (s, 1H), 7.68 (s, 2H), 7.35 (s, 1H), 7.34 (s, 1H), 7.08-7.04 (m, 2H), 6.87 (d, J=2.5 Hz, 1H), 6.62 (d, J=8.5 Hz, 1H), 5.08 (broad singlet, 2H), 4.41 (broad singlet, 2H), 4.07 (broad singlet, 2H), 3.37 (s, 3H), 3.29 (s, 3H), 2.75 (m, 1H), 1.16 (d, J=7.5 Hz, 6H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37]([OH:39])=O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].Cl.[NH2:41][C@H:42]([CH2:60][C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=1)[C:43]([NH:45][C@@H:46]([C:54]1[O:58][N:57]=[C:56]([CH3:59])[N:55]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44].C(N(CC)CC)C>CN(C)C=O>[C:24]([O:28][C:29]([N:31]1[CH2:32][CH2:33][CH:34]([C:37](=[O:39])[NH:41][C@@H:42]([C:43](=[O:44])[NH:45][C@@H:46]([C:54]2[O:58][N:57]=[C:56]([CH3:59])[N:55]=2)[CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:60][C:61]2[CH:70]=[CH:69][C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[CH:62]=2)[CH2:35][CH2:36]1)=[O:30])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Cc1noc([C@@H](Cc2ccccc2)NC(=O)[C@H](N)Cc2ccc3ccccc3c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1noc([C@@H](Cc2ccccc2)NC(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Yield: 87.7 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.92 g, 4.82 mmol) and 1-hydroxybenzotriazole monohydrate (0.74 g, 4.83 mmol) were added to a solution of N-tertbutoxycarbonyl-4-piperidine carboxylic acid (1.10 g, 4.80 mmol) in N,N-dimethylformamide (15 ml). After 30 min at 20° C. a mixture of (2R)-2-amino-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl]-3-(2-naphthyl)propionamide hydrochloride (1.50 g, 3.43 mmol) and triethylamine (0.35 g, 3.46 mmol) in N,N-dimethylformamide (15 ml) were added. After 18 h at 20° C. the reaction mixture was poured on ice water (180 ml) and extracted several times with ethyl acetate (total 180 ml). The organic phases were collected and washed with aqueous citric acid (10%, 25 ml), a saturated solution of sodium hydrogencarbonate (3×25 ml) and water (3×25 ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and crystallized from ethyl acetate to give 1.84 g of 4-{(1R)-1-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl]-2-(2-naphthyl)ethylcarbamoyl}piperidine-1-carboxylic acid tertbutyl ester.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22](=[O:37])(=[O:36])[N:23]([CH2:32][CH2:33][O:34][CH3:35])[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[CH:5]1)([CH3:3])[CH3:2].C([Li])CCC.CN([CH:46]=[O:47])C.O>C1COCC1>[CH:46]([C:5]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([S:22](=[O:36])(=[O:37])[N:23]([CH2:32][CH2:33][O:34][CH3:35])[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])=[CH:20][CH:21]=3)[N:10]=2)=[CH:7][N:6]=1)=[O:47]
Reactant: COCCN(COCC[Si](C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cncn3C(C)C)n2)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCCN(COCC[Si](C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C=O)n3C(C)C)n2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
4-(1-Isopropylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl)sulphamoyl]anilino}pyrimidine (Method 106; 1.22 g, 2.33 mmol), was dissolved in anhydrous THF (70 ml), under nitrogen. The solution was cooled to −78° C. and n-butyl lithium (3.48 ml of a 1.6 N solution in hexanes, 5.57 mmol), was added slowly, maintaining the temperature at less than −65° C. The reaction mixture was then stirred at −78° C. for 30 minutes, then DMF (345 μl, 4.46 mmol), was added and mixture allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was then poured into water (100 ml), and extracted with EtOAc (2×50 ml). The organic extracts were combined, washed with water (50 ml), brine (50 ml), and dried. The volatiles were removed and the residue was purified by chromatography on silica gel eluting with 3% MeOH in DCM, to give the title product, (307 mg, 24%), as a pale yellow foam. NMR: 0.02 (s, 9H), 0.83 (dd, 2H), 1.63 (d, 6H), 3.28 (s, 3H), 3.37 (t, 2H), 3.42 (dd, 2H), 3.52 (t, 2H), 4.78 (s, 2H), 5.71 (m, 1H), 7.40 (d, 1H), 7.82 (d, 2H), 7.92 (s, 1H), 8.01 (d, 2H), 8.78 (d, 1H), 9.91 (s, 1H); m/z: 573 [MH]−.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:13][O:14][C:15]1[C:22]([CH3:23])=[C:21]([CH3:24])[C:20]([O:25][CH3:26])=[C:19]([CH3:27])[C:16]=1[CH2:17]Br>C(OCC)C.O>[CH3:26][O:25][C:20]1[C:21]([CH3:24])=[C:22]([CH3:23])[C:15]([O:14][CH3:13])=[C:16]([CH3:17])[C:19]=1[CH2:27][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C)c(C)c(OC)c(CBr)c1C
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1c(C)c(C)c(OC)c(Cc2cccnc2)c1C
Yield: 90.3 %

Procedure:
A solution of 15.5 g (98.1 mmol) of 3-bromopyridine in 200 ml of ethyl ether was cooled to -78° C., to which 61.3 ml (98.1 mmol) of n-butyllithium (1.6 M hexane solution) was added dropwise. For 20 minutes after completion of the addition, the mixture was stirred at the same temperature, and then a solution of 26.8 g (93.1 mmol) of 2,5-dimethoxy-3,4,6-trimethylbenzyl bromide .in 100 ml of ethyl ether was added dropwise. After stirring at -78° C. to room temperature for 1 hour, the reaction mixture was diluted with water and extracted with ethyl acetate. Then the extract was extracted reversely with 2N-hydrochloric acid, and the water layer was made weakly alkaline with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate), to give 22.8 g (85.8%) of 3-(2,5-dimethoxy- 3,4,6-trimethylbenzyl)pyridine.
Reaction SMILES: [CH:1]([NH2:3])=O.[C:4]([BH3-])#N.[Na+].[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:25]=[C:24](N)[CH:23]=2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:25]=[C:24]([N:3]([CH3:1])[CH3:4])[CH:23]=2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [BH3-]C#N
Reactant: COc1ccc(-n2nc(N)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: NC=O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-n2nc(N(C)C)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
37% Aqueous formamide solution (6 ml) and sodium cyanoborohydride (1.39 g) were added successively to a solution of 5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-amine obtained by Example 14-2 (2.75 g) in methanol 30 ml. The reaction mixture was stirred at room temperature for 3 days, occasionally adding 37% aqueous formamide solution and sodium cyanoborohydride appropriate amount to consume all starting material.
Reaction SMILES: [C:1]([N:3]=[C:4]1[N:8]([C@@H:9]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH2:23][CH3:24])([CH2:21][CH3:22])[C@H:10]2[OH:25])[CH2:7][CH2:6][S:5]1)#[N:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1.C(OCC)(=O)C>[C:26]([O:25][C@H:10]1[C@H:9]([N:8]2[CH2:7][CH2:6][S:5][C:4]2=[N:3][C:1]#[N:2])[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]1([CH2:23][CH3:24])[CH2:21][CH3:22])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CCC1(CC)Oc2ccc(C#N)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC1(CC)Oc2ccc(C#N)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of trans-4-(2-cyanoiminothiazolidin-3-yl)-2,2-diethyl-3,4-dihydro-3-hydroxy-2H-1-benzopyran-6carbonitrile -(0.28 g) and acetic anhydride (0.15 ml) in pyridine (1.4 ml) was stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate, and then washed with 5% aqueous hydrochloric acid, saturated sodium bicarbonate solution and brine successively. The extract was dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue of trans-3-acetoxy-4-(2-cyanoiminothiazolidin-3-yl)-2,2-diethyl-3,4-dihydro-2H-1-benzopyran-6-carbonitrile, which was dissolved in toluene (12.5 ml) and thereto was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 ml). The reaction mixture was heated at 100° C. with stirring for an hour and 40 minutes. The solvent was evaporated in vacuo. The residue was triturated with ethyl acetate and recrystallized from 85% aqueous acetonitrile to give 4-(2-cyanoiminothiazolidin-3-yl)-2,2-diethyl-2H-1-benzopyran-6-carbonitrile (0.18 g).