Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[C:2]=[S:3].[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2([C:31]#N)[CH2:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)(=[O:19])=[O:18].C[OH:34].Cl>CN(C=O)C.O>[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:2](=[S:3])[N:1]([C:4]3[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:13])([F:15])[F:14])[CH:5]=3)[C:31](=[O:34])[C:27]32[CH2:30][CH2:29][CH2:28]3)=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1ccc(NC2(C#N)CCC2)cc1
Reactant: CO
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 15 %

Procedure:
A mixture of 4-isothiocyanato-2-trifluoromethylbenzonitrile (1a) (0.0.141 g, 0.62 mmol) and 1-(4-methanesulfonylphenylamino)cyclobutanecarbonitrile (45a) (0.11 g, 0.42 mmol) in dry DMF (2 ml) was stirred at room temperature for 3 days. To this mixture were added methanol (10 ml) and aq. 2N HCl (5 ml). The second mixture was refluxed for 3 h. After being cooled to room temperature, the reaction mixture was poured into cold water (10 ml) and extracted with ethyl acetate (3×30 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane:acetone, 97:3) to yield 4-[5-(4-methanesulfonylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-7-yl]-2-trifluoromethylbenzonitrile (45b) [RD145] (0.031 g, 0.065 mmol, 15%), the structure of which is illustrated in Formula 14, as a white powder.
Reaction SMILES: C(=O)C.C(N[C:8]([C:10]1[N:11]=[C:12]2[C:18]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:17][NH:16][C:13]2=[N:14][CH:15]=1)=[O:9])(C)C.[CH:25](N)([CH3:27])[CH3:26].C(C1N=C2C(C(=O)C(C)(C)C)=CNC2=NC=1)(=O)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[OH:9][CH:8]([C:10]1[N:11]=[C:12]2[C:18]([C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:17][NH:16][C:13]2=[N:14][CH:15]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: CC(C)NC(=O)c1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)c1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1
Agent: CC=O
Product: CC(C)C(O)c1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1

Procedure:
Substituting isobutyraldehyde for acetaldehyde in Step 2. MP=148-150 C, (M+H)+=276. 7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid isopropylamide Substituting carbon dioxide for acetaldehyde in Step 2. Then following general procedures described in these Examples, using isopropylamine and continuing with Step 3. MP=206-208 C, (M+H)+=289. 1-(2-Acetyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one. The product of Step 3 was treated with Dess-Martin periodinane, following general procedures described in these Examples. MP=221-223 C, (M+H)+=246.
Reaction SMILES: O1CCCC1.Cl.[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:9]=1.[C:28](Cl)(=[O:34])[CH2:29][CH:30]=[CH:31][CH2:32][CH3:33]>C(N(CC)CC)C>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:34])[CH2:29][CH:30]=[CH:31][CH2:32][CH3:33])[CH2:24][CH2:23]2)[N:9]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: CCC=CCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC=CCC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Reaction time: 0.33 h
Yield: 47.3 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.4 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride and 2.6 g of triethylamine, after which the mixture was stirred for 20 minutes. There was then added 0.8 g of 3-hexenoyl chloride, after which the mixture was stirred at room temperature for 15 hours. The resulting crystals were collected by filtration, washed with water and recrystallized from ethanol, to give 1.10 g of the desired Compound No. 7 in the form of pale yellow powdery crystals melting at 197.5°-198.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.Cl.[NH2:14][OH:15].N1C=CC=C[CH:17]=1>C(O)C>[CH3:1][O:2][C:3]1[C:10]([CH3:17])=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[N:14][OH:15]
Reactant: c1ccncc1
Reactant: NO
Reactant: COc1ccc(C=O)c(OC)c1
Agent: Cl
Solvent: CCO
Product: COc1ccc(C=NO)c(OC)c1C
Reaction time: 2 h

Procedure:
A mixture of 25.1 g 2,4-dimethoxybenzaldehyde, 19.46 g hydroxylamine hydrochloride and 22 mls pyridine in 150 mls ethyl alcohol was heated at reflux with stirring for two hours, allowed to cool, and concentrated in vacuo. The residue was treated with water and stirring and the resulting white solid was collected by filtration to give 26.8 g of the title compound, m.p. 110°-111° C.
Reaction SMILES: O=C[CH2:3][C@@H:4]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][C:15]=1[S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH3:42])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].[C:43](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.ClCCl.C(OCC)(=O)C>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH3:43])[CH2:42][CH2:3][C@@H:4]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][C:15]=1[S:24]([C:27]([F:30])([F:28])[F:29])(=[O:26])=[O:25])[CH2:5][S:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33]
Reactant: CNCCO[Si](C)(C)C(C)(C)C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NS(=O)(=O)c1ccc(N[C@H](CC=O)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CN(CCO[Si](C)(C)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Reaction time: 11.5 h
Yield: 49.5 %

Procedure:
To a solution of (R)-4-(4-oxo-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 45, 3.98 g, 8.25 mmol) and 2-(tert-butyldimethylsilyloxy)-N-methylethanamine (INTERMEDIATE 64, 1.56 g, 8.25 mmol) in 1,2-dichloroethane (27.5 ml) was added sodium triacetoxyborohydride (2.62 g, 12.37 mmol). The resulting mixture was stirred in the dark for 11.5 hours and then sodium hydroxide (0.5 M, aq., 50 ml) was added. The mixture was diluted with dichloromethane (70 ml) and stirred vigorously for 10 min. The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate. The organic layer was then diluted heavily with ethyl acetate and washed with saturated aqueous sodium chloride (×2) before being dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (ISCO, 330 g SiO2, 0→50% ethyl acetate in hexanes over 30 min, then isocratic hold for 30 min, then 50→100% ethyl acetate in hexanes over 20 min) to afford the title product (2.68 g, yield: 49.5%). Additional impure title product was also obtained (1.65 g), which was further purified by reverse phase HPLC (Column: Xbridge Phenyl OBD 19 mm×100 mm, 5 μm; eluting with 65→80% acetonitrile in water (10 mM NH4OAc, pH 8) over 15 min). Product fractions were combined, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford additional title product (1.05 g, yield: 19%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:15](=[O:46])[CH:16]([NH:28]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(NCC)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:47])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:15](=[O:46])[CH:16]([NH2:28])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22]
Reactant: COC(=O)c1ccc(C(=O)OC)c(NC(=O)C(CCCNC(=O)OC(C)(C)C)NC(=O)OCC2c3ccccc3-c3ccccc32)c1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COC(=O)c1ccc(C(=O)OC)c(NC(=O)C(N)CCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 125.8 %

Procedure:
The compound (236.0 mg) obtained in Example 14-1 was dissolved in anhydrous DMF (4.7 ml) and added with diethylamine (4.7 ml) and the whole was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (194.7 mg) as a colorless viscous solid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][CH:48]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[N:36]=1>CN(C)C=O.CN1CCCC1=O>[C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:26][C:27]1[CH:48]=[CH:47][CH:46]=[C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:44][CH2:45]4)=[O:42])[N:39]=3)[N:36]=2)[CH:28]=1)=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CC(C)(C)Oc1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c1
Yield: 67.3 %

Procedure:
Using 3-tert-butoxybenzoic acid (110 mg, 0.58 mmol), oxalyl chloride (63 μL, 0.73 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (4.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol) and N-methylpyrrolidone (4.0 mL) as starting materials and in the same manner as in Example 335, the title compound (160 mg, 57%) was obtained as a white powder.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N+](=[C:13]([C:17](=[O:19])[CH3:18])[C:14](=[O:16])[CH3:15])=[N-]>C1C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:13]([C:17](=[O:19])[CH3:18])[C:14](=[O:16])[CH3:15])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)c1ccc(O)cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: CC(=O)C(Oc1ccc(C(C)C)cc1)C(C)=O
Temperature: 25 °C
Yield: 39.4 %

Procedure:
To a refluxing solution of 4-isopropylphenol (0.548 g, 4.02 mmol) and rhodium(II) acetate (ca. 15 mgs) in benzene (10 mL) was added a solution of 3-diazo-pentane-2,4-dione (0.507 g, 4.02 mmol) in benzene (20 mL) over 40 minutes. The reaction mixture was allowed to cool to room temperature and was concentrated to afford a green oil. Flash chromatography over silica (ethyl acetate/hexanes) provided 0.371 g (39%) of the product as a white solid: 1H NMR (CDCl3) δ 14.4 (s, 1H), 7.15 (d, J=8.6 Hz, 2H), 6.82 (d, J=8.6 Hz, 2H), 2.87 (sept, J=7.0 Hz, 1H), 2.04, (s, 6H), 1.23 (d, J=7.0 Hz, 6H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=[CH2:10].[C:19]1(C)C=CC=CC=1.C1(OC)C=CC=CC=1.COCCO[AlH2-]OCCOC.[Na+]>CCCCCC>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:19])[CH3:10]
Reactant: C=C(c1ccccc1OC)c1ccccc1OC
Reactant: Cc1ccccc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: CCCCCC
Product: COc1ccccc1C(C)(C)c1ccccc1OC

Procedure:
1,1-Bis(2-methoxyphenyl)ethene (15.6 g), toluene (35 ml) and anisole (35 ml) were combined in a flask and 35 ml of a 3.7M hexane solution of Red-Al was added. The mixture was heated to reflux with stirring whereupon it turned dark red. After 2 hours the heat was removed and the mixture was allowed to stir overnight. The excess hydride reagent was carefully quenched with 1.0N hydrochloric acid. The mixture was then diluted with ether and the ethereal solution separated, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a golden-brown oil. This was triturated with hexane to obtain 3.70 of the title compound. The proton and carbon NMR spectra were consistent with the assigned structure.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](/[CH:19]=[N:20]/[NH:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1ccnc(N/N=C/c2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: Cc1ccn2c(-c3ccc4cccc(O[Si](C)(C)C(C)(C)C)c4n3)nnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
(E)-8-(tert-Butyldimethylsilyloxy)-2-((2-(4-methylpyridin-2-yl)hydrazono)methyl)quinoline (0.720 g, 1.83 mmol) was suspended in DCM (6 mL) at ambient temperature. Iodobenzene diacetate (0.650 g, 2.02 mmol) was added and the solution was allowed to stir at ambient temperature overnight. The mixture was concentrated to an orange oil and purified directly by column chromatography (20% EtOAc/DCM to 50% EtOAc/DCM) to provide the desired product (0.590 g, 82%).
Reaction SMILES: [CH2:1]([N:3]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:4]1[C:5]([CH3:13])=[C:6]([C:10]([OH:12])=O)[CH:7]=[N:8][CH:9]=1)[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][CH2:54][C:55]1[C:56](=[O:63])[NH:57][C:58]([CH3:62])=[CH:59][C:60]=1[CH3:61]>CN(C=O)C.O>[CH3:61][C:60]1[CH:59]=[C:58]([CH3:62])[NH:57][C:56](=[O:63])[C:55]=1[CH2:54][NH:53][C:10]([C:6]1[CH:7]=[N:8][CH:9]=[C:4]([N:3]([CH2:1][CH3:2])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]=1[CH3:13])=[O:12]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCN(c1cncc(C(=O)O)c1C)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(c1cncc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-[ethyl(oxan-4-yl)amino]-4-methylpyridine-3-carboxylic acid (300 mg, 1.13 mmol) in DMF (10 ml) was added DIPEA (395 μl, 2.27 mmol) and HATU (518 mg, 1.36 mmol). The reaction was stirred at room temperature for 5 min after which time 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 214 mg, 1.25 mmol) was added and the reaction was stirred at room temperature for 18 h. The reaction mixture was then poured onto 500 ml of water and the product was extracted into EtOAc (3×200 ml), the combined organic phase was washed with brine (2×100 ml), dried (Na2SO4) and evaporated. The crude product was then purified using preparative-HPLC and the resulting solid was triturated with diethyl ether and isolated by filtration to afford the title compound as an off white solid (115 mg, 25%). LC-MS 100%, m/z=399.2, 1H NMR (500 MHz, Acetone) δ 10.97 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 7.73 (s, 1H), 5.92 (s, 1H), 4.41 (d, J=5.3 Hz, 2H), 3.85 (dd, J=11.3, 3.0 Hz, 2H), 3.28 (td, J=11.7, 1.9 Hz, 2H), 3.15 (q, J=7.1 Hz, 2H), 3.09 (ddd, J=11.1, 7.2, 3.9 Hz, 1H), 2.32 (d, J=1.5 Hz, 6H), 2.23 (s, 3H), 1.69 (dd, J=12.6, 1.7 Hz, 2H), 1.55 (ddd, J=24.3, 12.2, 4.4 Hz, 2H), 0.85 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)[CH3:9].C(=O)([O-])[O-].[Na+].[Na+].[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:13]1[CH2:14][C@@H:12]1[CH2:11][O:10][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:26]1[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=1)[CH3:9]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(OC[C@H]1CO1)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(OC[C@H]1CO1)c1ccccc1-c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 26.8 %

Procedure:
(R)-2-[1-(2-Bromophenyl)ethoxymethyl]oxirane (8.24 g) was dissolved in toluene (38 ml) and ethanol (150 ml), 2M-aqueous sodium carbonate (80 ml), 4-cyanophenylboronic acid (5.65 g) and tetrakis(triphenylphosphine)palladium(0) (1.85 g) were successively added, and the mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted 3 times with diethyl ether. The organic layer was washed successively with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the title compound (2.40 g).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.CO[C:19]1C=CC(C(C2C=CC(OC)=CC=2)=O)=C[CH:20]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)([OH:7])[C:19]#[CH:20])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Product: C#CC(O)(c1ccc(C)cc1)c1ccc(C)cc1

Procedure:
The procedure of Step 1 of Example 1 was followed except that 4,4'-dimethylbenzophenone was used n place of 4,4'-dimethoxybenzophenone to produce 1,1-bis(4-methylphenyl)-2-propyn-1-ol.
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12]CC)=[O:11])[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].O.[OH-].[Li+].Cl>C(O)C>[CH2:1]([N:3]([C:8]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:16]=[CH:15][C:9]=1[C:10]([OH:12])=[O:11])[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(S(C)(=O)=O)cc1N(CC)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCN(c1cc(S(C)(=O)=O)ccc1C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 90.4 %

Procedure:
A mixture of ethyl 2-(N-ethyl-N-methylsulphonylamino)-4-methylsulphonylbenzoate (11.4 g) and lithium hydroxide monohydrate (1.37 g) in aqueous ethanol (50%) was stirred at room temperature for 19 hours. The mixture was then acidified with conc. hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulphate), filtered and evaporated to yield 2-(N-ethyl-N-methylsulphonylamino)-4-methylsulphonylbenzoic acid as a brown solid (9.48 g), NMR (acetone-d6); 1.15(t,3H), 2.98(s,3H), 3.22(s,3H), 3.85(q,2H), 8.0-8.25(m,3H).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([N:8]1[CH2:38][CH2:37][CH2:36][C@H:9]1[C:10]([N:12]([C:28](=[O:35])[C:29](=[O:34])[CH:30](N)[CH2:31][CH3:32])[C@@H:13]([C:18]([NH:20][C@H:21]([C:25]([OH:27])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:39]1([CH2:45][CH2:46][CH2:47][C:48]([O:50]C(=O)CCCC2C=CC=CC=2)=O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C([N:64](CC)CC)C.C(O)(=O)C>CO.C(Cl)Cl>[C:39]1([CH2:45][CH2:46][CH2:47][C:48]([NH:1][C@H:2]([C:6]([N:8]2[CH2:38][CH2:37][CH2:36][C@H:9]2[C:10]([N:12]([C:28](=[O:35])[C:29](=[O:34])[CH2:30][CH2:31][CH3:32])[C@@H:13]([C:18]([NH:20][C@H:21]([C:25]([OH:27])=[O:26])[CH:22]([CH3:23])[CH3:24])=[O:19])[CH:14]([NH2:64])[CH:15]([CH3:17])[CH3:16])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:50])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCC(N)C(=O)C(=O)N(C(=O)[C@@H]1CCCN1C(=O)[C@@H](N)C(C)C)[C@H](CC(C)C)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: O=C(CCCc1ccccc1)OC(=O)CCCc1ccccc1
Reactant: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCC(=O)C(=O)N(C(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)CCCc1ccccc1)C(C)C)[C@@H](C(=O)N[C@H](C(=O)O)C(C)C)C(N)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
23.6 mg of L-valyl-L-prolyl-3-amino-2-oxo-pentanoyl-D-leucyl-L-valine prepared by the manner shown in Example 8 were dissolved in 2 ml of methanol. The resultant solution was admixed with a solution of 30 mg of 4-phenyl-butanoic acid anhydride in 1 ml of methylene chloride and with 0.050 ml of triethylamine, and stirred at room temperature for 1 hour. The reaction mixture was acidified with acetic acid, and subjected to a purification operation by employing a column (300 ml) filled with "Sefadex LH20 " with methanol, so that 20.9 mg of phenylbutanoyl-L-valyl-L-prolyl-3-amino-2-oxopentanoyl-D-leucyl-L-valine were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH:7]([NH:17][C:18](N1C=CN=C1)=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28](=[O:39])[CH2:29][CH:30]([NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([I:37])[CH:32]=1>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH:17][C:18]([NH:38][C@H:30]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([I:37])[CH:32]=1)[CH2:29][C:28]([O:27][CH3:26])=[O:39])=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CC(N)c1cccc(I)c1
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)n1ccnc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)C[C@H](NC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1cccc(I)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 48.8 %

Procedure:
2-[(Imidazole-1-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester (370 mg, 1.05 mmol) was dissolved in DCE (10 mL) and cooled to 0° C. MeoTf (142 μL, 1.25 mmol) was added and the reaction was allowed to proceed for 20 min. (±)-3-Amino-3-(3-iodo-phenyl)-propionic acid methyl ester (356 mg, 1.045 mmol) was added and the reaction was allowed to warm to room temperature and then warmed to 55° C. and stirred overnight. The reaction was diluted with DCM (50 mL) and washed with water (30 mL), 5% aq. Citric acid (30 mL), sat. sodium bicarbonate (30 mL), water (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate and concentrated to afford the crude product. The product was purified by column chromatography to afford the desired product (303 mg, 0.51 mmol, 49%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.29 (s, 1H), 7.07-7.02 (m, 1H), 5.74 (br, 1H), 5.17 (br, 2H), 4.30 (m, 1H), 3.63 (s, 1.5H), 3.62 (s, 1.5H), 2.88-2.76 (m, 2H), 2.38-2.24 (m, 2H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 1H), 1.46 (s, 9H), 1.44 (s, 9H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:20])[CH:8]=1)(=O)=O.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:23]1([C:29]#[C:30][C:7]2[CH:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:20])[CH:8]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)cc1=O
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)cc(C#Cc2ccccc2)cc1=O

Procedure:
A solution of 4-trifluoromethylsulfonyloxy-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 2 above (2.0 g, 5.4 mmol), phenylacetylene (1.1 g, 11 mmol), triethylamine (3.6 mL, 25 mmol), and PdCl2(PPh3)2 (0.42 g, 0.6 mmol) in DMF (20 mL) was heated to 90° C. under inert atmosphere for 1 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and aqueous NaHCO3. The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 1:1 EtOAc:hexanes as eluant to give the title compound as an amorphous solid (1.5 g; TLC Rf=0.35, 1:1 EtOAc:hexanes; HPLC RT=8.64 min, method A).