Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([CH2:11][O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>>[NH2:1][C:2]1[N:10]=[C:9]([CH2:11][O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: COCc1ccc(C(N)=O)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COCc1ccc(C#N)c(N)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
2-Amino-6-methoxymethyl-nicotinamide (90 mg) described in Manufacturing Example 6-1 and phosphorus oxychloride (3.0 g) were stirred for 0.5 hour at 100° C. The reaction solution was added to 0° C. dilute aqueous sodium hydroxide and then extracted with ethyl acetate. The organic layer was concentrated and the residue was purified with silica gel chromatography (ethyl acetate) to obtain the titled compound (40 mg).
Reaction SMILES: CS([Cl:5])(=O)=O.[F:6][C:7]([F:57])([F:56])[C:8]1[CH:9]=[C:10]([CH:49]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:51]=1)[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][C@H:23]([CH2:27][O:28][CH3:29])[CH2:22]2)[CH2:15][C@H:14]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](O)([CH3:39])[CH3:38])=[C:33]([O:41][Si](C(C)(C)C)(C)C)[CH:32]=1)=[O:12].C(N(CC)CC)C.[ClH:65]>ClCCl.C(OCC)(=O)C.[OH-].[OH-].[Pd+2].CO>[ClH:5].[ClH:65].[F:55][C:52]([F:53])([F:54])[C:50]1[CH:49]=[C:10]([CH:9]=[C:8]([C:7]([F:6])([F:56])[F:57])[CH:51]=1)[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][C@H:23]([CH2:27][O:28][CH3:29])[CH2:22]2)[CH2:15][C@H:14]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[C:33]([OH:41])[CH:32]=1)=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: COC[C@@H]1CN(CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C(C)(C)O)c(O[Si](C)(C)C(C)(C)C)c3)C2)CCO1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC[C@@H]1CN(CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C(C)C)c(O)c3)C2)CCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (0.115 ml) was added to an ice-cooled solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-(tert-butyldimethylsilyloxy)-4-(1-hydroxy-1-methylethyl)benzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]-ethyl]piperazine (0.76 g) and triethylamine (0.35 ml) in dichloromethane (9 ml). After being stirred at the same temperature for 2 hours, the mixture was washed with water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give a mixture of the mesylated and unmesylated compound. The mixture was dissolved into methanol without further purification and the solution was hydrogenated over 20% palladium hydroxide-charcoal (0.1 g) at room temperature at 3 atmosphere for 5 hours. The reaction mixture was filtered through Celite® and washed with methanol. The filtrate and washing were combined and evaporated under reduced pressure. The resulting syrup was dissolved in tetrahydrofuran (6.5 ml) and thereto tetrabutylammonium fluoride (1M solution of tetrahydrofuran, 0.1 ml) was added below 10° C. After stirring at room temperature, the mixture was evaporated under reduced pressure and the residue was purified by column chromatography using a mixed solvent of dichloromethane and methanol (40:1) to give an oil. The oil was treated with 4N hydrogen chloride in ethyl acetate to give a powder of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-hydroxy-4-(1-methylethyl)benzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]-ethyl]piperazine dihydrochloride (150 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[OH:20])[CH2:15][CH2:14]3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:46].[OH-].[Na+]>C(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([CH2:12][N+:13]3([O-:46])[CH2:14][CH2:15][CH:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:23][CH:22]=4)([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=4)[OH:20])[CH2:17][CH2:18]3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccc(OCC3CC3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: [O-][N+]1(Cc2ccc(OCC3CC3)cc2)CCC(C(O)(c2ccc(C(F)(F)F)cc2)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.8 %

Procedure:
A stirred solution of 10.0 grams (0.018 mole) of N-[4-(cyclopropylmethoxy)phenylmethyl]-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine in methylene chloride was cooled to 0° C., and 3.1 grams (0.01 2 mole) of 50% 3-chloroperoxybenzoic acid was added in two portions. Upon completion of the addition the reaction mixture was allowed to warm to ambient temperature, where it stirred for about 18 hours. After this time, the reaction mixture was poured into aqueous 5% sodium hydroxide solution. The organic layer was separated and washed with aqueous 5% sodium hydroxide solution. The organic layer was then filtered through phase separated silicone treated paper. The filtrate was concentrated under reduced pressure, yielding 10.2 grams of N-[4-(cyclopropylmethoxy)phenylmethyl]-4-[bis(4-trifluoromethylphenyl)hydroxy-methyl]piperidine N-oxide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])=[CH:4][C:5]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([N:23]2[C:24](=[O:33])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]2=[O:32])=[CH:4][C:5]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:11])=[C:6]([CH:7]=1)[O:8][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]
Reactant: O=C1c2ccccc2C(=O)N1c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(O)cc1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(Cl)c(N2C(=O)c3ccccc3C2=O)cc1S(=O)(=O)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-chloro-2-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl-sulfonyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)phenol (0.26 g) and potassium carbonate (0.11 g) in N,N-dimethylformamide (3 mL) was added ethyl bromoacetate (0.078 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=9/1−1/9) to give ethyl 2-[5-chloro-2-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl-sulfonyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)phenoxy]acetate (0.29 g). To this material were added tetrahydrofuran (10 mL), methanol (5 mL), water (5 mL) and lithium hydroxide monohydrate (0.21 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). To the solution was added 1,1′-carbonyldiimidazole (0.16 g), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added methylamine (40% methanol solution, 2.5 mL), and the mixture was stirred at room temperature for 5 hours, and then stirred at 50° C. for 1 hour. The reaction mixture was poured into 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate) to give the title compound (0.14 g).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[N:10][CH:11]=[N:12][CH:13]=1)(C)(C)C.Cl>O1CCOCC1>[CH3:6][NH:7][C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[N:10][CH:11]=[N:12][CH:13]=1
Reactant: Cc1ccccc1-c1ncncc1N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNc1cncnc1-c1ccccc1C

Procedure:
Methyl-(4-o-tolyl-pyrimidin-5-yl)-carbamic acid tert-butyl ester (120 mg, 0.40 mmol) was treated with 4M HCl in dioxane (3 mL) for 45 minutes after which all volatiles were removed under reduced pressure to give methyl-(4-o-tolyl-pyrimidin-5-yl)-amine as waxy oil. This material was dissolved in dichloromethane (3 mL) and treated with N-ethyldiisopropyl-amine (210 μL, 1.2 mmol) and 3,5-bis-trifluoromethylbenzoyl chloride (166 mg, 0.60 mmol CAS RN 1271-19-8). After stirring for 1 h, the reaction mixture was loaded directly onto a silica gel column. Elution with 50% ethyl acetate in n-hexane yielded the desired compound as a yellow solid (78 mg, 44%). MS (ESI): m/z=440.1 [M+H]+.
Reaction SMILES: [CH:1]1([O:7][CH:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C:9]([NH:11]C2SC=CN=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)N[Si](C)(C)C>ClCCl.CN(C)C=O>[CH:1]1([O:7][CH:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C:9]([NH2:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=C(Nc1nccs1)C(OC1C=CCCC1)c1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)C(OC1C=CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A solution of rac-(cyclohex-2-enyloxy)-(3,4-dichloro-phenyl)-acetic acid (Example 3; 409 mg, 1.36 mmol) in dichloromethane (10 mL) and N,N-dimethylformamide (one drop) cooled to 0° C. was treated with oxalyl chloride (2.0 M solution in dichloromethane, 0.95 mL, 1.90 mmol). The reaction was stirred at 0° C. for 1 h, then 1,1,1,3,3,3-hexamethyldisilazane (1.0 mL, 4.75 mmol) was added and the resulting cloudy mixture was stirred at 25° C. for 16 h. The reaction was quenched with methanol (10 mL), washed with an aqueous solution of 5% sulfuric acid (2×15 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine (1×10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The reaction product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) to give rac-2-(cyclohex-2-enyloxy)-2-(3,4-dichloro-phenyl)-acetamide (311 mg, 76% yield) as a white solid: 103.6-108.9° C.; EI-HRMS m/e calcd for C14H15NCl2O2(M+) 299.0479, found 299.0492.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41]1([CH2:47][CH2:48][CH2:49][O:50][NH2:51])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:15])[NH:51][O:50][CH2:49][CH2:48][CH2:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NOCCCc1ccccc1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NOCCCc1ccccc1
Yield: 44.4 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and 3-phenylpropoxyamine (41 mg, 0.22 mmol) according to Method C with HPLC purification to give the title compound (53 mg). 1H-NMR (400 MHz, CD3OD) d 7.57 (s, 1H), 6.94 (d, J=8.3 Hz, 1H), 4.28 (m, 1H), 3.65 (m, 2H), 3.04 (dd, J=4.9 Hz, J=13.9 Hz, 1H), 2.97 (m, 1H), 2.73 (dd, J=9.6 Hz, J=13.8 Hz, 1H), 2.65 (t, J=7.7 Hz, 2H), 1.78 (m, 2H), 1.37 (s, 3H), 1.36 (s, 6H); IR (KBr) 3293, 2949, 1681, 1651 cm−1; HRMS m/z 663.2806 (calc. of monoisotopic mass for C35H41N3O10 gives 663.2792).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[CH3:36])[C:31]#[N:32].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>CN(C)C=O.C(OCC)(=O)C>[C:31]([C:30]1[CH:33]=[CH:34][C:35]([CH3:36])=[C:28]([NH:27][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([NH:17][C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)=[CH:19][CH:20]=2)[CH:29]=1)#[N:32]
Reactant: Cc1ccc(C#N)cc1N
Reactant: O=C(O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 80 °C
Yield: 64.6 %

Procedure:
To a stirred mixture of 4-(4-phenylquinazolin-2-ylamino)benzoic acid (1.37 g, 4.02 mmol), 3-amino-4-methylbenzonitrile (529 mg, 4.01 mmol), and Hunig's base (2.1 mL, 12 mmol) in dimethylformamide (10 mL) was added HATU (3.04 g, 8.00 mmol). The stirred mixture was heated to 80° C. overnight, then cooled to rt. The reaction was diluted with ethyl acetate and extracted with water. The organic layer was washed with saturated sodium bicarbonate and concentrated on a rotary evaporator. The residue was sonicated with acetonitrile and filtered to give a light yellow solid, which was again washed with water, acetonitrile, and dried under reduced pressure to give N-(5-cyano-2-methylphenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (1.18 g, 65%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 9.87 (s, 1H), 8.19 (d, 2H), 8.00 (d, 2H), 7.91-7.78 (m, 6H), 7.66-7.62 (m, 4H), 7.51 (d, 1H), 7.42 (ddd, 1H), 2.36 (s, 3H). MS (EI) for C29H21N5O: 456.1 (MH+).
Reaction SMILES: C([PH:5](=[O:7])[OH:6])CCC.C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:20]=[C:21]([CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>ClCCl>[CH2:25]([O:24][C:22]([CH:21]([CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[CH2:20][PH:5](=[O:6])[OH:7])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCCC[PH](=O)O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCC(C[PH](=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.4 %

Procedure:
Butylphosphinic acid (2.0 g, 16 mmol) in 80 mL of dry dichloromethane was cooled to 0° C. under an atmosphere of nitrogen. Triethylamine (6.7 g, 66 mmol) was added followed by trimethylsilyl chloride (58 mL, 58 mmol, 1.0 M in dichloromethane). The mixture was stirred at 0° C. for 10 minutes and dibenzyl 2-methylenepentanedioate (2)(6.4 g, 20 mmol) in 20 mL of dichloromethane was added. The cold bath was removed and the reaction warmed to room temperature and stirred overnight. The mixture was then cooled to 0° C. and quenched by the slow addition of 5% hydrochloric acid. The dichloromethane layer was then removed and washed with 5% hydrochloric acid and with brine. The organic layer was dried (MgSO4) and evaporated to give a clear light golden liquid. The liquid was purified by flash chromatography and eluted with 3:1 hexane/ethyl acetate containing 5% acetic acid. The desired fractions were combined and evaporated to give butyl[2,4-di(benzyloxycarbonyl)butylphosphinic acid (3,R=n-butyl, R1=H) (2.9 g, 40%) as a clear and colorless oil. Rf0.12 (3:1, Hex./EtOAc 5% AcOH). 1H NMR (d6-DMSO): 7.3 ppm (m, 10), 5.0 ppm (s,4H), 2.7 ppm (m, 1H) 2.3 ppm (y, 2H), 1.8 ppm (m, 2H), 1.3 ppm (m, 4H), 0.8 ppm (t, 3H)
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][N:13]([CH:54]([CH2:57][CH3:58])[CH2:55][CH3:56])[CH2:14][C:15]1[CH:16]=[C:17]([CH:51]=[CH:52][CH:53]=1)[C:18]([NH:20][C:21]1[S:22][C:23]2[CH2:50][CH2:49][CH2:48][CH2:47][C:24]=2[C:25]=1[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]2[CH:46]=[CH:45][C:40]([C:41]([O:43]C)=[O:42])=[CH:39][CH:38]=2)=[CH:31][CH:30]=1)=[O:27])=[O:19])[C:3](=[O:10])[O:4][CH2:5][C:6](=[O:9])[O:7]C.CO.[OH-].[Na+].[ClH:63]>C1COCC1>[ClH:63].[C:6]([CH2:5][O:4][C:3]([N:2]([CH3:1])[CH2:11][CH2:12][N:13]([CH2:14][C:15]1[CH:16]=[C:17]([CH:51]=[CH:52][CH:53]=1)[C:18]([NH:20][C:21]1[S:22][C:23]2[CH2:50][CH2:49][CH2:48][CH2:47][C:24]=2[C:25]=1[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][C:40]([C:41]([OH:43])=[O:42])=[CH:45][CH:46]=2)=[CH:33][CH:34]=1)=[O:27])=[O:19])[CH:54]([CH2:55][CH3:56])[CH2:57][CH3:58])=[O:10])([OH:9])=[O:7]
Reactant: CCC(CC)N(CCN(C)C(=O)OCC(=O)OC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)N(CCN(C)C(=O)OCC(=O)O)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To a mixture of 203 mg of methyl 4-{2-[4-({[2-({3-[7-methyl-3,6-dioxo-10-(pentan-3-yl)-2,5-dioxa-7,10-diazaundecan-11-yl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate, 4.0 mL of methanol and 4.0 mL of THF was added 1.5 mL of a 1.0 M aqueous sodium hydroxide solution at room temperature, followed by stirring for 14 hours at 60° C. 1.5 mL of 1.0 M hydrochloric acid was added to the reaction mixture under ice cooling, followed by concentration under reduced pressure. A mixed solvent (methanol/chloroform=15/85) was added to the residue, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% methanol/chloroform). A mixed solvent (acetonitrile/water=90/10) was added to the obtained product, 0.5 mL of 1.0 M hydrochloric acid was added thereto under ice cooling, and the solvent was removed under reduced pressure. The residue was subjected to lyophilization, thereby obtaining 186 mg of 4-(2-{4-[({2-[(3-{[(2-{[(carboxymethoxy)carbonyl](methyl)amino}ethyl)(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoic acid hydrochloride.
Reaction SMILES: CO.[OH-].[K+].[Br:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[OH:13].[S:14]([O:24][CH2:25][C:26]#[C:27][CH2:28][CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>C(O)(=O)C>[S:14]([O:24][CH2:25][CH2:26][C:27]#[C:28][CH2:29][O:13][C:7]1[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=1[Br:5])([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:15])=[O:16]
Reactant: Oc1ccc(F)cc1Br
Reactant: Cc1ccc(S(=O)(=O)OCC#CCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)OCCC#CCOc2ccc(F)cc2Br)cc1
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To MeOH (140 mL) solution containing KOH (4.73 g, 84.3 mmol) at 22° C. was added 2-bromo-4-fluorophenol (16.09 g, 84.2 mmol) and 2-pentyne-1,5-diol ditosylate (11.47 g, 28.1 mmol). After stirring 20 h acetic acid (3.5 mL) was added and the reaction stirred 1 h. The reaction was concentrated in vacuo and the residue extracted with CH2Cl2 (75 mL) and saturated K2CO3 (75 mL). The organic phase was separated and washed with saturated K2CO3. The aqueous phase was washed with CH2Cl2 (2×30 mL). The combined CH2 Cl2 layers were dried with dried with MgSO4, filtered, concentrated in vacuo. Silica gel chromatography (9:1 Hexane:EtOAc) yielded the title compound as a viscous oil (8.39 g, 70%).
Reaction SMILES: BrC1C2N(C(=O)N(CC3C=NC(C(F)(F)F)=CC=3)N=2)C(C)=CC=1C1C=CC(Cl)=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([CH3:44])[N:41]3[C:45](=[O:60])[N:46]([CH2:48][C:49]4[C:50](C)=[N:51][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:53][CH:54]=4)[N:47]=[C:40]3[C:39]=2[C:61]2[CH:66]=[CH:65][N:64]=[CH:63][CH:62]=2)=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([CH3:44])[N:41]3[C:45](=[O:60])[N:46]([CH2:48][C:49]4[CH:50]=[N:51][C:52]([C:55]([F:57])([F:58])[F:56])=[CH:53][CH:54]=4)[N:47]=[C:40]3[C:39]=2[C:61]2[CH:62]=[CH:63][N:64]=[CH:65][CH:66]=2)=[CH:34][CH:33]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cc(C)n2c1=O
Agent: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Product: Cc1cc(-c2ccc(Cl)cc2)c(-c2ccncc2)c2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Yield: 81 %

Procedure:
The title compound (20 mg, 81%) as a light yellow powder was prepared from 8-bromo-7-(4-chlorophenyl)-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (25 mg, 0.05 mmol) by procedures analogous to those used for the preparation of 7-(4-chlorophenyl)-5-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one. HPLC/MS: retention time=2.92 min, [M+H]+=496.3.
Reaction SMILES: C(N1C=C(C2SC(C(OCC)=O)=C(C)N=2)N=N1)C1C=CC=CC=1.[CH3:24][C:25]1[N:26]=[C:27]([C:35]2[N:36]=[N:37][N:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=3)[CH:39]=2)[S:28][C:29]=1[C:30]([O:32]CC)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([C:35]2[N:36]=[N:37][N:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:48])[F:49])=[CH:43][CH:42]=3)[CH:39]=2)[S:28][C:29]=1[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)c1sc(-c2cn(Cc3ccc(C(F)(F)F)cc3)nn2)nc1C
Agent: CCOC(=O)c1sc(-c2cn(Cc3ccccc3)nn2)nc1C
Product: Cc1nc(-c2cn(Cc3ccc(C(F)(F)F)cc3)nn2)sc1C(=O)O
Yield: 98 %

Procedure:
Following the procedure as described in Example 3, making variations as necessary to replace ethyl 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylate with ethyl 4-methyl-2-(1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 98% yield: MS (ES−) m/z 367.2 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1([CH2:12][CH3:13])[CH2:10][CH2:9][CH:8]=[CH:7][C:6]1=[O:11].S(C)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1([CH2:12][CH3:13])[CH2:10][CH2:9][CH:8]([CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH2:3])[CH2:7][C:6]1=[O:11]
Reactant: CCC1(CC(=O)OC)CCC=CC1=O
Solvent: CSC
Solvent: C1CCOC1
Product: C=CCCCCC1CCC(CC)(CC(=O)OC)C(=O)C1
Yield: 165.2 %

Procedure:
A solution of 1-ethyl-2-oxocyclohex-3-eneacetic acid methyl ester (25 g, 127.6 mmol), CuBr.Me2S (2.62 g, 12.8 mmol) and Me2S (25.5 mL) in 375 mL of tetrahydrofuran was cooled to -40° C. under nitrogen and treated dropwise with H2C=CHCH2CH2CH2CH2MgBr (166.6 mmol, 303 mL of a 0.55M solution in tetrahydrofuran). Fifteen minutes after the addition, the reaction mixture was quenched with 300 mL of 1M HCl and extracted with 4×120 mL of ether. Drying (MgSO4), concentration in vacuo and flash chromatography (114 mm diameter column, 10% ethyl acetate in petroleum ether eluent) afforded the oily product (29.51 g, 105.4 mmol, 83%) as a mixture of diastereomers. A portion of the diastereomers was separated by preparative HPLC affording 2.25 g of isomer A, the higher Rf material, as a yellow oil.