Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=2)[CH:11]=[CH:10][C:9]=1[F:24])([CH3:4])([CH3:3])[CH3:2].O1CCCC1>CO.[C].[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=2)[CH:11]=[CH:10][C:9]=1[F:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)cn2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A suspension of tert-butyl{2-fluoro-5-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate (3.49 g, 10 mmol) and 10% palladium-carbon (1.0 g) in methanol (20 mL)-tetrahydrofuran (20 mL) was vigorously stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure, and the residue was triturated with diethyl ether to give the title compound (3.00 g, 94%) as a white amorphous.
Reaction SMILES: C(OCC)(OCC)O[CH2:3][CH3:4].[C:11]([O:14][C@@H:15]1[C@H:21]2[C@H:22]3[C@H:31]([CH2:32][CH2:33][C@:18]2([CH2:19][CH3:20])[C:17](=[O:35])[CH2:16]1)[C@@H:30]1[C:25](=[CH:26][C:27](=[O:34])[CH2:28][CH2:29]1)[CH2:24][CH2:23]3)(=[O:13])[CH3:12]>CCO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:11]([O:14][C@@H:15]1[C@H:21]2[C@H:22]3[C@H:31]([CH2:32][CH2:33][C@:18]2([CH2:19][CH3:20])[C:17](=[O:35])[CH2:16]1)[C@@H:30]1[C:25]([CH:26]=[C:27]([O:34][CH2:3][CH3:4])[CH2:28][CH2:29]1)=[CH:24][CH2:23]3)(=[O:13])[CH3:12]
Reactant: CCOC(OCC)OCC
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C[C@H](OC(C)=O)[C@@H]34)[C@H]2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
Triethyl orthoformate (30 ml, 180 mmol) and p-Toluenesulfonic acid (300 mg, 1.57 mmol) were added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (30 g, 87 mmol) in EtOH (180 ml). The mixture was stirred at room temperature for 1 h, and then cooled to 0° C. The precipitate was filtered, washed with cooled ethanol and dried under vacuum to afford 15α-acetoxy-3-ethoxy-18-methyl-estra-3,5-dien-17-one (31.5 g, yield: 97%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:23][CH2:22][CH:21]3[CH2:24][CH:18]2[CH2:19][N:20]3C(OCC2C=CC=CC=2)=O)[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.CCO>C(Cl)Cl.[OH-].[OH-].[Pd+2]>[CH:18]12[CH2:24][CH:21]([NH:20][CH2:19]1)[CH2:22][CH2:23][N:17]2[C:4]1[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc2c(c(N3CCC4CC3CN4C(=O)OCc3ccccc3)n1)CCCc1ccccc1-2
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Nc1nc2c(c(N3CCC4CC3CN4)n1)CCCc1ccccc1-2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from Example 82A was treated with EtOH (1.5 mL) and 20% Pd(OH)2/C (15 mg), then stirred at ambient temperature under an H2 atmosphere for 16 hours, then diluted with 5:1 CH2Cl2:EtOH, filtered, concentrated and purified by chromatography (eluting with 2, 3.5, 5 and 10% (9:1 MeOH:saturated aqueous NH4OH) in CH2Cl2) to provide the title compound. 1H NMR (CDCl3) δ 1.65-1.86 (m, 2H), 2.01 (d, J=11.53 Hz, 2H), 2.20-2.27 (m, 3H), 2.40-2.49 (m, 1H), 2.62-2.69 (m, 2H), 3.20 (dd, J=11.53, 4.75 Hz, 1H), 3.32 (d, J=12.21 Hz, 1H), 3.46-3.58 (m, 2H), 3.76-3.81 (m, 1H), 4.50 (t, J=4.41 Hz, 1H), 4.71 (s, 2H), 7.20-7.24 (m, 1H), 7.31-7.39 (m, 2H), 7.71-7.75 (m, 1H); MS (M+H)+ m/z 322.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([NH2:13])=[CH:11][CH:12]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(F)cc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 43.9 %

Procedure:
Chloroacetyl chloride (0.68 mL, 8.58 mmol) was added dropwise to a stirred solution of 4-fluoro-N2-phenylbenzene-1,2-diamine (1.24 g, 6.13 mmol) and pyridine (2.0 mL, 24.5 mmol) in DCM (8 mL) at 0° C. under a nitrogen atmosphere. After stirring at 0° C. for 20 min, the mixture was slowly warmed to RT and stirring at RT was continued for 2 h. The mixture was partitioned between DCM and aqueous HCl (1M, 50 mL) cooled at 0° C. and the aqueous phase was further extracted with DCM (×3). The combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in cyclohexane) to afford the title compound as a white crystalline solid (750 mg, 44%). LCMS (Method C): RT 3.42 min [M+H]+ 279.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:11][C:9](=O)[C:6](=CO)[C:4](=[O:5])[O:3]1.[CH3:13]C(C1C(=O)OC(C)(C)OC1=O)=O>C1(C)C=CC=CC=1.C1(C)C(C)=CC=CC=1>[CH3:12][C:2]1([CH3:1])[O:3][C:4](=[O:5])[CH:6]=[C:9]([CH3:13])[O:11]1
Reactant: CC(=O)C1C(=O)OC(C)(C)OC1=O
Reactant: CC1(C)OC(=O)C(=CO)C(=O)O1
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: CC1=CC(=O)OC(C)(C)O1

Procedure:
The derivatives have not heretofore been known at all, but for the first time the present inventors have found a process for producing 2,2-dimethyl-1,3-dioxin-4-one as a compound belonging thereto. Namely, according to the process reported by the present inventors in Chem. Pharm. Bull. 31, (6) 1896 (1983), 2,2-dimethyl-1,3-dioxin-4-one was obtained from formyl Meldrum's acid in the presence of acetone and using a small amount of toluene or xylene as solvent, with a yield of 31%. This formyl Meldrum's acid seems to have a higher reactivity than that of similar acetyl Meldrum's acid. That is, in the case of the latter acid, its thermal decomposition yielded 2,2,6-trimethyl-1,3-dioxin-4-one, whereas in the case of the former acid, its mere heating in the absence of solvent formed only a resinous substance without yielding 2,2-dimethyl-1,3-dioxin-4-one, but when the former acid was heated in a xylene solvent containing acetone, the compound was obtained for the first time. However, its yield was not only low (yield: 31% as described above), but the loss of the raw material acid due to the resin formation was so great that the recovery of the raw material was impossible.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][C:23]([N:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)([CH3:25])[CH3:24])=[C:19]([O:39][CH3:40])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][C:23]([CH3:24])([N:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)[CH3:25])=[C:19]([O:39][CH3:40])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1C#CC(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1C#CC(C)(C)N1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A solution of tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (0.122 g, 0.225 mmol) in methylene chloride (4 mL) was added with trifluoroacetic acid (4 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and then the residue was dissolved in water (10 mL). The solution was added with saturated aqueous sodium hydrogencarbonate (10 mL), and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[3-methyl-3-(piperazin-1-yl)but-1-ynyl]benzofuran-3(2H)-one (0.0259 g, 26%).
Reaction SMILES: [H][H].C([O:10][CH2:11][C@@H:12]1[C@@H:16]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH2:14][C@H:13]1[OH:21])C1C=CC=CC=1.C(OCC)(=O)C>[C].[Pd].C(O)(=O)C>[CH2:17]([C@H:16]1[CH2:15][CH2:14][C@@H:13]([OH:21])[C@@H:12]1[CH2:11][OH:10])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC[C@H]1CC[C@@H](O)[C@@H]1COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCC[C@H]1CC[C@@H](O)[C@@H]1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
In an atmosphere of hydrogen, a mixture of 4.29 g of (1R,2S,3S)-2-benzyloxymethyl-3-butylcyclopentan-1-ol (prepared in Reference Example 7), 500 ml of 10% palladium-carbon, 20 ml of ethyl acetate and 10 ml of acetic acid was stirred for 16 hrs at room temperature. After stirring the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:3) as eluent to give 2.59 g of the title compound having the following physical characteristics in a 91.8% yield.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)(=[O:8])=[O:7])=[O:4]>[Pd].O.C(O)C>[F:19][C:2]([F:1])([F:18])[C:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)(=[O:7])=[O:8])=[O:4]
Reactant: O=C(NS(=O)(=O)c1cccc([N+](=O)[O-])c1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Nc1cccc(S(=O)(=O)NC(=O)C(F)(F)F)c1
Yield: 69.7 %

Procedure:
In the same way as that described in Example 11, Step 2, using 1-(trifluoromethylcarbonylaminosulphonyl)-3-nitrobenzene (2.7 g, 9.1 mmol), 10% palladium on carbon (0.25 g, 9% (w/w)) in water (3 ml) and ethanol (70 ml), the title compound (1.7 g, 70%) was afforded as a colourless solid. mp 106°-108° C. 1H NMR (360 MHz, D6 -DMSO) δ 6.59 (1H, m), 6.88 (1H, m), 7.02 (2H, m).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=1>O>[Cl:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:12]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Solvent: O
Product: FC(F)(F)c1cnc(N2CCNCC2)c(Cl)c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 104.1 %

Procedure:
Piperazine (40 g) was melted by heating at 140° C. and 2,3-dichloro-5-trifluoromethylpyridine (10 g) was added thereto. The mixture was stirred at 120° C. for 2 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with brine, dried and concentrated under reduced pressure to give 1-(3-chloro-5-trifluoromethyl-2-pyridyl)piperazine (12.8 g) as a brown solid.
Reaction SMILES: [Cl:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH3:8][C:9](=[C:11]([CH3:13])[CH3:12])[CH3:10]>CCOCC>[Cl:1][S:2]([N:5]1[C:11]([CH3:13])([CH3:12])[C:9]([CH3:10])([CH3:8])[C:6]1=[O:7])(=[O:4])=[O:3]
Reactant: CC(C)=C(C)C
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOCC
Product: CC1(C)C(=O)N(S(=O)(=O)Cl)C1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 0.06 mol CSI (chlorosulfonyl isocyanate) in dry ether under nitrogen, 0.06 mol of 2,3-dimethyl-but-2-ene was added dropwise at a temperature of 30° to 35° C. The reaction mixture was stirred for a further 1 hour while it was cooled to room temperature. The solution was then cooled in a salt-ice bath and the product which crystallized out as white solid was filtered off and carried through to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Br.[CH3:33][C:34]1[N:38]([CH2:39][C:40]#[CH:41])[CH:37]=[N:36][CH:35]=1.CN(C=O)C>N(CC)CC.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.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:41]#[C:40][CH2:39][N:38]4[C:34]([CH3:33])=[CH:35][N:36]=[CH:37]4)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCn1cncc1C
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Br
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cc1cncn1CC#Cc1cc(CN2CCOCC2)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 5-methyl-1-prop-2-ynyl-1H-imidazole hydrobromide (120.4 mg). Anhydrous DMF (10 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vacuum to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and saturated NaHCO3. The layers are separated. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluant 1% MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), 3% MeOH in CH2Cl2 (1L), 4% MeOH in CH2Cl2 (2L), and 6% MeOH in CH2Cl2 (1L)). Product-containing fractions are combined and concentrated to afford a residue. The residue is recrystallized from hot acetonitrile to afford 87.7 mg of the title compound as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][C:16]=2[Cl:23])=[O:14])=[C:11]([Cl:26])[CH:10]=1.C([O-])(O)=O.[Na+]>ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[Cl:23])=[O:14])=[C:11]([Cl:26])[CH:10]=1
Reactant: COc1ccc(C(=O)c2ccc(Nc3ccccc3N)cc2Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ccccc1Nc1ccc(C(=O)c2ccc(O)cc2Cl)c(Cl)c1
Reaction time: 0.25 h

Procedure:
A solution of 4-(2-aminophenylamino)-2,2′-dichloro-4′-methoxybenzophenone (Compound 112) (1.00 g, 2.6 mmol) in dichloromethane (40 ml) was cooled to −78° C. under argon. Borontribromide (1.0 ml, 10.4 mmol) in dichloromethane (5 ml) was added dropwise under stirring. After 15 min the reaction mixture was allowed to come to room temperature over 1 h, and then at 45° C. for 16 hours. The reaction mixture was poured into saturated NaHCO3 and then extracted with EtOAc several times. The organic phases was collected, dried (MgSO4), filtered, and concentrated in vacuo to give the crude product. Concentration in vacuo from a solution of methanol removed traces of boric acid. The crude product was further purified by flash chromatography using EtOAc/pentane 3:2 as eluent.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]3[CH:13]=[C:14]([C:17]#[C:18][C:19]4([OH:26])[CH2:24][CH:23]5C[CH:20]4C[CH2:22]5)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH3:27])[N:3]=1.C(C1(O)CCC[O:32]C1)#C>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]3[CH:13]=[C:14]([C:17]#[C:18][C:19]4([OH:26])[CH2:24][CH2:23][CH2:22][O:32][CH2:20]4)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH3:27])[N:3]=1
Reactant: C#CC1(O)CCCOC1
Reactant: Cc1nc2ccc(C#CC3(O)CC4CCC3C4)cc2n1-c1ncnc(N)n1
Product: Cc1nc2ccc(C#CC3(O)CCCOC3)cc2n1-c1ncnc(N)n1

Procedure:
The title compound was prepared by the procedure described for 2-((1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)ethynyl)bicyclo[2.2.1]heptan-2-ol, by substituting 2-ethynylbicyclo [2.2.1]heptan-2-ol (1-b) with 3-ethynyltetrahydro-2H-pyran-3-ol. The title product, 3-((1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)ethynyl)tetrahydro-2H-pyran-3-ol was purified by silica gel chromatography: 1H NMR (400 MHz, DMSO) delta 1.66-1.78 (m, 4H), 1.97-2.05 (m, 1H), 3.01 (s, 3H), 3.36-3.71 (m, 4H), 7.47 (dd, J=1.6, 8.4 Hz, 1H), 7.71 (dd, J=0.4, 8.4 Hz, 1H), 8.17 (s, 1H), 8.24 (s, 1H), 8.48 (dd, J=0.4, 1.6 Hz, 1H), 8.71 (s, 1H); LC-MS: m/z=+350.9 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@H:19]([C@@H:27]([OH:33])[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(OCC)(=O)C>[NH2:8][C@H:9]([C:16]([NH:18][C@H:19]([C@@H:27]([OH:33])[CH2:28][CH2:29][CH:30]([CH3:31])[CH3:32])[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1
Reactant: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1
Yield: 91.5 %

Procedure:
A solution of 2(S)-(N-t-butoxycarbonyl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (383 mg) in trifluoroacetic acid (10 ml) was stirred at 0° C. for 30 minutes. After concentration of the mixture in vacuo, the residue was dissolved in ethyl acetate (20 ml). The solution was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo to give 2(S)-(L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (275 mg) as an amorphous powder.
Reaction SMILES: [Br:1][C:2]([F:14])([F:13])[CH:3]([F:12])[CH2:4][CH2:5][S:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.S(Cl)([Cl:18])(=O)=O.O>ClCCl>[Br:1][C:2]([F:13])([F:14])[CH:3]([F:12])[CH2:4][CH2:5][S:6][C:7]1[S:8][C:9]([Cl:18])=[CH:10][N:11]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: FC(CCSc1nccs1)C(F)(F)Br
Solvent: ClCCl
Solvent: O
Product: FC(CCSc1ncc(Cl)s1)C(F)(F)Br

Procedure:
The compound from Step 1 (30.6 g) in dichloromethane (130 cm3) was treated at ambient temperature with sulfuryl chloride (9.6 cm3) in dichloromethane (30 cm3) over 1 hour with stirring under an atmosphere of nitrogen. The reaction was stirred for a further 1 hour, poured slowly into water (250 cm3) and stirred for 0.25 hours. The organic phase was separated, the aqueous phase extracted with dichloromethane (2×75 cm3), the combined organic phases washed with aqueous sodium hydrogen carbonate, brine and dried (MgSO4). The solvent was evaporated under reduced pressure and the residue fractionated by chromatography (silica; eluant 5% diethyl ether in hexane) to give 2-(4-bromo-3,4,4-trifluorobutylthio)-5-chlorothiazole (28.0 g); 1H NMR: δ 2.20-2.45 (2H,m); 3.25-3.50(2H,m); 4.70-5.0(1H,m); 7.45(1H,s); (oil).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:31][CH2:30][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[Cl:22])[CH2:34][CH2:33]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: Clc1ccccc1N1CCNCC1
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCN(c2ccccc2Cl)CC1

Procedure:
The the hydrochloride of title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(2-chlorophenyl)piperazine. Drying in vacuo at 50° C. for 3½ h gave the title compound; 1H NMR (DMSO-d6): δ 8.61–8.55 (br, 1H), 8.29–8.20 (dd-like, 1H), 7.53–7.41 (m, 1H), 7.39–7.17 (m, 7H), 7.14–7.03 (m, 1H), 4.58 (br s, NH+water), 3.85–3.55 (br m, 4H), 3.12–2.99 (br m, 4H); HPLC-MS: m/z=478 (M+H); IR (KBr): ν 1733 (C═O) cm−1.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH:9]=O)=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1.[N+:13]([C:16]1[CH:17]=[C:18]([CH2:22][C:23]#[N:24])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][N:2]1[C:3]2[N:4]=[C:5]([S:11][CH3:12])[N:6]=[CH:7][C:8]=2[CH:9]=[C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)[C:23]1=[NH:24]
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Reactant: CNc1nc(SC)ncc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ncc2cc(-c3cccc([N+](=O)[O-])c3)c(=N)n(C)c2n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
To a solution of 4-(methylamino)-2-(methylsulfanyl)pyrimidine-5-carbaldehyde (10.0 g, 55 mmol) and (3-nitrophenyl)acetonitrile (10.5 g, 65 mmol) in DMF (150 mL) was added K2CO3 (38 g, 275 mmol) at RT. The mixture was stirred at 100° C. for 18 h. After cooling, the reaction was diluted with DMF (50 mL) and filtered. The filtrate was concentrated to give crude 8-methyl-2-(methylsulfanyl)-6-(3-nitrophenyl)-8H-pyrido[2,3-d]pyrimidin-7-ylideneamine (9.0 g, 50% yield) which was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]=1)[OH:4].[C:20]1([C@H:26]([N:28]=[C:29]=[O:30])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.C1C=CC=CC=1.CCOCC>[O:11]([C:7]1[N:6]=[C:5]([CH:3]([O:4][C:29](=[O:30])[NH:28][CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:27])[C:2]([F:1])([F:18])[F:19])[CH:10]=[CH:9][CH:8]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC(c1cccc(Oc2ccccc2)n1)C(F)(F)F
Reactant: C[C@@H](N=C=O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(NC(=O)OC(c1cccc(Oc2ccccc2)n1)C(F)(F)F)c1ccccc1

Procedure:
A stirred solution of 2.40 g (8.91 mmol) of α-trifluoromethyl-6-phenoxy-2-pyridinemethanol, 1.38 g (9.36 mmol) of (R)-(+)-1-phenylethyl isocyanate, and 22 mg (0.18 mmol) of 4-dimethylaminopyridine in 9 ml of benzene under a nitrogen atmosphere was heated at 50° C. for 17 hours. The reaction mixture was then diluted with 150 ml of ether and washed with 25 ml of 1N aqueous HCl, 25 ml of saturated aqueous NaHCO3, and 25 ml of saturated aqueous NaCl. The organic layer was dried (MgSO4) and concentrated under reduced pressure. Repeated chromatography of the residue on silica gel with benzene afforded first 1.77 g (48%) of the [R-(R*,R*)] diastereomer: Rf =0.10 (SiO2, benzene); 1H NMR (CDCl3) δ 1.52 (d, 6.8 Hz, 3H), 4.83 (quintet, 7.1 Hz, 1H), 6.01 (q, 6.1 Hz, 1H), 6.83 (d, 8.2 Hz, 1H), 7.11-7.37 (br m, 12H), and 7.68 (t, 7.8 Hz, 1H); and then 1.77 g (48%) of the [S-(R*,S*)] diastereomer: Rf =0.09 (SiO2, benzene); 1H NMR (CDCl3) δ 1.47 (d, 6.8 Hz, 3H), 4.80 (quintet, 7.0 Hz, 1H), 5.98 (q, 6.9 Hz, 1H), 6.86 (d, 8.3 Hz, 1H), 7.13-7.42 (br m, 12H), and 7.72 (t, 7.8 Hz, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:14])([F:13])[CH2:7][S:8][CH2:9][C:10](O)=[O:11]>>[F:5][C:6]([F:14])([F:13])[CH2:7][S:8][CH2:9][C:10]([Cl:3])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CSCC(F)(F)F
Product: O=C(Cl)CSCC(F)(F)F

Procedure:
Thionyl chloride (21.9 g, 184 mmol) and trifluoroethylmercaptoacetic acid (15.9 g, 91 mmol) were stirred together overnight. The excess reagent was removed in vacuo and the product was distilled; bp 62°-68°/20 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[C:34]([Cl:35])=[C:33]([CH2:36][CH3:37])[CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[C:34]([Cl:35])=[C:33]([CH2:36][CH3:37])[CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: CCc1ccnc(C(=O)CBr)c1Cl
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: CCc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)OC)c1Cl

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-3-chloro-4-ethylpyridine hydrobromide*.