Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-2:1].[Al+3:2].[O-2].[O-2].[Al+3].[Sm:6]>>[O-2:1].[Al+3:2].[O-2:1].[O-2:1].[Al+3:2].[O-2:1].[Sm+3:6].[O-2:1].[O-2:1].[Sm+3:6]
Reactant: [Sm]
Agent: [Al+3]
Agent: [O-2]
Product: [Sm+3]

Procedure:
Aluminum oxide disks (0.9 inch (2.29 cm) in diameter×0.12 inch (0.30 cm) thick) fabricated by the processes described in Example 1 were selected for evaluating the samarium glaze. Calculations were made based on the density of the samarium glaze (3.2 grams per cubic centimeter) and the surface area of the Al2O3 disks to provide the weight of samarium oxide frit (powdered glass) to yield samarium glaze thicknesses on the Al2O3 disks of 0.001 inch (0.025 millimeter), 0.003 inch (0.076 millimeter), 0.005 inch (0.127 millimeter), 0.007 inch (0.178 millimeter) and 0.009 inch (0.229 millimeter). The calculated weight of samarium frit was placed in the center of each disk. The Al2O3 disks with frit were placed in a furnace and heated to 1300° C. for 60 minute time periods. The frit melted, flowed over the top surface of the disks providing a uniform thickness glaze which was very smooth and transparent to the visible light spectrum. Subsequent tests of this glaze indicated an extremely strong bond to the Al2O3 substrate by virtue of the nominal 15% porosity of the substrate. Furthermore the very smooth nature of the glaze provided a surface which did not collect dirt or debris and could be wiped clean just like a glass window. Absorption measurements were made on all five disks (0.001 to 0.009 inch or 0.0254 to 0.229 millimeter thicknesses) in an integrating sphere spectrophotometer from 220 nanometers to 2400 nanometers. Absorption was found at precisely 1.06 microns. There was zero absorption for a BaSO4 standard and an uncoated (noglaze) Al2O3 disk. The absorption for the 0.001 inch thick glaze was significant and progressed in textbook fashion as the thickness increased from 0.001 inch (0.025 millimeter), 0.003 inch (0.076 millimeter), 0.005 inch (0.127 millimeter), 0.007 inch (0.178 millimeter) and 0.009 inch (0.229 millimeter).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=O)=[CH:5][CH:4]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)c2c(C)cccc12
Reactant: C1CCNC1
Product: COc1ccc(C(=O)N2CCCC2)c2c(C)cccc12

Procedure:
4-Methoxy-8-methyl-1-naphthoic acid (Step-5 of Intermediate-22) was reacted with pyrrolidine by following the similar procedure as described in Step-6 of Intermediate-22.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([C:10]2[N:15]3[N:16]=[C:17]([NH2:19])[N:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].Cl[C:21]([O:23][CH3:24])=[O:22]>N1C=CC=CC=1>[CH3:24][O:23][C:21](=[O:22])[NH:19][C:17]1[N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=3)[N:15]2[N:16]=1
Reactant: COC(=O)Cl
Reactant: CC(C)c1cccc(-c2cccc3nc(N)nn23)c1
Solvent: c1ccncc1
Product: COC(=O)Nc1nc2cccc(-c3cccc(C(C)C)c3)n2n1
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 5-[3-(propan-2-yl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine (23.6 mg, 0.0935 mmol, 1 equiv) in pyridine was added methyl chloroformate (36.1 uL, 0.468 mmol, 5.00 equiv) at 24° C. After 3 h, the reaction mixture was concentrated in vacuo. The resulting residue was partitioned between saturated aqueous sodium bicarbonate solution (5 mL) and ethyl acetate (5 mL). The aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by preparative HPLC provided a white solid (17.7 mg, 61%). LCMS (ESI) m/z: 311.2. 1H NMR (500 MHz, DMSO-d6), δ: 10.45 (s, 1H), 7.88 (m, 1H), 7.81 (m, 1H), 7.65-7.72 (m, 2H), 7.48 (t, J=7.6 Hz, 1H), 7.42 (m, 1H), 7.28 (dd, J=7.0, 1.6 Hz, 1H), 3.67 (s, 3H), 3.00 (m, 1H), 1.28 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[CH:22]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:3]=1[CH:22]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([OH:25])=[O:24]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1Oc1ccccc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2sc3c(c2c(Oc2ccccc2)c1C(OC(C)(C)C)C(=O)O)CCCC3
Temperature: 65 °C
Yield: 34.4 %

Procedure:
To a solution of methyl 2-[2-methyl-4-(phenyloxy)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate 18 mg, 0.041 mmol) in methanol (0.5 mL) was added a solution of sodium hydroxide 10 N (50 μl, 0.500 mmol) and the mixture was heated at 65° C. for 18 h. After cooling, the organic volatiles were removed under reduced pressure and the aqueous phase was then acidified with a solution of hydrochloric acid 2N until a precipitate was formed. The solid was filtered, washed with water and dried under reduced pressure to afford 0.006 g (34%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.CCN(C(C)C)C(C)C.[NH2:34][CH2:35][CH:36]([CH3:39])[C:37]#[N:38].C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:38][CH2:37][CH:36]([CH3:39])[C:35]#[N:34])[N:8]=1
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Reactant: CC(C#N)CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C#N)CNc1nccc(-c2c(Br)nc(C3CC3)n2COCC[Si](C)(C)C)n1
Temperature: 90 °C
Yield: 100 %

Procedure:
A solution of 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (2.5 g, 5.8 mmol), DIEA (2.0 mL, 11.6 mmol), and 3-amino-2-methylpropanenitrile (1.49 g, 17.7 mmol) in NMP (10 mL) was treated with Na2CO3 (1.23 g, 11.6 mmol) and the resulting reaction mixture heated at 90° C. overnight. The reaction was allowed to cool to room temperature and was partitioned between EtOAc (75 mL) and water (100 mL). The layers were separated and the organic portion was washed with saturated aqueous NaHCO3 solution (100 mL), brine (150 mL), dried (Na2SO4) and concentrated to a brown residue. Purification by flash chromatography (0-50% EtOAc-heptane) afforded 3-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)-2-methylpropanenitrile (2.79 g, 5.8 mmol) as a white solid: LCMS (m/z) 477.1 (MH+), tR=0.98 minute.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].CO.C[O-].[Na+].Cl[CH:13]=[CH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:19]=1>C(OCC)C>[OH:30][CH:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][CH2:16][CH:15]=[CH:14][CH2:13][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=C(O)CCS
Reactant: CCCCCC(O)c1cccc(OCCC=CCl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCCC(O)c1cccc(OCC=CCSCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9.15 ml. (0.105 mole) 3-mercaptopropionic acid are dissolved in 70 ml. methanol and stirred with 315 ml. 1 M sodium methylate solution for 10 minutes at ambient temperature under an atmosphere of nitrogen. Subsequently, 19.79 g. (0.07 mole) 1-chloro-4-[3-(1-hydroxyhexyl)-phenoxy]-but-1-ene in 70 ml. methanol are added dropwise thereto in the course of 15 minutes. The reaction mixture is further stirred for 3 hours a ambient temperature and the solvent is then stripped off. The residue is taken up in diethyl ether and extracted several times with 2 M aqueous sodium hydroxide solution. The aqueous solution is acidified with 2 M hydrochloric acid and the desired compound is extracted with methylene chloride. After drying and stripping off the solvent, there are obtained 22.5 g. (91% of theory) of the title compound in the form of an oil.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:30]=[CH:31][C:32]=2[F:33])[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:30]=[CH:31][C:32]=3[F:33])[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CCCC(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 25 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}butanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.39 (dd, 1H, J=2.8, 6.8 Hz), 7.33–7.21 (m, 11H), 7.00 (t, 1H, J=5.6 Hz), 6.92 (t, 1H, J=9.2 Hz), 4.89 (s, 1H), 3.38 (dd, 2H, J=6.4, 12.0 Hz), 2.91–2.88 (m, 2H), 2.74 (m, 1H), 2.36 (t, 2H, J=6.4 Hz), 2.29 (t, 2H, J=7.6 Hz), 1.97 (dt, 2H, J=2.4, 11.6 Hz), 1.77–1.62 (m, 8H), 0.97 (t, 3H, J=7.2 Hz); ESMS m/e: 516.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[C:14]([NH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CC(C)=O)cc1N
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CC(C)=O)cc1NC(C)=O
Reaction time: 3 h
Yield: 97 %

Procedure:
To the mixture of compound 11 (0.25 g, 1.39 mmol) in chloroform (30 ml) was added acetic anhydride (1.2 ml) and catalytic amount of DMAP (10 mg) at 0° C. After stirring at such temperature for 3 hours, no more starting materials were detected on TLC. The reaction was quenched by adding ice water, extracted with CH2Cl2 twice. The organic layer was washed with brine, dried over Na2SO4. Removal of the solvent afforded the crude product. Purification of the crude product by using silica gel column gave 0.3 g (97%) of desired product 12. 1HNMR(CDCl3): 8.25 (d, J=1.2 Hz, 1H), 7.79 (br, 1H), 6.81 (m, 2H), 3.86 (s, 3H), 3.64 (s, 2H), 2.20 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1([CH3:29])[CH2:16][O:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18]=2OC)=[N:13]1.O>O1CCCC1>[CH3:26][O:25][C:19]1[C:18]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:17]([C:14]2[O:15][CH2:16][C:12]([CH3:11])([CH3:29])[N:13]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: Br[Mg]CCc1ccccc1
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(OC)c1OC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2=NC(C)(C)CO2)c(CCc2ccccc2)c1OC
Reaction time: 16 h

Procedure:
A solution of phenylethyl magnesium bromide (1M in tetrahydrofuran (40 ml) was added to a stirred solution of 4,5-dihydro 4,4-dimethyl-2-(2,3,4-trimethoxyphenyl) oxazole (5.3 g 0.02M) in dry tetrahydrofuran under a nitrogen atmosphere. The mixture was stirred at 20° for 16 hours. Water (200 ml) was added and the aqueous phase thoroughly extracted with diethyl ether (3×200 ml). The organic solution was dried over magnesium sulphate, filtered and evaporated to leave an oil which was purified by column chromatography on SiO2 eluting with ether/petroleum ether (50/50) to give a colorless oil (6.2 g); MS m/e 339.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])[N:4]=1.[OH:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:26]=[CH:27][CH:28]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:15][C:14]1[O:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][C:10]=1[CH2:9][CH2:8][C:5]1[N:4]=[C:3]([CH2:2][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:26]=[CH:27][CH:28]=2)[O:7][N:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCc1noc(CCl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCc2nc(CCc3nc(-c4ccccc4)oc3C)no2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 47.3 %

Procedure:
To a mixture of 5-chloromethyl-3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazole (0.61 g), methyl 2-(3-hydroxyphenyl)acetate (0.30 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.09 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water, 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.37 g, 43%) of methyl 2-[3-[[3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazol-5-yl]methoxy]phenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[C:5]([NH2:21])=[C:4]([SH:22])[N:3]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32](O)=O)=[CH:26][CH:25]=1>>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]2[S:22][C:4]3[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([N:8]4[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]4)[C:5]=3[N:21]=2)=[CH:26][CH:25]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc(S)c2N)CC1
Product: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(Br)cc3)sc2n1
Yield: 70 %

Procedure:
This compound was synthesized from tert-butyl 4-(2,5-diamino-6-mercaptopyrimidin-4-yl)piperazine-1-carboxylate using 3-(4-bromophenyl)propionic acid, yielding the title compound in 70% yield.
Reaction SMILES: CN(C=O)C.[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]1[NH:15][C:16](=[O:37])/[C:17](=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]2)=[C:25]([O:35][CH3:36])[CH:24]=1)/[CH2:18][CH2:19][CH2:20]Cl.[H-].[Na+]>O>[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]1[N:15]1[CH2:20][CH2:19][CH2:18]/[C:17](=[CH:22]\[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]3)=[C:25]([O:35][CH3:36])[CH:24]=2)/[C:16]1=[O:37]
Reactant: COc1cc(/C=C(\CCCCl)C(=O)NC2Cc3ccccc3C2)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(/C=C2\CCCN(C3Cc4ccccc4C3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a DMF (50 mL) solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid indan-2-ylamide (6.9 g), sodium hydride (40% mineral oil content, 740 mg) was added at room temperature, and the reaction solution was agitated at room temperature for 1 hour and 30 minutes. The reaction solution was poured into iced water after the reaction ended, and the deposited solids were separated by filtering. 4.9 g of the title compound was obtained by recrystallizing the obtained solid from a mixed solvent of ethyl acetate, ethanol, and hexane. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14]C(=O)C)[CH:9]=2)[C:5](=[O:18])[N:4]([C:19]2[CH:24]=[CH:23][C:22]([S:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[C:3]1=[O:30].C[O-].[Na+]>CO>[NH2:14][C:10]1[CH:9]=[C:8]([CH2:7][N:6]2[C:2]([CH3:31])([CH3:1])[C:3](=[O:30])[N:4]([C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[C:5]2=[O:18])[CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)Nc1cc(CN2C(=O)N(c3ccc(SC(F)(F)F)cc3)C(=O)C2(C)C)ccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)C(=O)N(c2ccc(SC(F)(F)F)cc2)C(=O)N1Cc1ccnc(N)c1
Yield: 74.6 %

Procedure:
500 mg (1.11 mmol) of N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}acetamide are dissolved in MeOH, 1.5 mmol of NaOMe are added and the resulting mixture is refluxed for 4 hours. The solvent is removed, the residue is taken up in CH2Cl2 and washed twice with 10% NaHCO3 solution and with water, and the organic phase is evaporated off. 340 mg (75%) of 1-(2-aminopyrid-4-ylmethyl)-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione are isolated in this manner.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[N:49][CH:50]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:60][C:58]1[S:57][C:47]2[C:48]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:49][CH:50]=[C:45]([O:44][CH3:43])[C:46]=2[N:59]=1)=[O:8]
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: COc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cccc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)c1

Procedure:
From 3-methoxybenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 401 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([O:10]C)=O)=[CH:4][CH:3]=1.[NH3:12]>CO>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccc(Cl)nn1
Temperature: 0 °C
Yield: 99 %

Procedure:
Dissolve methyl 6-chloropyridazine-3-carboxylate (0.498 g, 2.89 mmol) in methanol (28 mL). Cool the solution to 0° C. with an acetone/dry ice bath. Bubble ammonia into the reaction mixture then allow it to warm to 0° C. over 1 hour before concentrating to give the title compound (0.451 g, 99%): TOF MS ES+ 157.0 (M)+, HRMS calcd for C5H4N3OCl 157.0043 (M)+, found 157.0010, time 4.45 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.1 TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 10-20% over 5 min then 20-95% over 18], tR=5.2 min, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:12]=[O:13])[C:5]([CH:18]([CH3:20])[CH3:19])=[C:4]([Cl:21])[N:3]=1.[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CC(=O)OCC>[Cl:1][C:2]1[N:3]=[C:4]([Cl:21])[C:5]([CH:18]([CH3:19])[CH3:20])=[C:6]([O:8][C:9]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:11]([CH:12]3[O:24][CH2:23][CH2:22][O:13]3)[CH:10]=2)[N:7]=1
Reactant: OCCO
Reactant: Cc1cc(C=O)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2nc(Cl)nc(Cl)c2C(C)C)cc(C2OCCO2)c1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A mixture of (6) (1.71 g, 5.25 mmol), ethylene glycol (0.88 ml, 15.75 mmol), and p-toluenesulfonic acid (263 mg, 0.26 mmol) in toluene (20 ml) was refluxed for 3 hr., using a reflux condenser equipped with a Dean-Stark trap. After cooling to room temperature, the mixture was diluted with EA, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:15)) to afford 1.79 g (92%) of a colorless syrup; 1H NMR (200 MHz, CDCl3) δ 1.40 (6H, d, J=7.0 Hz), 2.40 (3H, s), 3.58 (1H, m), 3.99-4.16 (4H, m), 5.82 (1H, s), 6.92 (1H, s), 7.03 (1H, s), 7.21 (1H, s).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[F:20][CH:21]([F:35])[O:22][C:23]1[CH:24]=[C:25]([CH:32]=[CH:33][CH:34]=1)[CH2:26][NH:27][C:28](=[O:31])[CH2:29][NH2:30]>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:30][CH2:29][C:28]([NH:27][CH2:26][C:25]2[CH:32]=[CH:33][CH:34]=[C:23]([O:22][CH:21]([F:20])[F:35])[CH:24]=2)=[O:31])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCC(=O)NCc1cccc(OC(F)F)c1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NCC(=O)NCc2cccc(OC(F)F)c2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Yield: 41.2 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.175 g, 0.58 mmol), N-[3-(difluoromethoxy)benzyl]glycinamide (0.159 g, 0.69 mmol) and TEA (0.23 g, 2.31 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was purified by preparative HPLC to yield the title compound (0.118 g, 41%). 1H NMR (500 MHz, CDCl3): δ 7.46-7.35 (m, 5H), 7.35-7.28 (m, 1H), 7.09-7.01 (m, 2H), 6.99-6.94 (m, 1H), 6.50 (t, 1H), 6.02-5.94 (m, 1H), 5.91-5.82 (m, 1H), 4.37-4.31 (m, 2H), 3.53-3.48 (m, 2H), 1.71 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 167.3, 159.3, 139.9, 134.9, 131.5, 130.5, 130.2, 129.0, 125.1, 124.5, 119.4, 119.0, 116.0, 113.9, 109.9, 62.0, 46.8, 43.4, 27.8; Mass Spectrum: M−H+ 494.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@:8]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C@H:12]([CH:13]=[O:14])[C@@H:11]([CH3:15])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[C:26]([F:29])([F:28])[F:27].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][C@:8]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C@H:12]([CH:13]([OH:14])[C:26]([F:29])([F:28])[F:27])[C@@H:11]([CH3:15])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1OC[C@@](NC(=O)OC(C)(C)C)(c2ccccc2F)[C@@H]1C=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H]1OC[C@@](NC(=O)OC(C)(C)C)(c2ccccc2F)[C@@H]1C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 492 %

Procedure:
[(3S,4S,5R)-3-(2-Fluoro-phenyl)-4-formyl-5-methyl-tetrahydro-furan-3-yl]-carbamic acid tert-butyl ester (Preparation Example 30-(2)) (2.00 g, 0.62 mmol) dissolved in THF (20 mL). Trimethyl(trifluoromethyl) silane (175.89 mg, 1.23 mmol) was added followed by TBAF (0.080 g, 0.30 mmol). The reaction mixture was stirred at RT and monitored by LCMS (Agilent Method A), retention time 5.61 min (MH+ 294). The reaction went to completion after 2 h. The reaction was then concentrated, saturated aqueous ammonium chloride (10 ml) was added and extracted with DCM (2×20 ml). The combined organic phases were combined, dried over MgSO4 concentrated and purified by flash chromatography (Hexane/EtOAc 5-40%). 1.20 g (49% yield) of the title compound was isolated as a mixture of the 2 epimers (85/15).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1>>[CH3:28][S:27][C:24]1[CH:25]=[CH:26][C:21]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][CH:2]([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:22][CH:23]=1
Reactant: CSc1ccc(Br)cc1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Product: CSc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)O4)CC2)cc1
Yield: 40.8 %

Procedure:
By using 1-(2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (130 mg, 0.50 mmol) synthesized in Reference example 56 and 4-bromothioanisole (203 mg, 1.0 mmol), the reaction was carried out in the same manner as Example 23 to obtain the title compound 78 mg (yield 41%).