Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.O=P(Cl)(Cl)[Cl:18]>C(N(CC)C1C=CC=CC=1)C>[Cl:18][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)Cc1c(C)nc(SC)nc1O
Solvent: CCN(CC)c1ccccc1
Product: COC(=O)Cc1c(C)nc(SC)nc1Cl
Yield: 72 %

Procedure:
Methyl (4-hydroxy-6-methyl-2-methylmercapto-5-pyrimidinyl)-acetate (4.0 g, 17 mmol) is heated in a mixture of phosphoroxychloride (40 ml) and N,N-diethylaniline (5.5 ml) for 2 hours at 100° C. The excess phosphoroxychloride was removed by evaporation under vacuum and the residue poured into ice-water. Extraction with ethyl acetate, drying and filtration over silicagel gives methyl (4-chloro-6-methyl-2-methylmercapto-5-pyrimidinyl)-acetate as a crystalline solid (3.1 g, 72%), having a m.p. of 88° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:12])([CH3:1])[CH2:11][CH2:10]2)=[O:19]
Reactant: O=C(Cl)CCCCCl
Reactant: CC1(C)CCc2ccccc2O1
Product: CC1(C)CCc2cc(C(=O)CCCCCl)ccc2O1

Procedure:
Using 2,2-dimethylchroman (19.7 g) and 5-chlorovaleryl chloride (20.7 g) according to the same method as that of Reference Example 1, the title compound was obtained as colorless crystals (22.0 g) having a melting point of 50 to 51° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].[O:6]=[C:7]=[N:8][CH:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:11]([CH3:21])([CH2:12][N:13]=[C:14]=[O:15])[CH2:10]1>O1CCCC1>[OH:1][CH2:2][CH2:3][N:4]([C:14]([NH:13][CH2:12][C:11]1([CH3:21])[CH2:10][CH:9]([NH:8][C:7]([N:4]([CH2:3][CH2:2][OH:1])[NH2:5])=[O:6])[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16]1)=[O:15])[NH2:5]
Reactant: NNCCO
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Solvent: C1CCOC1
Product: CC1(C)CC(NC(=O)N(N)CCO)CC(C)(CNC(=O)N(N)CCO)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a rapidly stirred mixture of 2-hydroxyethylhydrazine 16.74 g (0.22 moles) in 250 ml tetrahydrofuran was added dropwise isophorone diisocyanate ◯2 in 0.10 moles (22.23 g) in 180 ml tetrahydrofuran. After addition was complete, the solution was clear and colorless. The solution was stirred for an additional three hours at room temperature. The solvent was removed by rotary evaporation to yield a colorless syrup. Characterization by IR and NMR showed it to be predominantly the postulated structure. The sample was utilized without further purification in screening for antioxidant effectiveness.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[Cl-].[Al+3].[Cl-].[Cl-].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:9])[C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[O:11])=[CH:20][CH:19]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)CCCCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCCC(=O)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
Suberoyl chloride (40.8 g, 0.1933 mol) was added over a 30-45 minute period to a mechanically stirred suspension of aluminum chloride (64.4 g, 0.483 mol) in fluorobenzene (181 ml, 1.93 mol) maintained at 5°-10° C. The yellow slurry was allowed to warm to room temperature and was stirred overnight. The reaction mixture was poured onto approximately 1000 g of ice containing 75 ml of concentrated hydrochloric acid. The resulting suspension was separated by decantation and washed several times with water. The organic layer was distilled to remove excess fluorobenzene and the solid residue collected by filtration, washed with water, and dried at 100° C. The crude solid was recrystallized from approximately 500 ml of toluene to afford 43.0 g (67% yield) of 1,6-bis(4-fluorobenzoyl)hexane; mp 123°-124° C.; 'H NMR (CDCl3) δ1.0-2.1 (m, 8H, CH2), 2.97 (t, 4H, O=CCH2, J=7.0 Hz), 6.9-8.3 (m, 8H, aromatic). Anal. Calcd. for C20H20F2O2 : C, 72.71%; H, 6.10%; F, 11.50%. Found: C, 72.50%; H, 5.86%; F, 11.19%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: COc1ccc(CBr)cc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: COc1ccc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)cc1
Yield: 35 %

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-(bromomethyl)-4-methoxybenzene. Yield 35%, colorless gel (195 mg, 35%). 1H NMR (DMSO-d6, 400 MHz): □s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 3.71 (s, 3H), 4.48 (s, 2H), 5.18 (s, 2H) 6.87 (d, J=8.8 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.80 (s, 1H), 8.18 (s, 1H). MS 424 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.11 μM.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([C:23]1[CH:24]=[N:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[N:27][CH:28]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH3:36][Si:37]([CH3:53])([CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:13]([C:23]1[CH:24]=[N:25][C:26]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][Si:37]([CH3:53])([CH3:36])[CH2:47][CH2:48][Si:49]([CH3:50])([CH3:51])[CH3:52])=[CH:33][CH:34]=2)=[N:27][CH:28]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCCCCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCc1cnc(-c2ccc(OCCCCCCCC[Si](C)(C)CC[Si](C)(C)C)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diethylazodicarboxylate (0.065 g, 0.375 mmol) in THF (5.0 ml) was added dropwise to a stirred solution of 4-(5-decylpyrimidin-2-yl)-phenol (0.094 g, 0.300 mmol), compound 17 (0.083 g, 0.300 mmol) and triphenylphosphine (0.098 g, 0.375 mmol) in THF (10 ml). The treaction mixture was stirred at room temperature for 24 h, the solvent removed in vacuo and the residues purified by column chromatography [silica gel eluted with hexane/ethyl acetate (9:1)] to yield a colorless solid that was recrystallized from acetonitrile.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN1CCCC1=O.[CH:22]([NH2:25])([CH3:24])[CH3:23]>O>[CH:22]([NH:25][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])([CH3:24])[CH3:23]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a mixture of 5.23 g of 4-fluoro-3-nitro-benzo trifluoride and 25 ml of N-methylpyrrolidone was added 3.69 g of isopropylamine under ice cool, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into water, the deposited solid was collected by filtration. This solid was washed with water, then, dried under reduced pressure to obtain 5.90 g of N-isopropyl-2-nitro-4-trifluoromethylaniline.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.[CH3:16][O:17][C:18]1[C:23](B(O)O)=[CH:22][CH:21]=[CH:20][N:19]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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>[C:12]([C:4]1[CH:3]=[C:2]([C:23]2[C:18]([O:17][CH3:16])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:7]=[CH:6][C:5]=1[O:8][CH:9]([F:11])[F:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: COc1ncccc1B(O)O
Reactant: CC(C)(C)c1cc(Br)ccc1OC(F)F
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: CO
Solvent: ClCCl
Product: COc1ncccc1-c1ccc(OC(F)F)c(C(C)(C)C)c1
Temperature: 115 °C
Yield: 57.5 %

Procedure:
step 2—A sealed tube containing 20 (129 mg, 0.464 mmol), 2-methoxy-3-pyridine boronic acid (37, 108 mg, 0.706 mmol, CASRN 163105-90-6), Pd(PPh3)4 (39 mg, 0.034 mmol) and Na2CO3 (147 mg, 1.387 mmol) in a mixture of MeOH (3 mL) and DCM (1 mL) was heated in a microwave synthesizer at 115° C. for 30 min. The organic volatiles were removed under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (0 to 5% EtOAc) to afford 82 mg (58%) of 3-(3-tert-butyl-4-difluoromethoxy-phenyl)-2-methoxy-pyridine (22) as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=1.[ClH:15]>>[ClH:15].[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: COc1ccc(CCCCCN)cc1
Agent: Cl
Product: NCCCCCc1ccc(O)cc1

Procedure:
20.8 g of 4-(5-aminopentyl)anisole are heated with 350 ml of semiconcentrated hydrochloric acid in a glass bomb for 10 hours to 180° C. The solution is concentrated by evaporation in vacuo, the residue is dissolved in ethanol and treated with activated charcoal. The residue remaining after evaporation is used further as a crude product.
Reaction SMILES: [Cl-].[Li+].[CH3:3][O:4][C:5](=[O:29])[C:6]1[CH:11]=[C:10]([Sn](CCC)(CCC)CCC)[CH:9]=[C:8]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)[CH:7]=1.[CH:30]([C:33]1[C:34](OS(C(F)(F)F)(=O)=O)=[N:35][S:36][N:37]=1)([CH3:32])[CH3:31]>C1COCC1.[Pd]>[CH3:3][O:4][C:5](=[O:29])[C:6]1[CH:7]=[C:8]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)[CH:9]=[C:10]([C:34]2[C:33]([CH:30]([CH3:32])[CH3:31])=[N:37][S:36][N:35]=2)[CH:11]=1
Reactant: CC(C)c1nsnc1OS(=O)(=O)C(F)(F)F
Reactant: CCC[Sn](CCC)(CCC)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2nsnc2C(C)C)c1
Temperature: 25 °C
Yield: 35.4 %

Procedure:
Lithium chloride (0.094 g) and palladium II tetrakis(triphenylphosphine) (0.048 g) were suspended in dry THF under nitrogen atmosphere. To this suspension was added a solution of 3-(5-Methyl-pyridin-2-yl)-5-tripropylstannanyl-benzoic acid methyl ester (0.656 g, 1.27 mmol) and trifluoro-methanesulfonic acid 4-isopropyl-[1,2,5] thiadiazol-3-yl ester (0.26 g, 0.942 mmol) in 6 mL of dry THF. The reaction mixture was heated to reflux for 70 hours. The reaction mixture was cooled to room temperature and ice water was added. After one hour the mixture was extracted wtih EtOAc and the combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (17:1 EtOAc/hexanes) to give 0.118 g of 3-(4-isopropyl-[1,2,5] thiadiazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, MS (M+H)=354.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1>O1CCCC1>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:43][CH2:42][CH2:41][CH2:40][O:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:10])=[CH:29][CH:28]=1
Reactant: NCCCOc1cccnc1
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NCCCOc2cccnc2)c2ccc(OC)cc2)cc1
Yield: 82.5 %

Procedure:
As described in Example 134, a solution of (E)-5,5-bis (4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.0 g) and 3-(3-pyridinyloxy)proPanamine (0.4 g) in tetrahydrofuran (10 mL) was stirred overnight at room temperature. After the usual work up, the crude product was crystallized from ethyl acetate-hexane to give 0.85 g of (E)-5.5-bis(4-methoxyphenyl)-N-[3-[(3-pyridinyl)oxy]propyl]-2,4-pentadienamide, mp 146°-147° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][N:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+].Cl>C(O)C.O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:3]([N:11]=[N:12][N:13]=2)[CH:4]=1)(=[O:10])[CH3:9]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccc2nnnn2c1

Procedure:
To a stirred solution of 8.4 gm. (51.6 mmoles) of 2-chloro-5-acetylpyridine and 8.4 gm. (129 mmoles) of sodium azide in 150 ml of ethanol and 150 ml of water was added 75 ml of 10% HCl over a period of 20 minutes. The reaction mixture was then heated to reflux for 18 hours, cooled in an ice bath and the resulting crystals filtered off to give a first crop of 6.0 gm. A second crop of 1.0 gm. was obtained for a total of 7.0 gm. of A, (84.% yield), m.p. 159°-160° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:9])[CH3:8])=[N:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1>C1COCC1>[CH3:13][C:14]1[N:15]=[C:16]([CH2:20][N:1]2[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:9])[CH3:8])=[N:2]2)[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cccc(CBr)n1
Reactant: CC(=O)Nc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccn(Cc2cccc(C)n2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
Intermediate 1 (97 mg, 0.774 mmol) was dissolved in 8 mL of THF (anh), at 0° C. NaH (ALDRICH, 31 mg, 0.774 mmol) was added, and mixture of reaction was stirred at 0° C. for 30 minutes. A solution of Intermediate 11 (144 mg, 0.774 mmol) in 2 mL THF (anh) was added to the mixture. Reaction was heated at 75° C. overnight. Mixture of reaction was partitioned between distilled water, EtOAc (×3) and DCM. Organic layers were dried over MgSO4 (anh) and filtered. Solvent was evaporated under vacuum. Residue was purified by silica chromatography column using a linear gradient of DCM/MeOH as eluents to give the title compound (133 mg, 0.578 mmol, 75% yield). 1H NMR (300 MHz, DMSO-d6) ppm: 10.40 (br s, 1H), 7.72 (d, 1H), 7.60-7.66 (m, 1H), 7.17-7.16 (m, 1H), 6.74-6.77 (m, 1H), 6.49 (d, 1H), 5.24 (s, 2H), 2.44 (s, 3H), 1.95 (s, 3H). [ES+MS] m/z 231 (MH+).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:15][C:16]3([NH:20]C(=O)OCC4C=CC=CC=4)[CH2:19][O:18][CH2:17]3)[NH:13][CH:14]=2)=[CH:6][CH:5]=1.[H][H]>CO.C(OCC)(=O)C>[F:32][C:2]([F:1])([F:31])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([CH2:15][C:16]3([NH2:20])[CH2:17][O:18][CH2:19]3)[NH:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: O=C(NC1(Cc2nc(-c3ccc(OC(F)(F)F)cc3)c[nH]2)COC1)OCc1ccccc1
Reactant: [H][H]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1(Cc2nc(-c3ccc(OC(F)(F)F)cc3)c[nH]2)COC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzyl [3-({4-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)oxetan-3-yl]-carbamate (Preparation 11, 311 g, 695 mmol) was dissolved in methanol (3.2 L). 5% Palladium on carbon E105 R/W (EVONIK) (22 g, 7 wt %) was added and the reaction hydrogenated at 40° C., 100 psi for 18 hours. Hydrogen uptake was monitored and showed the reaction to be complete after 4 hours. The mixture was cooled to room temperature and filtered over Arbocel©. The filter cake was washed with methanol (2×1 L) and the filtrate concentrated in vacuo to afford a solid. The solid was dissolved in ethyl acetate (1 L) and filtered through a carbon tablet to remove traces of palladium. The solution was warmed to 50° C. and heptane (1 L) added. The solution was cooled slowly whereupon at 40° C. crystallisation was observed. The mixture was stirred at room temperature for 72 hours. The solid was collected by filtration and washed with ethyl acetate: heptane (1:1, 250 mL). The solid was dried in vacuo at 40° C. for 18 hours to afford the title compound as a crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:13])=[O:12].[CH:14]([C:17]1[N:18]=[C:19]([C:22](NC2C(C)=C(OC)C=CC=2C(=O)C)=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15]>>[CH:14]([C:17]1[N:18]=[C:19]([C:22]([NH:1][C:2]2[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=2[C:11](=[O:12])[CH3:13])=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Reactant: COc1ccc(C(C)=O)c(N)c1Cl
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1Cl

Procedure:
The title product 51 was prepared (79%) from (2-amino-3-chloro-4-methoxyphenyl)-(methyl)ketone (50) following the procedure reported for 2′-[[(4-isopropylthiazole-2-yl)(oxo)methyl]amino]-4′-methoxy-3′-methylacetophenone (35): m/z=353 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:10])=[O:9])=[CH:5][CH:4]=1.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1.C([BH3-])#N.[Na+]>CN(C=O)C>[CH:24]1([NH:1][CH2:2][C:3]2[S:7][C:6]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:9])=[O:10])=[CH:5][CH:4]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCCCCCCCCCCCNS(=O)(=O)c1ccc(CN)s1
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCNS(=O)(=O)c1ccc(CNC2CCCC2)s1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The resin-bound 5-(aminomethyl)-N-dodecylthiophene-2-sulfonamide (example 125, step c, 0.23 mmol) was swelled in a 1% HAc in DMF mixture for 15 min at rt Cyclopentanone (97 mg, 1.15 mmol) and sodium cyanoborohydride (144 mg, 2.3 mmol) were then added and the reaction mixture shaken 14 h at rt. The resin was washed successively with DMF (1×15 min), MeOH (1×15 min), THF (1×15 min), MeOH (3×10 min), DMF (3×10 min), MeOH (1×5 min), THF (3×10 min), MeOH (1×5 min), DCM (3×10 min) and with Et2O (1×10 min). The resin was then dried under vacuum to afford the title compound which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[N:29][CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[N:3]=[C:4]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[C:5]3[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=3[N:7]=2)[CH:28]=[N:29][CH:30]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: CC(C)n1ccc2c(NCCc3ccc(O)cc3)nc(Cl)nc21
Product: CC(C)n1ccc2c(NCCc3ccc(O)cc3)nc(-c3cncc(F)c3)nc21

Procedure:
Following the procedure of Example 15d, 4-(2-(2-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl)phenol (20 mg, 0.06 mmol) was reacted with 5-fluoropyridin-3-ylboronic acid. The crude residue was purified by reverse-phase HPLC (C18 column, eluting with ACN—H2O 0.05% TFA) to afford the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8][CH:9]([CH3:17])[CH2:10][CH:11](O)[CH2:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([S:8][CH:9]([CH3:17])[CH2:10][CH:11]=[CH:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CC(O)CC(C)Sc1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=CCC(C)Sc1cccc(F)c1
Yield: 92.5 %

Procedure:
1.00 Gram of 6-(3-fluorophenylthio)-4-hydroxy- 2-heptanone was dissolved in 100 ml of toluene, and 0.02 g of p-toluene sulfonic acid was added thereto. The resulting mixture was refluxed for 2.5 hours with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 0.96 g of 6-(3-fluorophenylthio)-3-hepten-2-one. (trans : cis =5.6 : 1) (purity: 89.3%). The yield was 92.5%.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([Se:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][N:24]=2)=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1)(=O)C.[OH-].[Na+]>C1COCC1.C(O)C>[OH:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([Se:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=2)=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:18])([CH3:19])[C:16]=2[CH:17]=1
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCCOC(C)=O)C(C)(C)CCC3(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc([Se]c3ccc(C(=O)O)cn3)c(OCCO)cc21

Procedure:
In a manner similar to that of Example 2, by reaction of 419 mg (0.81 mmol) of ethyl 6-[3-(2-acetoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl]nicotinate with 320 mg (8 mmol) of sodium hydroxide in a THF/ethanol mixture (4 ml/4 ml), 273 mg (75%) of a white powder are obtained. m.p.: 170° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:7])([CH3:4])[CH3:3].[CH3:18][C:19]([O:22][C:23]([NH:25]/[C:26](/N1N=CC=C1)=[N:27]/[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:31]([O:30][C:28]([N:27]=[C:26]([NH:25][C:23]([O:22][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:24])[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C:15]([OH:17])=[O:16])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)n1cccn1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCCN)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N=C(NCCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.5 %

Procedure:
A solution of N-α-Boc-D-lysine 12 (10.0 g, 40.6 mmol) in CH2Cl2 (200 mL) was charged with N,N′-bis-Boc-1-guanylpyrazole (11.3 g, 36.6 mmol) and triethylamine (11.0 mL, 81.3 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was washed with 10% aqueous citric acid (2×100 mL) and the solvent was removed under reduced pressure. The residue was dissolved in 1 N NaOH (300 mL), 1 N HCl was added to adjust the pH to 5-6, and the mixture was extracted with CH2Cl2 (500 ml). The CH2Cl2 layer was separated and the aqueous layer was extracted with CH2Cl2 (2×250 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford compound 8 (18.5 g, 94%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 4.13-4.03 (m, 1H), 3.36 (t, J=6.8 Hz, 2H), 1.91-1.77 (m, 1H), 1.74-1.55 (m, 3H), 1.52 (s, 9H), 1.51-1.38 (m, 2H), 1.47 (s, 9H), 1.43 (s, 9H).