Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(OCC)(=O)C>[CH3:17][S:18]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)(=[O:20])=[O:19]
Reactant: O=Cc1cccc(O)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.8 %

Procedure:
To a mixture of 3-hydroxybenzaldehyde (25.31 g), triethylamine (23.07 g) and ethyl acetate (500 mL) was added methanesulfonyl chloride (26.12 g) at 0° C. The mixture was stirred at room temperature for 15 hrs. The reaction mixture was washed successively with water, 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-formylphenyl methanesulfonate as a pale-yellow oil (41.40 g, yield 100%).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.Cl[C:20]1C2C(=CC=CC=2)C(C=O)=C2C=1C=CC=C2.C(I)C>>[CH2:1]([S:2][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH:17]=[O:18])=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH3:20]
Reactant: CSc1c2ccccc2c(C=O)c2ccccc12
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Solvent: CCI
Product: CCSc1c2ccccc2c(C=O)c2ccccc12

Procedure:
Using the procedure described in 3A, 10-chloro-9-anthracenecarbaldehyde (Aldrich) and ethyl iodide (Fisher) gave an oil which solidified to give 10-ethylthio-9-anthracenecarbaldehyde mp 74°-75.5° (C, H, S).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][C:9](O)=[O:10])=[CH:4][CH:3]=1.B.O1CCCC1.O>O1CCCC1>[F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: O=C(O)CCOc1ccc(F)cc1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: OCCCOc1ccc(F)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
3-(4-Fluorophenoxy)propanoic acid (16.6 g, 90 mmol) was stirred in 100 mL of tetrahydrofuran under a nitrogen atmosphere. The solution was cooled to 5° C. and borane (120 mL, 120 mmol, 1M in tetrahydrofuran) was added dropwise at a rate to keep the temperature of the reaction near 5° C. Once the addition was complete, the solution was allowed to stir at room temperature overnight. The reaction was then cooled below 10° C. and 18 mL of a tetrahydrofuran/water mixture was added. The tetrahydrofuran was removed by evaporation under reduced pressure and the resulting cloudy mixture was diluted with about 200 mL of water. This mixture was extracted three times with diethyl ether. The combined extracts were washed with water, twice with 10% aqueous sodium bicarbonate, and once with brine. The combined extracts were then dried over sodium sulfate, filtered, and concentrated to give 15.24 g of a product oil. Yield: 99%. MS(FD) M+171.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH3:12])[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[O:18]=[N+:19]=[O:20].C(OCC)(=O)C>C(#N)C>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH3:12])[C:10]([N+:19]([O-:20])=[O:18])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]=O
Reactant: CCc1cc2cccc(Br)n2n1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1nn2c(Br)cccc2c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To a solution of 7-bromo-2-ethylpyrazolo[1,5-a]pyridine (1.1 g) dissolved in acetonitrile (20 mL) was added nitronium tetrafluoroborate (1.3 g) was added thereto while cooling with ice, and the reaction mixture was stirred for 30 minutes. The reaction mixture was then added to ice water, extraction was performed with ethyl acetate, and the organic extract was washed with water and brine. The obtained organic extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and the title compound (670 mg) was obtained as yellow crystals from the n-hexane:ethyl acetate (10:1) fraction.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]([CH:13]2[CH2:15][CH2:14]2)=[O:12])[CH:5]=1)([O-])=O.[OH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([C:27]([OH:29])=[O:28])=[N:22][CH:21]=[CH:20]2.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH:13]1([C:11]([NH:10][C:6]2[CH:5]=[C:4]([O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[C:23]([C:27]([OH:29])=[O:28])=[N:22][CH:21]=[CH:20]4)[CH:9]=[CH:8][N:7]=2)=[O:12])[CH2:15][CH2:14]1
Reactant: O=C(Nc1cc([N+](=O)[O-])ccn1)C1CC1
Reactant: O=C(O)c1nccc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1nccc2cc(Oc3ccnc(NC(=O)C4CC4)c3)ccc12
Temperature: 20 °C

Procedure:
Cyclopropanecarboxylic acid (4-nitro-pyridin-2-yl)-amide (200 mg, 0.965 mmol), 6-hydroxy-isoquinoline-1-carboxylic acid (183 mg, 0.965 mmol), and potassium carbonate (267 mg, 1.93 mmol) are stirred in dimethylsulphoxide (10 mL) at 90° C. for 24 h. After cooling to 20° C., the dimethylsulphoxide is partially evaporated under reduced pressure, water is added, the solution is carefully acidified with trifluoroacetic acid and the resulting solution is purified using a MPLC reverse phase chromatography (Merck LiChroprep® RP-18, acetonitrile/water 0.1% trifluoroacetic acid) to afford the title compound as a solid. M-H, 348.1; HPLC tR: 3.29 min.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.C[O-].[Na+].S(OC)(O[CH3:21])(=O)=O>CS(C)=O>[CH3:21][O:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=Cc1ccc(O)c2ncccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(C=O)c2cccnc12
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
To a solution of 0.76 g (4.39 mmol) of 8-hydroxyquinoline-5-carboxaldehyde (G. R. Clemo and R. Howe, J. Chem. Soc., 1955, 3522) in 5 mL of dimethyl sulfoxide was added 0.24 g (4.4 mmol) of sodium methoxide, while keeping the mixture under nitrogen. After stirring for 5 min, 0.56 g (4.4 mmol) of dimethyl sulfate was added. The reaction was stirred for 1 hr and the solvent removed under vacuum. The residue was partitioned between dichloromethane (100 mL) and 0.5N sodium hydroxide (50 mL); the organic layer was washed with water (100 mL), dried over anhydrous magnesium sulfate, and concentrated to give 0.61 g (74%) of 8-methoxyquinoline-5-carboxaldehyde, mp 121°-122° after recrystallization from ethanol-hexane (2:25). Anal. Calcd for C11H9NO2 : C, 70.58; H, 4.85; N, 7.48. Found: C, 70.55; H, 4.91; N, 7.44.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([CH2:27][C:28]([NH2:30])=[O:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].OC(C(F)(F)F)=O.N1[CH2:41][CH:40](C2C=CC3C4N=C(C5N(C(C)C)N=CN=5)SC=4CCOC=3C=2)[CH2:39]1.C(NC(=O)CCl)(C)C>>[CH:40]([NH:30][C:28](=[O:29])[CH2:27][N:25]1[CH2:24][CH:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH2:26]1)([CH3:41])[CH3:39]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Agent: CC(C)NC(=O)CCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)CN1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1

Procedure:
Following the procedure of 319, a suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) and N-isopropyl-2-chloroacetamide gave 470 isolated as a yellow solid (91 mg, 26%). LCMS: RT=3.31 min, [M+H]+=467. 1H NMR δ (ppm) (DMSO-d6): 8.26 (1 H, d, J=8.18 Hz), 8.05 (1 H, s), 7.40 (1 H, d, J=8.06 Hz), 7.17 (1 H, dd, J=8.24, 1.83 Hz), 6.99 (1 H, d, J=1.78 Hz), 5.83-5.73 (1 H, m), 4.35-4.29 (2 H, m), 3.86-3.80 (1 H, m), 3.69-3.58 (3 H, m), 3.41-3.35 (2 H, m), 3.18 (2 H, d, J=6.73 Hz), 3.00 (2 H, s), 1.50 (6 H, d, J=6.59 Hz), 1.03 (6 H, d, J=6.59 Hz)
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])[CH:7]=[CH:6][C:5]=1[OH:31])[CH2:2][CH3:3].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][O:31][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:23][CH:24]=3)[O:16][C:17]=2[CH3:18])=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3])[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: CCCc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1OCC(=O)OCC
Temperature: 55 °C

Procedure:
A mixture of 2-propyl-4-[2-(5-methyl-2-biphenyl-4-yl-oxazole-4-yl) ethoxy]phenol (0.90 mmol) (see Ex. 60, part B), ethyl 2-bromoethanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-2-propylphenoxy}ethanoic acid ethyl ester, 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=8.3 Hz, 2H), 7.67 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 7.44 (t, J=7.5 Hz, 2H), 7.36 (t, J=7.3 Hz, 1H), 6.72 (brs, 1H), 6.64 (brs, 2H), 4.59 (s, 2H), 4.54 (q, J=7.3 Hz, 2H), 4.20 (t, J=6.6 Hz, 2H), 2.97 (t, J=6.8 Hz, 2H), 2.58-2.61 (m, 2H), 2.38 (s, 3H), 1.61 (sextet, J=7.3 Hz, 2H), 1.27 (t, J=7.3 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18]C)=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[S:7][C:6]=2[C:16]=1[Cl:17].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[S:7][C:6]=2[C:16]=1[Cl:17]
Reactant: COc1cc2cc(C3CCCCC3)sc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1cc2cc(C3CCCCC3)sc2c(Cl)c1Cl
Reaction time: 5 h

Procedure:
A mixture of 5.0 of 6,7-dichloro-2-cyclohexyl-5-methoxybenzo[b]thiophene and 50 g of pyridine hydrochloride is stirred at 195° for 5 hrs. The cooled mixture is diluted with 250 ml of water and the resulting aqueous mixture is extracted with 3×250 ml ether. The organic layers are combined, washed with 150 ml of 2 N hydrochloric acid, 2×100 ml of water, dried over anhydrous magnesium sulfate and filtered. The solvent is removed and the residue is chromatographed on a sillical gel column using hexane and then 1:1 ether-hexane as eluting solvents. Evaporation of the eluents gives 3.2 g of 6,7-dichloro-2-cyclohexyl-5-hydroxybenzo[b]thiophene. Crystallization from pentane gives the analytical sample, mp 59°-60°.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:23]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:24]=2[C:25](O)=[O:26])[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:65]([NH:68][NH2:69])(=[O:67])[CH3:66]>CN(C)C=O>[C:65]([N:68]([C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:23]=1[CH:5]1[C:4]([C:1](=[O:3])[CH3:2])=[C:9]([CH3:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[C:7](=[O:21])[N:6]1[CH3:22])[NH2:69])(=[O:67])[CH3:66]
Reactant: CC(=O)NN
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)N(N)C(C)=O
Reaction time: 0.08 h

Procedure:
2-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-m 4-yl]-5-cyano-benzoic acid (intermediate 6) (47.0 mg, 0.10 mmol)) and triethylamine (35.8 μL, 0.26 mmol) are suspended in N,N-dimethylformamide (2 mL), stirred for 5 min and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (41.0 mg, 0.11 mmol) is added. The mixture is stirred for 10 min and acetic acid hydrazide (12.2 mg, 0.16 mmol) is added. The mixture is stirred overnight at room temperature. Another equivalent of acetic acid hydrazide is added to bring the reaction to completion. The crude product is purified by reversed phase HPLC. Yield 15 mg; ESI mass spectrum [M+H]+=514; Retention time HPLC: 0.95 min (HPLC method Z018_S04).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH2:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:22]([C:20]3[N:21]=[C:16]4[CH:15]=[CH:14][C:13]([Br:12])=[CH:18][N:17]4[CH:19]=3)=[O:23])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(NCc1ccc2c(c1)OCO2)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using benzo[d][1,3]dioxol-5-ylmethanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[H][H].I[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1>CN(C=O)C.O>[S:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Ic1cccs1
Reactant: c1c[nH]cn1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1csc(-n2ccnc2)c1
Temperature: 150 °C

Procedure:
Under nitrogen, solid imidazole (34 g, 0.5 mol) is added cautiously to a slurry of 20.9 g (0.55 mol) 50% NaH dispersion in 500 ml dry DMF. After hydrogen evolution ceases, 115 g (0.55 mol) 2-iodothiophene in 100 ml DMF is added. The reaction is heated at 150° C. for 18 hours. After cooling, the reaction is diluted with 2 liters of water and the product extracted into EtOAc (2×400 ml). After drying, (Na2SO4) the solvent is removed to give crude 1-(2-thienyl)imidazole. The product is purified by vacuum distillation.
Reaction SMILES: B(Br)(Br)Br.[C:5]([C:9](Cl)(Cl)Cl)([F:8])([F:7])[F:6].[OH:13]S(O)(=O)=O.F[C:19](F)(F)[C:20](Cl)=[O:21]>C(O)C>[CH2:20]([O:21][C:9](=[O:13])[C:5]([F:8])([F:7])[F:6])[CH3:19]
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Reactant: O=S(=O)(O)O
Reactant: O=C(Cl)C(F)(F)F
Agent: BrB(Br)Br
Solvent: CCO
Product: CCOC(=O)C(F)(F)F

Procedure:
Into the experimental apparatus described in Example 1, 2 g HgSO4 and 10 g BBr3 are added. A solution of 93.7 g CF3CCl3, 162 g SO3 and 4 g H2SO4 are added in drops. The trifluoroacetylchloride leaving the reflux condenser is passed through a wash flask with H2SO4 and subsequently fed into a reaction vessel with ethanol. In the process, trifluoracetic acid ethylester is formed.
Reaction SMILES: C(OC([N:8]=[C:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:12]=[C:11]([CH2:24][CH3:25])[S:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[NH:8]=[C:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[CH:12]=[C:11]([CH2:24][CH3:25])[S:10]1
Reactant: CCc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)OC(C)(C)C)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
A mixture of 2-(t-butoxycarbonylimino)-3-(3-trifluoromethylphenyl)-5-ethylthiazoline (1 g) and trifluoroacetic acid (3 g) in chloroform (20 ml) was stirred at room temperature for 3 hours, followed by addition of water (50 ml) thereto. The resultant mixture was neutralized with potassium carbonate, extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was subjected to column chromatography to give 0.3 g of 2-imino-3- (3-trifluoromethylphenyl) -5-ethylthiazoline (Compound (x)).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:24]=[CH:23]2)=[CH:18][CH:17]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[N:24]=[CH:23]2)=[CH:18][CH:17]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(OC(CC(C)C)c2ccc(-n3cnc(C(F)(F)F)c3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)CC(Oc1ccc(C(=O)O)cc1)c1ccc(-n2cnc(C(F)(F)F)c2)cc1
Reaction time: 8 h
Yield: 103.6 %

Procedure:
Methyl 4-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)butoxy)benzoate (65 mg, 0.15 mmol) was dissolved in methanol (1.5 mL) and 1M NaOH (0.75 mL) was added at room temperature. The resulting mixture was stirred overnight. The reaction mixture was diluted with water (10 mL), acidified with 1M HCl (1 mL) and extracted with ethyl acetate (2×10 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give (+/−)-4-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)butoxy)benzoic acid (65 mg, 100%) as a gum. 1H NMR (400 MHz, CDCl3, δ): 7.98 (d, J=9 Hz, 2H), 7.88 (s, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.58 (s, 1H), 7.39 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 5.33 (dd, J=9, 4.6 Hz, 1H), 2.05 (m, 1H), 1.96-1.83 (m, 1H), 1.67-1.60 (m, 1H), 1.04 (d, J=6.6 Hz, 3H), 0.99 (d, J-6.6 Hz, 3H). MS (M+1): 419.0.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([O:12][CH2:13][CH2:14][N:15]2[CH:20]([CH3:21])[CH2:19][N:18]([C:22]3[S:23][C:24]([Br:27])=[CH:25][N:26]=3)[CH2:17][CH:16]2[CH3:28])[CH:6]=1.[OH-].[Na+].CO.O1CCCC1>[Cl-].[Na+].O.O>[Br:27][C:24]1[S:23][C:22]([N:18]2[CH2:19][CH:20]([CH3:21])[N:15]([CH2:14][CH2:13][O:12][C:7]3[CH:6]=[C:5]([CH2:4][C:3]([OH:29])=[O:2])[CH:10]=[CH:9][C:8]=3[CH3:11])[CH:16]([CH3:28])[CH2:17]2)=[N:26][CH:25]=1
Reactant: COC(=O)Cc1ccc(C)c(OCCN2C(C)CN(c3ncc(Br)s3)CC2C)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(CC(=O)O)cc1OCCN1C(C)CN(c2ncc(Br)s2)CC1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
A mixture of [3-[2-[4-(5-bromothiazole-2-yl)-2,6-dimethyl piperazine-1-yl]ethoxy]-4-methylphenyl]acetic acid methyl ester (8.49 g), 2N aqueous sodium hydroxide solution (22 mL), methanol (50 mL) and tetrahydrofuran (50 mL) was stirred at room temperature for 1.5 hours. To the reaction solution were added water and brine. The mixture was washed with ethyl acetate. The water layer was neutralized with 2N hydrochloric acid and extracted with chloroform. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was washed with diisopropyl ether to give the title compound (5.81 g).
Reaction SMILES: [C:1]1([CH:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[H][H]>[Pd].CO>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:9][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[CH:14][CH:13]=1
Reactant: CC(N)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CNC(C)c2ccccc2)cc1
Reaction time: 6 h

Procedure:
100 ml of methanol and 100 mmol of 1-phenylethylamine are initially taken, and 100 mmol of 4-methoxybenzaldehyde are added dropwise at 24° C. in the course of 15 minutes. Stirring is effected for 6 hours at 24° C., the completeness of the iminization is checked by GC, 0.5 g of Pd/C (10% by weight) is added and the crude mixture is hydrogenated with hydrogen for 5 hours at atmospheric pressure. A sample is taken and the composition is investigated by GC analysis.
Reaction SMILES: CC1C(=O)NC(=O)NC1=O.N1C=C(C)C(=O)NC1=O.N1C=CC(=O)NC1=O.[C@@H:28]1(N2C=C(C)C(=O)NC2=O)[O:35][C@H:32]([CH2:33][OH:34])[C@@H:30]([OH:31])[CH2:29]1.[NH:45]1[C:54](=[O:55])[C:53]2[NH:52][CH:51]=[N:50][C:49]=2[N:48]=[C:46]1[NH2:47]>>[C@@H:28]1([N:50]2[C:49]3[N:48]=[C:46]([NH2:47])[NH:45][C:54](=[O:55])[C:53]=3[N:52]=[CH:51]2)[O:35][C@H:32]([CH2:33][OH:34])[C@@H:30]([OH:31])[CH2:29]1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: CC1C(=O)NC(=O)NC1=O
Agent: Cc1c[nH]c(=O)[nH]c1=O
Agent: O=c1cc[nH]c(=O)[nH]1
Product: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Yield: 75 %

Procedure:
FIG. 1 shows formation of 5-methyl barbituric acid. Since the acid is decomposed so as to disappear, it has been clarified that uracil thymine dehydrogenase and barbiturase are present in the uracil·thymine decomposing enzyme. In the case of FIG. 1, thymidine disappeared substantially completely, though the starting material guanine was found to remain only slightly. Deoxyguanosine was formed in an amount of 14.9 mM (yield of 75%). Compared with FIG. 2 covering the case where uracil·thymine decomposing enzyme solution was not present, FIG. 1 supports that the desired product of deoxyguanosine was formed in a very large amount.
Reaction SMILES: [O:1]=[C:2]1[C@@H:6](OS(C)(=O)=O)[CH2:5][CH2:4][NH:3]1.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([CH:22]2[CH2:27][CH2:26][N:25]([CH:6]3[CH2:5][CH2:4][NH:3][C:2]3=[O:1])[CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:19]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CS(=O)(=O)O[C@H]1CCNC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)cc1)C1CCN(C2CCNC2=O)CC1
Temperature: 85 °C
Yield: 7.8 %

Procedure:
To a 10 mL microwave vial was added methanesulfonic acid (S)-2-oxo-pyrrolidin-3-yl ester (4.97 mmol, 890 mg) and (4-fluoro-phenyl)-piperidin-4-yl-methanone hydrochloride (4.97 mmol, 1.21 g) in DIEA (24.8 mmol, 5 mL) was heated to 85° C. for 105 min. The DIEA was decanted and flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate afforded the title compound (112 mg, 7.8% yield). MS (ESI) m/e 291.2 (M+H+), calculated 290.33; HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.303 min.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=3[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=3[C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(CCCI)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(C2CCCCC2)C2(CCNCC2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccccc1CN1CN(C2CCCCC2)C2(CCN(CCCC(=O)c3ccccc3)CC2)C1=O
Yield: 65.5 %

Procedure:
tert-Butyl 2-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.30 g, 0.585 mmol), 4-iodobutyrophenone (0.17 g, 0.585 mmol), and potassium carbonate (0.12 g, 0.878 mmol) in N,N-dimethylformamide (8 mL) were stirred at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.22 g, 65%); MS for C35H47N3O4 m/z 574 (M+H)+.