Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][CH:17]=1>CC(C)=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:1]2[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]2)=[CH:18][CH:17]=1
Reactant: O=S1(=O)CCNCC1
Reactant: ClCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1

Procedure:
To a well stirred suspension of thiomorpholine 1,1-dioxide (0.36 g, 2.7 mmol) and potassium carbonate (0.37 g, 2.7 mmol) in acetone (5 mL) was added 1-bromo-4-chloromethyl-benzene (0.50 g, 2.4 mmol). The mixture was stirred for 48 hours at room temperature. The mixture was filtered and the volatiles were evaporated. The residue was suspended in ether (100 mL), filtered and evaporated to a solid. The material was purified via chromatography utilizing an ISCO automated purification apparatus (24 g silica gel column 10%→100% ethyl acetate in hexane). 4-(4-Bromo-benzyl)-thiomorpholine 1,1-dioxide was isolated as a white solid (0.72 g, 97%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.47 (d, J=7.6 Hz, 2H), 7.19 (d, J=7.7 Hz, 2H), 3.60 (s, 2H), 3.08-2.94 (m, 8H). MS=304, 306 (MH)+. 114b) N-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-8-[4-(methylsulfonyl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(4-bromo-benzyl)-thiomorpholine 1,1-dioxide (90.0 mg, 0.296 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.039 g, 29%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (d, J=6.7 Hz, 1H), 8.23 (d, J=7.4 Hz, 2H), 8.09 (d, J=8.0 Hz, 2H), 7.67 (d, J=6.9 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H), 7.29 (d, J=7.8 Hz, 2H), 7.04 (t, J=7.2 Hz, 1H), 6.94 (s, 1H), 3.62 (s, 2H), 3.10 (s, 3H), 3.08-3.03 (m, 4H), 3.02-2.97 (m, 4H). MS=512 (MH)+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([N+:17]([O-])=O)=[C:12]([CH2:13][C:14](O)=[O:15])[C:5]=2[O:4]1.[OH-].[Na+].[H][H]>[Pd]>[OH2:1].[OH:1][CH2:2][C@@H:3]1[O:4][C:5]2=[C:12]3[C:11](=[CH:10][CH:9]=[C:6]2[O:7][CH2:8]1)[NH:17][C:14](=[O:15])[CH2:13]3
Reactant: O=C(O)Cc1c([N+](=O)[O-])ccc2c1O[C@@H](CO)CO2
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: O
Product: O=C1Cc2c(ccc3c2O[C@@H](CO)CO3)N1
Temperature: 65 °C
Reaction time: 3 h
Yield: 155.6 %

Procedure:
A Parr hydrogenation shake flask is charged with [(3S)-3-(hydroxymethyl)-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl]acetic acid (20.00 g, 74.2 mmol), NaOH (0.33 N, 300 mL, 99 mmol) and palladium (10% on carbon, 1.6 g). The vessel is pressurized to 50 psi with hydrogen and shaken for 3 h, at which point the pressure is released and the mixture is filtered through celite. The solution is acidified with concentrated. HCl (20 mL) and heated to 65° C. for 7 h. The heating is discontinued, and the suspension is stirred overnight. The precipitate is collected by vacuum filtration, and the filter cake is washed with water (50 mL) and dried under suction to give the title compound (13.81 g, 84%) as a tan powder. LCMS (Standard Method): 1.81 min, 222 (M+H)+. 1NMR (300 MHz, DMSO-d6) δ 10.17 (br s, 1H), 6.66 (d, J=8.2 Hz, 1H), 6.27 (d, J=8.2, 1H), 5.03 (br s, 1H), 4.25-4.13 (m, 2H), 3.98-3.91 (m, 1H), 3.65-3.57 (m, 2H), 3.31 (br s, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(=O)CC>[CH3:24][C:18]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc([N+](=O)[O-])cc1
Yield: 46 %

Procedure:
A mixture of 139.1 g. (1 mol) 4-nitrophenol, 1 liter butan-2-one and 207.3 (1.5 mol) pulverized, anhydrous potassium carbonate is stirred for 2 hours at reflux temperature, then 292.5 g. (1.5 mol) ethyl 2-bromo-2-methylpropionate are added thereto and the reaction mixture maintained at reflux temperature for a further 92 hours. After the addition of a further 69.1 g. (0.5 mol) potassium carbonate and 97.5 g. (0.5 mol) ethyl 2-bromo-2-methyl-propionate, the reaction mixture is stirred for a further 20 hours at reflux temperature. The reaction mixture is then filtered with suction and the filtrate is evaporated in a vacuum (for the removal of excess ethyl ester, finally at a high vacuum). The residue is taken up in diethyl ether, filtered and the ethereal phase now extracted several times with 1 N aqueous sodium hydroxide solution. After washing until neutral and drying, it is evaporated, 153 g. (60% of theory) of an oily crude product being obtained. After distillation at 155.5°-156° C./0.05 mm.Hg., there is obtained a yield of 46% of theory of pure ethyl 2-methyl-2-(4-nitrophenoxy)-propionate in the form of a yellow oil with a refractive index of nD20 =1.5288.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](O)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+].[NH3:29]>O>[NH2:29][C:5]1[C:6]2[C:7](=[O:17])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Reactant: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(O)c2c1C(=O)c1ccccc1C2=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
79.5 g of 1,4-dihydroxyanthraquinone, 210 ml of water, 5.6 g of sodium dithionite, 60 g of 50% strength by weight sodium hydroxide solution and 240 g of 25% strength by weight ammonia solution were introduced into a pressure-resistant apparatus. The apparatus was then sealed pressure-tight and its contents were heated to 100° C., giving rise to an autogenous pressure of 2.5 bar. The reaction mixture was held under these conditions for 3 h, then cooled down and depressurized. The precipitate found was filtered off with suction, washed salt-free with water and dried to leave 74.9 g of 1-amino-4-hydroxyanthraquinone (purity according to GC: 90.7%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=O)[CH2:3]1.[NH3:11].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]>C(O)C>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]2[C:5]3[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]=3[NH:11][C:4]3[CH2:3][C:2]([CH3:10])([CH3:1])[CH2:7][C:6](=[O:8])[C:5]2=3)=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]
Reactant: O=Cc1ccc(Br)c([N+](=O)[O-])c1
Reactant: N
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: CCO
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Br)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A solution of 1.94 g of 5,5-dimethyl-1,3-cyclohexanedione and 1.5 ml of a 25% aqueous solution of ammonia in 10 ml of absolute ethanol was heated at reflux under an atmosphere of nitrogen for 2 hours. The mixture was cooled to room temperature and 1.588 g of 4-bromo-3-nitro-benzaldehyde were added. The mixture was then heated at reflux for a further 18 hours, cooled and filtered. The residue was washed with 25 ml of cold diethyl ether and crystallized from dimethylformamide/water to give 2.36 g of 9-(4-bromo-3-nitro-phenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione as a yellow crystalline solid of melting point >300° C.
Reaction SMILES: C(NC(C)C)(C)C.[F:8][C:9]1[C:10]([CH:15]([N:17]2[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]2[CH3:23])[CH3:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[I:24]I>O1CCCC1>[F:8][C:9]1[C:10]([CH:15]([N:17]2[C:18]([CH3:23])=[CH:19][CH:20]=[C:21]2[CH3:22])[CH3:16])=[N:11][CH:12]=[CH:13][C:14]=1[I:24]
Reactant: II
Reactant: Cc1ccc(C)n1C(C)c1ncccc1F
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc(C)n1C(C)c1nccc(I)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A dry 250 ml 3-neck roundbottom flask equipped with a thermometer, rubber septum, magnetic stirrer, and nitrogen inlet was charged with 30 ml of anhydrous tetrahydrofuran and 2.1 ml (14.67 mmole) of dry diisopropylamine. The stirring solution was cooled to -78° C. afterwhich 9.5 ml (15.11 mmole) of 1,6 n-butyllithium in hexanes was added over 10 minutes by syringe. The solution was stirred 30 minutes longer and 3.2 g (14.67 mmole) of N-[(3-Fluoropyrid-2-yl)eth-2-yl]-2,5-dimethylpyrrole in 30 ml of dry tetrahydrofuran was added dropwise via syringe over 30 minutes, keeping the internal temperature below -65° C. After stirring 30 minutes longer, a solution of 4.0 g (15.80 mmole) of iodine in 30 ml of dry tetrahydrofuran was added by canula over 10 minutes. The mixture was warmed to room temperature (a color change, quenching, occurred at -30° C.) and stirred overnight under nitrogen. The solution was diluted to 200 ml with ethyl ether, extracted with aqueous saturated sodium bicarbonate (1×), brine (1×), and dried over sodium sulfate. Filtration and concentration gave a dark solid which was purified by flash silica gel chromatography (20% ethyl acetate in hexanes) to give the titled compound as a white solid, 3.9 g (77%): mp 156°-158° C.; IR (KBr, cm-1) 3000, 2950, 1574, 1408, 752; 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 1H), 7.85 (t, 1H), 5.60 (s, 2H), 4.05 (t, 2H), 3.00 (dt, 2H), 2.10 (s, 6H); MS (FD) m/e 344 (Mt). Anal. Calc'd. for C13H14FIN2 : C, 45.37; H, 4.10; N, 8.14. Found: C, 45.07; H, 4.03; N, 8.06.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](=O)[NH:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2.P(Cl)(Cl)([Cl:23])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16]([Cl:23])=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(cc1OC)-c1cc(=O)[nH]c(=O)n1CC2
Product: COc1cc2c(cc1OC)-c1cc(Cl)nc(=O)n1CC2

Procedure:
A mixture of 30.0 g of 9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido(6,1-a)isoquinolin-2,4-dione and 300 ml of phosphorus oxychloride is heated on a steam bath for 4 hours. The excess of phosphorus oxychloride is distilled under reduced pressure. The residue is poured into a cold solution of sodium hydroxide. A yellow solid precipitates which is collected by filtration. The product is purified by passage through a silica gel column using chloroform as eluent. Yield 28.0 g, m.p. 235°-236° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[N-:13]=[N+]=[N-].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC#N.O>[N+:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][NH2:13])([O-:12])=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1ccccc1CCBr
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: NCCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(2-Bromoethyl)-2-nitrobenzene (6.96 g, 30.5 mmol) in CH3CN was added a solution of NaN3 (6 g, 91.6 mmol) in water (20 ml) and the reaction mixture was refluxed for 20 hours. The solution was cooled and extracted with DCM (3×). The organics were combined, washed with brine, dried (MgSO4) and evaporated to dryness. The residue was taken up in toluene (160 ml) and to this was added PPh3 (8 g, 30.5 mmol) and the reaction mixture was stirred at RT for 16 hours. The solvent was evaporated to dryness and the residue was treated with acetic acid (30 ml) and 48% HBr in acetic acid (30 ml) at 100° C. for 1 h. The reaction mixture was cooled, concentrated and extracted with DCM. The aqueous was brought to pH ˜10 with NaOH (aq.) and extracted with EtOAc (3×). The organics were combined, washed with brine, dried (MgSO4) and evaporated to dryness (4.2 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([O-:15])[CH3:14].[Na+].Cl.[CH2:18](O)C>>[Cl:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([O:15][CH2:13][CH3:14])[N:11]=1)[C:5]([O:7][CH2:8][CH3:18])=[O:6]
Reactant: CCO
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)c1cc(Cl)nc(OCC)c1
Temperature: 70 °C

Procedure:
Methyl 2,6-dichloroisonicotinate (2.62 g) was partially dissolved in ethanol (50 mL) and a freshly prepared solution of 0.72 mol/L solution of sodium ethanolate (17.7 mL) was added at room temperature and then heated at 70° C. for 3 hours. The reaction was neutralized by the addition of 2N hydrochloric acid (6.5 mL) and then concentrated. The resulting solid was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude reaction was purified by column chromatography using an eluant of 2-4% ethyl acetate/hexane to provide the title compound (1.7 g) with the following physical data.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[C:7]([CH3:13])[C:6]=1[CH3:14])(=[O:3])[CH3:2].C=O.[CH2:17]([OH:21])[CH2:18][CH2:19][CH3:20].[CH2:22](NCC)C.C(O)(=O)C>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH2:22][O:21][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([OH:12])=[C:7]([CH3:13])[C:6]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)cc(O)c(C)c1C
Reactant: CCCCO
Reactant: CCNCC
Agent: C=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCOCc1c(C)c(OC(C)=O)c(C)c(C)c1O
Reaction time: 9.5 h

Procedure:
4-Acetoxy-2,3,5-trimethylphenol (18.42 g; 100.0 mmol), 87.3% paraformaldehyde (4.13 g; 120.0 mmol), 1-butanol (48.18 g; 650.0 mmol), diethylamine (0.73 g; 10.0 mmol) and acetic acid (3.03 g; 2.5 mmol) were mixed together, then the mixture was reacted under reflux with stirring for 9.5 hours. After completion of the reaction, toluene was added into the resulting mixture for extraction of the resulting product in toluene, and then the toluene phase was separated. After the separated toluene phase was sequentially washed with water, an aqueous 1% dilute sulfuric acid solution, an aqueous 5% sodium hydrogen carbonate solution and water, the toluene phase was distilled under reduced pressure to distill off compounds with low boiling points, to give 4-acetoxy-2,3,5-trimethyl-6-butoxymethyl-1-hydroxybenzene.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:9]#[N:10].[C:11]([OH:20])(=[O:19])[CH:12]([CH:14]([C:16]([OH:18])=[O:17])[OH:15])[OH:13]>CO>[C:16]([CH:14]([CH:12]([C:11]([O-:20])=[O:19])[OH:13])[OH:15])([O-:18])=[O:17].[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[C:9]#[N:10]
Reactant: N#CC1CC2CCN1CC2
Reactant: O=C(O)C(O)C(O)C(=O)O
Solvent: CO
Product: N#C[C@@H]1CC2CCN1CC2
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Reaction time: 1.5 h
Yield: 15 %

Procedure:
In the same manner as in a document (Mi, Y.; Corey, E. J. Tetrahedron Lett. 2006, 47, 2515-2516), optical resolution by a diastereomer salt method was performed to synthesis the title compound. That is, to a solution of 1-azabicyclo[2.2.2]octane-2-carbonitrile (20.0 g) produced in Example 164, step E, in methanol (100 mL) was slowly added a solution of (+)-tartaric acid (22.0 g) in methanol (100 mL) at 0° C. The reaction system was stirred for 90 min, and concentrated, and the obtained solid was crystallized 4 times from methanol to give (+)-tartrate of (2S)-1-azabicyclo[2.2.2]octane-2-carbonitrile (3.0 g, >90% ee). To the obtained solid was added water (50 mL), and sodium hydrogen carbonate was added to reach pH 8. The mixture was extracted with dichloromethane (100 mL×3), and the extract was washed with brine, dried, and concentrated. The obtained white solid (1.4 g) was dissolved in concentrated hydrochloric acid (50 mL), and the reaction mixture was heated under reflux overnight. After concentration, to the residue was slowly added a solution of sodium hydroxide (0.83 g) in water (10 mL) at 0° C. The mixture was concentrated, concentrated hydrochloric acid (5 mL) was added, and the mixture was concentrated again. The obtained white solid was extracted with methanol (10 mL). Insoluble material was filtered off, and the filtrate was concentrated to give the title compound (1.7 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:21])[CH:7]([O:18][CH2:19][CH3:20])[CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[CH3:4].Cl[CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[CH:31]=2)[O:27][C:28]=1[CH3:29]>CN(C)C=O.O>[CH2:3]([O:5][C:6](=[O:21])[CH:7]([O:18][CH2:19][CH3:20])[CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[CH:31]=2)[O:27][C:28]=1[CH3:29])[CH3:4]
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Reactant: COc1cc(OC)cc(-c2nc(CCl)c(C)o2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2cc(OC)cc(OC)c2)oc1C)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
0.048 g (1.10 mmol) Sodium hydride (55% in mineral oil) was added in one portion below 5° C. and under argon to a stirred solution of 0.261 g (1.00 mmol) rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester and 0.321 g (1.20 mmol) 4-chloromethyl-2-(3,5-dimethoxy-phenyl)-5-methyl-oxazole in 15.0 ml N,N-dimethylformamide. The reaction mixture was warmed up to room temperature and then stirred for 16 hours at ambient temperature. It was then diluted with cold water and extracted two times with ethyl acetate. The combined organic phases were dried over MgSO4, filtered and evaporated. The residue formed was purified by flash-chromatography (silica gel; eluent: gradient of hexane and ethyl acetate) to give 0.413 g (84%) rac-3-{1-[2-(3,5-dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-2-ethoxy-propionic acid ethyl ester as light yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH:25]([CH3:27])[CH3:26])[CH:19]=[O:20].Cl>C(O)C.O.C(OCC)(=O)C>[CH2:7]([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH:25]([CH3:27])[CH3:26])[CH:19]=[O:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)Oc1ccc(C=O)cc1O
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)Oc1ccc(C=O)cc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Potassium carbonate (1.83 g, 13.2 mmol) and benzyl chloride (1.55 mL, 13.5 mmol) were added to a suspension of 3-hydroxy-4-isopropoxybenzaldehyde described in Production Example 171 (1.84 g, 10.2 mmol) in ethanol (20 mL) under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 90° C. for 2 hours. The mixture was cooled to 0° C. and then 2 M hydrochloric acid, ethyl acetate, and water were added for partition. The organic layer was washed with a saturated saline solution, and the resultant was dried over anhydrous sodium sulfate, and then filtered. The solvent was evaporated, the resultant residue was dissolved in dichloromethane, and the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate=19:1-3:1). The target fraction was concentrated under vacuum to obtain the title compound (2.59 g, 94%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>CO.ClCCl.C(OCC)C>[ClH:27].[ClH:27].[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:16]=[N:15][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:19][CH:18]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: Fc1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Reaction time: 24 h

Procedure:
4-[5-(4-Fluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (0.99 g) was dissolved in a mixture of methanol (30 ml) and dichloromethane (10 ml) and treated dropwise with a 1.0 M solution of HCl in diethyl ether (60 ml). After stirring for 24 h, the resultant suspension was filtered and the precipitate was washed with 1:1 diethyl ether/methanol, followed by diethyl ether and dried under vacuum, to furnish the title compound as an off white solid (0.86 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH2:11]([NH:13][CH2:14][CH2:15][CH:16]=[O:17])[CH3:12]>C1C=CC=CC=1>[CH2:11]([N:13]([CH2:14][CH2:15][CH:16]=[O:17])[C:9]([NH:8][C:6]1[S:7][C:3]([O:2][CH3:1])=[N:4][N:5]=1)=[O:10])[CH3:12]
Reactant: COc1nnc(N=C=O)s1
Reactant: CCNCCC=O
Solvent: c1ccccc1
Product: CCN(CCC=O)C(=O)Nc1nnc(OC)s1

Procedure:
A mixture of 5-methoxy-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-ethylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1 -ethyl-3-(5-methoxy-1,3,4-thiadiazol-2 -yl)ureido]propionaldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12](O)=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].C[N:31]1CC[O:34][CH2:33][CH2:32]1.ClC(OCC(C)C)=O.C(CN)O>CC(N(C)C)=O.ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:31][CH2:32][CH2:33][OH:34])=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29]
Reactant: CN1CCOCC1
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: NCCO
Product: Cc1ccc(C(=O)NCCO)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 59.6 %

Procedure:
To a cold solution of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (4.0 g, 9.5 mmol) in anhydrous dimethylacetamide (20 mL, −20° C.) and N-methylmorpholine (1.56 mL, 14.25 mmol) was added a solution of isobutyl chloroformate (1.84 mL, 14.25 mmol) in anhydrous dichloromethane (5 mL). The reaction mixture stirred under nitrogen atmosphere at −20° C. for 10 min and then at room temperature for 30 min. At which time it was cooled back down to 0° C. and ethanolamine (0.86 mL, 14.25 mmol) and DMAP (ca.) were added. The reaction mixture stirred for 30 min at 0° C., then at room temperature overnight. The solvent was removed by vacuum distillation and the residue was diluted with acetonitrile/water (1:1 v/v) to be purified by reverse phase HPLC using a 10–90% acetonitrile in water containing 0.5% TFA (30 min) gradient at a 80 mL/min flow rate. The appropriate fractions (M+H m/z=464) were collected, concentrated to a reduced volume, freeze-dried and lyophilized. The resulting white solid was diluted with dichloromethane (30 mL) and washed with 5% NaHCO3 (2×50 mL). The organic extracts were washed with water (2×25 mL) and dried over Na2SO4 (anhydrous). The organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (2.625 g, 59%) as a white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.9 (dd, 1H, J=2 Hz), 7.69 (d, 1H, J=2 Hz), 7.62 (m, 1H), 7.55 (d, 1H, J=8.4 Hz), 7.01 (m, 2H), 5.58 (q, 2H, J=12.4 Hz), 3.68 (t, 2H, J=5.6 Hz), 3.46 (t, 2H, J=5.6 Hz), 2.17 (s, 3H), 2.12 (s, 3H); ES-HRMS m/z 464.1153 (M+H C22H21ClF2N3O4 requires 464.1183).