Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=1[CH2:5][NH:6][C:7](=[O:10])[CH2:8]Cl.[I-:17].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=1[CH2:5][NH:6][C:7](=[O:10])[CH2:8][I:17]
Reactant: [I-]
Reactant: COc1ccc(CNC(=O)CCl)c(OC)c1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(CNC(=O)CI)c(OC)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 132.1 %

Procedure:
To a solution of N-(2,4-Dimethoxy-benzyl)-2-chloro-acetamide (2.2074 g, 9.0584 mmol) in acetone (20 mL) was added sodium iodide (4.121 g, 27.49 mmol). The reaction mixture was stirred at 50° C. for two hours, and then filtered to remove inorganic salts. The filtrate was evaporated in vacuo, re-suspended in ethyl acetate, and filtered again. The filtrate was evaporated in vacuo to provide 4.01 g of N-(2,4-Dimethoxy-benzyl)-2-iodo-acetamide, which was carried forward without purification. LCMS (Method E, ESI): RT=1.46 min, m+H=336.2; 1H NMR (400 MHz, CDCl3) δ: 7.17 (d, J=8.2, 1H), 6.55 (s, 1H), 6.47 (d, J=2.2, 1H), 6.44 (dd, J=8.2, 2.3, 1H), 4.36 (d, J=5.8, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.68 (s, 2H).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][C@H:14]([CH2:18][OH:19])[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[C:23](O)[CH:24]=[CH:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:20][C:21]1[CH:26]=[C:25]([CH:24]=[CH:23][CH:22]=1)[O:19][CH2:18][C@H:14]1[O:15][CH2:16][CH2:17][N:12]([CH2:11][CH2:10][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)[CH2:13]1
Reactant: Oc1cccc(Cl)c1
Reactant: OC[C@@H]1CN(CCN2CCc3ccccc32)CCO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1cccc(OC[C@@H]2CN(CCN3CCc4ccccc43)CCO2)c1
Yield: 40.2 %

Procedure:
Compound 23s was synthesised with essentially the same procedure as compound 18s (Example 16), from compound 51 (Example 10; 52 mg, 0.2 mmol), 3-chlorophenol (39 mg, 0.3 mmol), triphenylphosphine (78 mg, 0.3 mmol), DEAD (0.05 ml, 0.3 mmol), and THF (1 ml). The crude residue was purified twice by flash column chromatography (silica, DCM/MeOH 1:0 to 8:2) to afford the title compound as a colourless oil (30 mg; 40%). Analyses were performed on the free base, and the free base was converted to the HCl salt for testing.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([CH:43]=[CH:44][CH:45]=[O:46])=[C:31]([CH:40]([CH3:42])[CH3:41])[S:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:25][CH:24]=1>C1COCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([CH:43]=[CH:44][CH:45]([OH:46])[CH2:17][C:15](=[O:16])[CH2:14][C:13]([O:19][CH2:20][CH3:21])=[O:18])=[C:31]([CH:40]([CH3:42])[CH3:41])[S:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)c1sc(-c2ccccc2)c(-c2ccc(F)cc2)c1C=CC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=Cc1c(C(C)C)sc(-c2ccccc2)c1-c1ccc(F)cc1
Reaction time: 1 h
Yield: 121.5 %

Procedure:
To a solution of 2.6 g of diisopropylamine in 30 ml of THF at 0° was added 1.67 g of n-butyllithium (1.16 m in hexane). Then a solution of 1.7 g of ethyl acetoacetate in 10 ml of THF was added dropwise. After stirring at 0° for 1 hour, the mixture was cooled to -20°, then a solution of 3.3 g of the title product of Step 3, above, in 20 ml of THF was added dropwise. The reaction was stirred at -20° for 1 hour. Then was quenched with saturated aqueous ammonium chloride solution. The mixture was extracted with MTBE and then methylene chloride and the organic solutions were combined and dried, adn the solvent evaporated under reduced pressure to give 5.5 g of crude title product of this step as an oil. This was used without further purification in the next step (Step 5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[NH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:35]1[CH2:36][CH2:37][CH:32]([CH2:31][NH:30][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[NH:10]2)=[O:28])[CH2:33][CH2:34]1
Reactant: NCC1CCOCC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCC2CCOCC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 4-aminomethyl tetrahydropyran (34.5 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (10.8 mg, 10.2%) as an off-white powder. HRMS (ES+) m/z Calcd for C29H35Cl2N3O2S+H [(M+H)+]: 528.2179. found: 528.2180.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:16]1([CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14][CH2:15]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CC1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: CO
Product: CC1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Yield: 156.5 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (20 g, 0.093 mol), 4-methylcyclohexanone (21.31 g, 0.187 mol) and pyrrolidine (12.63 g, 0.178 mol) in methanol (400 mL) was refluxed for overnight. The reaction mixture was concentrated in vacuo, diluted with an equal volume of H2O and then added HCl until pH=1. The resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-4′-methylspiro(chroman-2,1′-cyclohexan)-4-one (45 g, 100%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:26][CH2:27]O)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH:16]=3)[CH2:10]2)=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:26][CH2:27][Br:32])[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH:16]=3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)Oc1cccc(C(=O)N2CCC(CCO)(c3ccc(C(F)(F)F)cc3)C2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)Oc1cccc(C(=O)N2CCC(CCBr)(c3ccc(C(F)(F)F)cc3)C2)c1
Reaction time: 1 h

Procedure:
Combine 2-[3-(4-trifluoromethyl-phenyl)-1-(3-isopropoxy-benzoyl)-pyrrolidin-3-yl]-ethanol (10 mmol), carbon tetrabromide (12.5 mmol), and dichloromethane (15 mL). Cool in an ice bath. Add in portions, triphenylphosphine (15 mmol). After 1 h, concentrate in vacuo to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: [CH:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1)([CH2:3][CH3:4])[CH3:2].[C:15]1([C:21]2[O:22][C:23]([C:29]([F:32])([F:31])[F:30])=[C:24]([C:26](O)=[O:27])[N:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]([NH:12][C:26]([C:24]2[N:25]=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:22][C:23]=2[C:29]([F:31])([F:32])[F:30])=[O:27])=[CH:10][CH:11]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CCC(C)Nc1ccc([N+](=O)[O-])cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCC(C)Nc1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Yield: 41 %

Procedure:
sec-Butyl-(5-nitro-pyridin-2-yl)-amine (97.5 mg, 0.5 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (135 mg, 0.525 mmol), Et3N (352 uL, 2.5 mmol) and BOP (232 mg. 0.525 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-sec-butylamino-pyridin-3-yl)-amide as a light purple solid (83 mg). ES-MS calcd for C20H19F3N4O2 (m/e) 404.40, obsd 405.1 (M+H).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH2:5])[CH2:2]1.Cl[CH2:7][CH2:8][N:9]=[C:10]=[O:11].[H-].[Na+]>C1COCC1>[O:1]1[CH2:4][CH:3]([N:5]2[CH2:7][CH2:8][NH:9][C:10]2=[O:11])[CH2:2]1
Reactant: NC1COC1
Reactant: O=C=NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCN1C1COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A 0° C. solution of 3-oxetanamine (0.200 g, 2.74 mmol) in THF (15 mL) was treated drop-wise with 2-chloroethyl isocyanate (0.257 mL, 3.01 mmol), allowed to warm to RT as the cooling bath expired, then concentrated to dryness. The residue was treated with toluene and concentrated to dryness (twice) to afford a white solid. The solid was dissolved in THF (15 mL), cooled to −20° C., under Ar, treated with NaH (60% in mineral oil, 0.274 g, 6.84 mmol), allowed to warm to RT and stirred overnight. The mixture was cooled to 0° C., quenched with satd. NH4Cl, warmed to RT, treated with brine and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated to dryness. The aqueous layer was treated with solid NaCl until saturated, extracted with 1:1 EtOAc/THF (4×), then frozen and lyophilized. The lyophilized solid was stirred with EtOH for 1 h, the liquid decanted and the process repeated. The EtOH extracts were combined with the EtOAc/THF extracts, concentrated to dryness, then treated with 10% MeOH/DCM and the solids removed via filtration. The filtrate was combined with the initial EtOAc extracts and purified via silica gel chromatography (MeOH/DCM) to afford 1-(oxetan-3-yl)imidazolidin-2-one (270 mg, 69%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 6.52 (s, 1 H), 4.86 (m, 1 H), 4.71 (t, J=6.6 Hz, 2 H), 4.62 (t, J=7.2 Hz, 2 H), 3.58 (m, 2 H), 3.29 (m, 2 H); MS (ESI) m/z: 143.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[C:12]([CH:15]([CH3:17])[CH3:16])[N:11]=[C:10]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=2)=[CH:4][CH:3]=1.BrN1C(=[O:30])CCC1=O.C([O-])(O)=O.[Na+].O>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14][OH:30])=[C:12]([CH:15]([CH3:17])[CH3:16])[N:11]=[C:10]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Temperature: 25 °C
Yield: 95 %

Procedure:
N-(4-(4-fluorophenyl)-5-methyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (112.5 mg, 0.33 mmol, 1 equiv.) and N-bromosuccinimide (NBS) (118.7 mg, 0.66 mmol, 2 equiv.) were dissolved in 2 mL of acetonitrile. The mixture was irradiated with light of a wavelength A=310 nm for 4 hours at ambient temperature (about 20° C.). The obtained yellow solution was diluted with 1 mL of acetonitrile. After 2 mL of saturated NaHCO3 solution was added, the obtained mixture was further stirred under reflux for 4 hours. Then the mixture was cooled to room temperature, water (10 mL) was added and the mixture was extracted with CH2Cl2 (3×10 mL). The combined organic phases were washed with 10 mL of brine, and the obtained solution was dried with Na2SO4. Solvent was removed under the reduced pressure to give 110.8 mg (95%) of crude N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (III) which contained 77% of N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (III) as determined by 1H-NMR integral. This product can be further purified by crystallization from MTBE/hexane mixture to afford pure material (HPLC area %=99.6) with Tm=140-141° C.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11](S(Cl)(=O)=O)=CC=1.[OH-].[K+]>C(OCC)C>[CH:6]([C:11]1[CH2:12][CH:13]=[CH:8][CH:18]=1)=[CH:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCCCCO
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCCC=CC1=CC=CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a flask containing 10.36 g of 5-hexene-1-ol, 24.11 g of p-toluenesulfonyl chloride and 200 mL of diethylether were added and well mixed. The solution was cooled down to −10° C., and 353.5 g of well ground KOH was slowly added for 10 min to the solution. The solution was stirred for 30 minutes at −15˜5° C. The solution was then poured to 200 mL of ice-water. Ether solution was separated with a funnel. Then the ether solution was dried with anhydrous MgSO4, filtered, and then ether was removed from the filtrate under reduced pressure. The remained product was clear and sticky. This product was dissolved in 120 mL of anhydrous THF. This solution was cooled down to 0° C. and 65 mL of 2N THF solution of NaCp was added to the cold solution. This solution was stirred for about 3˜5 hours, and mixed with 200 mL of water and 200 mL of hexane in a separatory funnel. The organic layer was extracted and dried by MgSO4 and filtered. Slightly yellow filtrate was vacuum dried in 0.2 torr at 55° C. to produce 9.643 g of product, pure Hexenylcyclopentadiene (Yield: 65%). This compound, 9.643 g, was dissolved in 100 mL of THF and cooled down to −78° C. using dry ice/aceton slush. To this solution, 26 mL of nBuLi (2.5M, hexane) was added and the solution was stirred overnight with a slow warming to room temperature. This solution was then added to a flask containing 0.5 equivalent of ZrCl4(THF)2 at 55° C. and was agitated for 3 days. The solvent was removed under reduced pressure and 200 mL of hexane was added and heated. Filtration at 55° C. was followed by a removal of hexane and produced the white solid product (Yield: 65%). Spectroscopic analysis of the product by a NMR method is as follows:
Reaction SMILES: [CH3:1][CH:2]([S:4]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([S:16](CCC(OC)=O)(=[O:18])=[O:17])=[CH:13][CH:14]=2)[CH:9]=[N:8]1)(=[O:6])=[O:5])[CH3:3].C[O-].[Na+].C1C(=O)N([Cl:35])C(=O)C1>C1COCC1>[CH3:1][CH:2]([S:4]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([S:16]([Cl:35])(=[O:18])=[O:17])=[CH:13][CH:14]=2)[CH:9]=[N:8]1)(=[O:6])=[O:5])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)CCS(=O)(=O)c1ccc2c(cnn2S(=O)(=O)C(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)n1ncc2cc(S(=O)(=O)Cl)ccc21
Reaction time: 0.33 h

Procedure:
To a solution of methyl 3-{[1-(propan-2-ylsulfonyl)-1H-indazol-5-yl]sulfonyl}propanoate (300 mg, 0.80 mmol) in THF (4 mL) was added sodium methoxide (1.6 mL, 0.5 M, 0.80 mmol). The reaction mixture was stirred for 20 minutes, then the solvents were removed under reduced pressure and the residue was stripped down from heptanes to generate a white foam. This foam was suspended in DCM (4 mL) at 0° C. and then NCS (106 mg, 0.80 mmol) was added and the reaction mixture was stirred for 1 hour. The reaction was quenched by the addition of brine (4 mL) and the phases were separated using a phase separator. The aqueous layer was washed with DCM. The combined organic layers were concentrated under reduced pressure, and the crude was purified on silica gel eluting with hexanes and ethyl acetate to afford the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([C:9]2[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)=[O:8])=[CH:4][CH:3]=1.C[O-].[Na+].[O:25]1CCOC[CH2:26]1.O>CO>[CH3:26][O:25][C:2]1[S:6][C:5]([C:7]([C:9]2[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: O=C(c1ccc(Br)s1)c1nc(C(F)(F)F)nc2ccsc12
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)c2nc(C(F)(F)F)nc3ccsc23)s1
Yield: 71 %

Procedure:
A suspension of 5-bromo-2-thienyl 2-trifluoromethylthieno[3,2-d]pyrimidin-4-ylmethanone (0.2 g, 0.51 mmol) in MeOH (15 mL) was treated with sodium methoxide (0.11 g, 2.04 mmol), refluxed for 1 h, treated with dioxane (0.1 mL) to aid dissolution, refluxed for 18 h, cooled, treated with water (15 mL) and concentrated in vacuo. The resulting aqueous mixture was extracted with EtOAc (2×25 mL), the combined extracts washed with brine (25 mL), dried (MgSO4), concentrated in vacuo and the resulting red oil dissolved in heptane-EtOAc (50:50), filtered through a pad of SiO2, concentrated in vacuo and the resulting solid recrystallised [heptane-EtOAc (19:1)] to give the title compound (0.124 g, 71%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([O:13][CH3:14])=[O:12].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=1
Reactant: COC(=O)CBr
Reactant: O=c1ccc(Br)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)Cn1cc(Br)ccc1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To solution of 5-bromopyridin-2(1H)-one (2.5 g, 14.37 mmol) and methyl 2-bromoacetate (2.418 g, 15.81 mmol) in DMSO (12 mL) was added K2CO3 (2.383 g, 17.24 mmol). The mixture was stirred at 60° C. for 4 hours, filtered, and purified via preparative HPLC, eluting with a gradient of 10-90% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) to give the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[C:12]2[CH:11]=[CH:10][C:9](=[O:26])[NH:8][C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+]>O1CCCC1.O>[Cl:25][C:22]1[S:21][C:20]([C:18]2[O:17][N:16]=[C:15]([CH2:14][N:13]3[C:12]4[CH:11]=[CH:10][C:9](=[O:26])[NH:8][C:7]=4[CH:6]=[C:5]3[C:3]([OH:4])=[O:2])[CH:19]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc2[nH]c(=O)ccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2[nH]c(=O)ccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 20 mg) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid methyl ester and 1.9 mg lithium hydroxide in a mixture of 2 ml tetrahydrofuran and 1 mL water was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure and the residue was coevaporated twice with toluene. The residue was directly subjected to the subsequent reaction without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[OH:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[C:18](=[O:20])[CH3:19]>CN(C=O)C>[CH2:7]([O:17][C:15]1[CH:14]=[CH:13][C:12]([C:18](=[O:20])[CH3:19])=[C:11]([OH:10])[CH:16]=1)[CH3:8]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(C)=O)c(O)c1
Reaction time: 4 h
Yield: 69.4 %

Procedure:
Potassium carbonate (13.6 g, 99 mmol) followed by ethyl iodide (2.4 mL, 29.6 mmol) were added to a solution of 2′,4′-dihydroxyacetophenone (5 g, 33 mmol) in DMF (50 mL). The mixture was stirred for 4 hours and then partitioned between H2O and EtOAc. The organic layer was washed with satd NaHCO3, brine, dried over Na2SO4 and concentrated to a clear oil. Purification by column chromatography gave the product as a white solid (3.7 g, 63%). 1H NMR (400 MHz, CDCl3): δ 1.43 (t, J=6.8 Hz, 3 H), 2.55 (s, 3 H), 4.07 (d, J=7.1 Hz, 2 H), 6.40 (s, 1 H), 6.43 (d, J=8.8 Hz, 1 H), 7.62 (d, J=8.8 Hz, 1 H), 12.74 (s, 1 H).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([Cl:28])[C:26]=1[F:27])[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:24]=[C:25]([Cl:28])[C:26]=1[F:27]
Reactant: Nc1cc(Cl)c(F)c(Cl)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cc(Cl)c(F)c(Cl)c1
Yield: 64.9 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 360 mg of 3,5-dichloro-4-fluoroaniline in place of the 2,4-difluoroaniline. 259 mg of N-(3,5-dichloro-4-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [ClH:1].Cl.[CH:3]1(NC(C2C3C=C(C4C([Cl:24])=CN=C(NCCCC5(CC)CCN(C)CC5)N=4)SC=3C=CC=2)=O)CC1.Cl.Cl.[CH3:40][N:41]([CH3:70])[C:42]([C:44]1[CH:45]=[CH:46][C:47]2[CH:51]=[C:50]([C:52]3[C:57]([CH3:58])=[CH:56][N:55]=[C:54]([NH:59][CH2:60][CH2:61][CH2:62][CH:63]4[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]4)[N:53]=3)[S:49][C:48]=2[CH:69]=1)=[O:43]>>[ClH:24].[ClH:1].[CH3:70][N:41]([CH3:40])[C:42]([C:44]1[CH:45]=[CH:46][C:47]2[CH:51]=[C:50]([C:52]3[C:57]([CH3:58])=[CH:56][N:55]=[C:54]([NH:59][CH2:60][CH2:61][CH2:62][CH:63]4[CH2:64][CH2:65][N:66]([CH3:3])[CH2:67][CH2:68]4)[N:53]=3)[S:49][C:48]=2[CH:69]=1)=[O:43]
Reactant: CCC1(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CCN(C)CC1
Reactant: Cc1cnc(NCCCC2CCNCC2)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1
Agent: Cl
Product: Cc1cnc(NCCCC2CCN(C)CC2)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1

Procedure:
Using the method of 2-{5-chloro-2-[3-(4-ethyl-1-methylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-[5-methyl-2-(3-piperidin-4-yl-propylamino)-pyrimidin-4-yl]-benzo[b]thiophene-6-carboxylic acid dimethylamide di-hydrochloride and isolated as yellow foam. ES+(m/z) 452 [M(free base)+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.Br[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2c[nH]cn2)cc1
Reactant: Brc1cccs1
Product: Clc1ccc(-c2cn(-c3cccs3)cn2)cc1
Yield: 7 %

Procedure:
The procedure described above in Example 29 for Formula IIc-iii was followed, starting from 4-(4-chlorophenyl)-1H-imidazole (125 mg, 0.595 mmol) and 2-bromothiophene, to prepare the desired 4-(4-chlorophenyl)-1-(thiophen-2-yl)-1H-imidazole (11 mg, 0.042 mmol, yield 7.0%) as a reddish sticky solid. The HPLC purity of the final product was 95.62%. LC-MS [M+H] 261 (C13H9ClN2S+1 expected 261.02). The 1H-NMR spectra was in accordance with the chemical structure.