Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3](/[CH:15]=[CH:16]/[P:17]([O:23]C(C)C)([O:19]C(C)C)=[O:18])[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:14].Br[Si](C)(C)C>CN(C)C=O>[OH:1][CH2:2][CH:3](/[CH:15]=[CH:16]/[P:17]([OH:19])([OH:23])=[O:18])[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:14]
Reactant: CC(C)OP(=O)(/C=C/C(CO)Cn1cnc2c(N)ncnc21)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2CC(/C=C/P(=O)(O)O)CO
Yield: 40.6 %

Procedure:
A solution of (E)-9-[2-hydroxymethyl-4-(diisopropoxyphosphoryl)but-3-enyl]adenine (107 mg, 280 μmol) and bromotrimethylsilane (0.86 g, 5.61 mmol) in N,N-dimethylformamide (5 ml) was stirred at room temperature under dry nitrogen for 18 h. The solvent was removed and the residue azetroped with methanol (×3). The residue was purified by column chromatography on reverse phase silica gel eluting with water to give (E)-9-(2-hydroxymethyl-4-phosphonobut-3-enyl)adenine as a white solid (34 mg, 40%), m.p. >300° C.; λmax (MeOH) 262 (10,704)nm; υmax (KBr) 3435, 1695, 1640, 1415, 1263, 1229 and 1030 cm-1 ; δH [(CD3)2SO/D2O] 2.73 (1H, m, CH), 3.37 (2H, d, J 6 Hz, CH2O), 4.13 (1H, dd, J 7 Hz and 14 Hz, CH2N), 4.30 (1H, dd, J 7 Hz and 14 Hz, CH2N), 5.65 (1H, pseudo-t, J 17 Hz, PCH=CH), 6.06 (1H, ddd, J 8Hz, 19 Hz, PCH=CH), 8.10 (1H, s, H-2/H-8), 8.17 (1H, s, H-2/H-8); FABMS (thioglycerol) 300 (MH+) (Found: C, 37.83; H, 4.83; N, 21.75%. C10H14N5O4P.H2O requires C, 37.86; H, 5.08; N, 22.07%).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[C:21]([NH:27][CH3:28])[N:20]=3)[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[Cl:25][C:24]1[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([NH:4][C:36](=[O:38])[CH3:37])[CH2:6][CH2:7]3)[CH2:18][CH2:17]2)=[N:20][C:21]([NH:27][CH3:28])=[N:22][C:23]=1[Cl:26]
Reactant: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](NC(C)=O)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.28 g (4.6 mmol) trans-(4-{4-[2-(4-amino-cyclohexyl)-ethyl]-piperazin-1-yl}-5,6-dichloro-pyrimidin-2-yl)-methyl-amine trihydrochloride was suspended in dichloromethane (50 ml). Triethylamine (3.5 ml, 25.3 mmol) was added followed by the addition of acetyl chloride (0.49 ml, 6.9 mmol). The reaction mixture was stirred for 24 hours at room temperature. The precipitate was filtered, washed with water and purified using column chromatography to give the title compound (1.39 g, 70%), MS (EI): 430.2 (MH+); 1H NMR (300 MHz, DMSO-d6 (TMS)+1 drop of cc. DCl, □ (ppm)): 0.89-0.96 m (2H); 1.06-1.35 m (3H); 1.55-1.82 m (6H); 1.79 s (3H); 2.76 (3H); 2.98-3.18 m (4H); 3.37-3.58 m (5H); 4.16-4.29 m (2H); 7.90 br (residual NH); 11.35 br (residual NH).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[N:28]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[N:28]2)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1cccc2ncccc12
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc3ncccc23)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 60 mg (0.417 mmol) of 5-aminoquinoline was added. The resulting mixture was stirred at room temperature for four hours and the final product was collected by filtration and washed with diethylether to yield the title compound (80 mg, 74.8% yield).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7]Br)=[N:4][CH:3]=1.[SH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:1][C:2]1[S:6][C:5]([CH2:7][S:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:4][CH:3]=1
Reactant: BrCc1ncc(Br)s1
Reactant: COC(=O)CCS
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CCSCc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
5-Bromo-2-(bromomethyl)-1,3-thiazole (1.34 g, 5.22 mmol) was dissolved in DMF (15 mL). Methyl 3-mercaptopropionate (0.689 g, 5.74 mmol) and DIEA (0.876 g, 6.78 mmol) were added, and the reaction was stirred at room temperature for 3 h. The reaction was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Flash chromatography (0-30% ethyl acetate in hexanes) afforded methyl 3-{[(5-bromo-1,3-thiazol-2-yl)methyl]sulfanyl}propanoate (1.45 g, 94%) as a pale yellow oil. MS ESI: [M+H]+ m/z 295.9/297.9.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1)(=O)=O.O[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:24]([C:23]1[CH:26]=[CH:27][C:20]([O:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:16])[O:17][CH3:18])=[CH:10][CH:9]=2)=[CH:21][CH:22]=1)=[O:25]
Reactant: COC(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Nc1ccc(CCOc2ccc(C=O)cc2)cc1
Yield: 75.8 %

Procedure:
7 g (26 mmole) 4-[(methoxycarbonyl)amino]phenethyl methanesulfonate, 6.2 g (51 mmole) 4-hydroxybenzaldehyde and 7.05 g potassium carbonate in acetonitrile was refluxed for 3 h. The solvent was evaporated in vacuo, 1 M sodium hydroxide was added and the product was extracted with dichloromethane, washed with brine, dried and the solvent was evaporated. The reaction was not completed and therfore restarted with 3.1 g 4-hydroxybenzaldehyde and 3.5 g potassium carbonate in acetonitrile and refluxed for 4 h. The solvent was evaporated and the residue was stirrred in dichloromethane over night. The precipitate was filtered off and the solvent was evaporated to give 5.9 g (yield 75.8%) of methyl N-{4-[2-(4-formylphenoxy)ethyl]phenyl}carbamate wich was used without further purification.
Reaction SMILES: [CH2:1](I)[CH3:2].[OH:4][C:5]1[CH:6]=[C:7]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]1[O:12][CH2:11][CH:10]([C@H:19]3[CH2:24][CH2:23][C@H:22]([NH:25][C:26]([C:28]4[CH:29]=[CH:30][C:31]5[S:36][CH2:35][C:34](=[O:37])[NH:33][C:32]=5[CH:38]=4)=[O:27])[CH2:21][CH2:20]3)[CH2:9][C:8]2=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]1[O:12][CH2:11][CH:10]([C@H:19]3[CH2:24][CH2:23][C@H:22]([NH:25][C:26]([C:28]4[CH:29]=[CH:30][C:31]5[S:36][CH2:35][C:34](=[O:37])[NH:33][C:32]=5[CH:38]=4)=[O:27])[CH2:21][CH2:20]3)[CH2:9][C:8]2=1)[CH3:2]
Reactant: CCI
Reactant: O=C1CSc2ccc(C(=O)N[C@H]3CC[C@H](C4COc5cnc6ccc(O)cc6c5C4)CC3)cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CO3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl iodide (6 μL, 0.07 mmol, 1.0 eq) is added at room temperature to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [trans-4-(6-hydroxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-amide (40 mg, 0.07 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by sodium hydride (55% purity, 3.2 mg, 0.07 mmol, 1.0 eq). After 2 hours stirring at room temperature, 1.0 additional equivalent of ethyl idodide and sodium hydride are added to the reaction mixture that is stirred at room temperature for one hour. Then solvent is evaporated and the crude is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [trans-4-(6-ethoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-amide as an off-white lyophilizated powder (11 mg, 27% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)N)=[O:8])=[CH:5][CH:4]=1.[C:22]([OH:29])(=[O:28])[CH2:23][CH2:24][C:25]([CH3:27])=O>O>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]2[C:11]3[C:16](=[CH:15][C:14]4[O:17][CH2:18][O:19][C:13]=4[CH:12]=3)[C:24]([CH2:23][C:22]([OH:29])=[O:28])=[C:25]2[CH3:27])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(=O)CCC(=O)O
Reactant: NN(C(=O)c1ccc(Cl)cc1)c1ccc2c(c1)OCO2
Agent: Cl
Solvent: O
Product: Cc1c(CC(=O)O)c2cc3c(cc2n1C(=O)c1ccc(Cl)cc1)OCO3
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A mixture of 1.9 g of N1 -(p-chlorobenzoyl)-3,4-methylenedioxyphenylhydrazine hydrochloride and 20 g of levulinic acid was heated for 1 hour at 55° - 60°C and for 3 hours at 80° - 90°C. The reaction mixture was cooled to a room temperature, and poured into 200 ml of water. The precipitates were collected by filtration and washed with water. The crystals obtained by twice recrystallizing from acetone-water (5 : 1) gave 1.19 g of 1-(p-chlorobenzoyl)-2-methyl-5,6-methylenedioxy-3-indolylacetic acid having a melting point of 217° - 218°C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[NH:13][C:12]1=[O:25])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:33]([C:36]1[CH:46]=[CH:45][C:39]([CH2:40][O:41][CH2:42][CH2:43]Cl)=[CH:38][CH:37]=1)([O-:35])=[O:34].P([O-])([O-])([O-])=O>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[N:13]([CH2:43][CH2:42][O:41][CH2:40][C:39]2[CH:45]=[CH:46][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=2)[C:12]1=[O:25])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(COCCCl)cc1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)Sc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CCOCc2ccc([N+](=O)[O-])cc2)[C@@H]1CC(=O)Sc1ccccc1
Reaction time: 2 h
Yield: 93.8 %

Procedure:
747 mg (1.97 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-[(phenylthio)carbonylmethyl]-2-azetidinone and 398 mg (3.94mmole) of triethylamine were dissolved in 20 ml of methylene chloride. To the solution were added 960 mg (3.94 mmole) of p-nitrobenzyloxyethyl chloride, with ice cooling under a stream of nitrogen. The mixture was stirred for 2 hours and then a 0.1M phosphate buffer solution (pH 7.2) was added to the reaction mixture to complete the reaction. The organic layer was separated and washed with water, after which it was dried. The solvent was distilled off and the resulting residue was purified by column chromatography through 15 g of silica gel, to give 1,032 mg (yield 89%) of the desired product as an oil from the fractions eluted with mixtures of hexane and ethyl acetate in volume ratios from 6:1 to 3:1.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([F:19])=[C:14](B(O)O)[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][CH:3]=2)[CH:11]=1
Reactant: Nc1ncc(Br)nn1
Reactant: OB(O)c1cc(Br)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Nc1ncc(-c2cc(Br)ccc2F)nn1
Temperature: 90 °C
Yield: 41 %

Procedure:
6-Bromo-1,2,4-triazin-3-amine (9.1 g, 40.8 mmol), 5-bromo-2-fluorophenylboronic acid (98.9 g, 40.8 mmol), (dppf)PdCl2 (3.0 g, 4.0 mmol), nitrogen-sparged dioxane (81.6 mL), and aq. 2 N K2CO3 (17 mL) were combined and heated in a round bottom flask at 90° C. for 4 h. The hot mixture was filtered through a pad of celite and diluted with EtOAc and washed with water. Concentration followed by trituration with DCM afforded a tan solid (4.5 g), m/z=269.0 [M+H].
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[C:5]([O:13][CH3:14])[CH:4]=1.[F:15][C:16]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[F:15][C:16]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:17]=1[C:18]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[C:5]([O:13][CH3:14])[CH:4]=1)=[O:19]
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: O=C(Cl)c1cc(I)ccc1F
Agent: [Mg]
Product: COc1cc(C(=O)c2cc(I)ccc2F)cc(OC)c1OC

Procedure:
First, magnesium was added to 1-bromo-3,4,5-trimethoxybenzene as a starting material, as shown in Reaction 6, and then 2-fluoro-5-iodobenzoyl chloride was added thereto to obtain a Compound 21 derivative [(2-fluoro-5-iodophenyl)(3,4,5-trimethoxyphenyl)methanone]. Using NaOMe, the fluoro group of thus obtained compound was substituted with a methoxy group to obtain (2-methoxy-5-iodophenyl)(3,4,5-trimethoxyphenyl)methanone. Thus obtained (2-methoxy-5-iodophenyl)(3,4,5-trimethoxyphenyl)methanone (320 mg, 0.75 mmol) was dissolved in tetrahydrofuran (50 ml), and 2-(tributylstannyl)thiazole (475 mg, 1.27 mmol) and Pd(PPh3)2Cl2 (26 mg, 0.04 mmol) were slowly added thereto at room temperature. The mixture was heat refluxed for 8 hours. After completion of the reaction, the reaction mixture was extracted with water and EtOAc. The organic layer was washed with brine, and dried over anhydrous MgSO4. The solid substance was filtered off, and the filtrate was vacuum concentrated. The resulting residue was purified by column chromatography (SiO2, n-Hex/EA=1/2) to obtain Compound 583 (140 mg, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:18]([C:19]3[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[CH:16][CH:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:32]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:18]([C:19]3[C:20]([C:25]([F:27])([F:28])[F:26])=[N+:21]([O-:32])[CH:22]=[CH:23][CH:24]=3)[N:17]=[CH:16][CH:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2ccnn2-c2cccnc2C(F)(F)F)cc([N+](=O)[O-])c1OC
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2ccnn2-c2ccc[n+]([O-])c2C(F)(F)F)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-pyrazol-1-yl]-2-trifluoromethyl-pyridine (0.50 g, 1.27 mmol) in dichloromethane (10 mL) cooled in an ice-water bath was added urea-hydrogen peroxide complex (0.26 g, 2.76 mmol) in one portion followed by trifluoroacetic anhydride (0.53 g, 2.52 mmol) dropwise. The resulting mixture was allowed to stir at room temperature overnight and then the insoluble material was filtered off. The filtrate was washed with water and brine, then dried over anhydrous sodium sulphate, filtered and evaporated to leave an off-white solid. Recrystallisation from ethanol afforded 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-pyrazol-1-yl]-2-trifluoromethyl-pyridine 1-oxide, 0.34 g (65%).
Reaction SMILES: N#N.C[O:4][C:5]([C:7]1[N:8]=[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:21])[CH3:20])[CH:14]=2)[O:10][CH:11]=1)=[O:6].[OH-].[Na+]>C1COCC1.Cl>[C:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][C:9]1[O:10][CH:11]=[C:7]([C:5]([OH:6])=[O:4])[N:8]=1)(=[O:21])[CH3:20]
Reactant: COC(=O)c1coc(Cc2cccc(C(C)=O)c2)n1
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1cccc(Cc2nc(C(=O)O)co2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(3-acetyl-benzyl)-oxazole-4-carboxylic acid methyl ester (330 mg, 1.27 mmol) in THF (12 mL) was treated at rt with 1N NaOH (6 mL, 6.00 mmol) and the reaction mixture was stirred for 1 h at rt. The reaction mixture was poured in 1N HCl and extracted twice with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a colorless oil. LC-MS-conditions 02: tR=0.78 min, [M+AcCN+H]+=287.05.
Reaction SMILES: [Br-].[C:2]([CH:4](C)[CH2:5]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[Na].C[Si]([N-][Si](C)(C)C)(C)C.[C:37]([O:41][C:42]([NH:44][C:45]([CH3:52])([CH:50]=O)[C:46]([O:48][CH3:49])=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[C:37]([O:41][C:42]([NH:44][C:45]([CH3:52])(/[CH:50]=[CH:5]\[CH2:4][C:2]#[N:3])[C:46]([O:48][CH3:49])=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C#N)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(C)(C=O)NC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)C(C)(/C=C\CC#N)NC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
3-Cyanobutyltriphenylphosphonium bromide (0.990 g, 0.0025 mol) is taken up in dry THF (30 mL) and purged with argon. To this sodium is added bis(trimethylsilyl)amide (3 mL 1.0M solution in THF, 0.003 mol) at 20° C. to 25° C. and the reaction mixture is stirred at this temperature for 10 min. After a yellow color change is observed, a solution of the methyl 2-[(tert-butoxycarbonyl)amino]-2-methyl-3-oxopropanoate product of Example 1c (578 mg, 0.0025 mol) in THF (20 mL) is then added and the reaction mixture is stirred under argon for 8 h at 25° C. It is then concentrated on rotovap and the residual mass is taken up in EtOAc (100 mL) and washed with DI water (20 mL). The organic layer is dried over anhydrous MgSO4, decolorized with activated charcoal (1.0 g), filtered through Celite and concentrated on a rotovap to give crude reaction product as a dark brown oil. Column chromatography of this crude product affords the desired title product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[CH:11][N:12]([CH3:13])[C:4]=2[CH:3]=1.[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[N:7]=[C:6]([C:8]#[N:9])[C:5]3[N:10]=[CH:11][N:12]([CH3:13])[C:4]=3[CH:3]=2)=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: Cn1cnc2c(C#N)nc(Cl)cc21
Reactant: COCCOCOc1ccc(B(O)O)cc1C(F)(F)F
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COCCOCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of 6-chloro-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile is (5.9 g), 4-(2-methoxy-ethoxymethoxy)-3-trifluoromethyl-phenyl-boronic acid (9.92 g), potassium phosphate (11.1 g), tris(dibenzylideneacetone)dipalladium (1.4 g) and tricyclohexylphosphine (1.03 g) in dioxane (190 ml) and water (60 ml) was heated at 100° C. under nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was then extracted with ethyl acetate (500 ml×2), the combined organic layers were dried over sodium sulphate and solvent was then removed under reduced pressure. To the residue was then added methanol (20 ml), and the solid product, 6-(4-(2-methoxy-ethoxymethoxy)-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile was collected by filtration (8.95 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C:11]([CH2:19][CH:20]=[CH2:21])([CH2:17][CH3:18])[C:12](OCC)=[O:13])C>C1COCC1>[CH2:19]([C:11]([CH2:17][CH3:18])([CH2:12][OH:13])[CH2:10][OH:9])[CH:20]=[CH2:21]
Reactant: C=CCC(CC)(C(=O)OCC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(CC)(CO)CO
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred suspension of lithium aluminum hydride (7.8 g, 0.20 mol) in THF (350 mL) was added 2-allyl-2-ethylmalonic acid diethyl ester (23.5 g, 0.10 mol) in THF (150 mL) over 2 h. After stirring at rt for 2 days, the reaction was carefully quenched with dilute sulfuric acid (7%, 250 mL). The product was extracted with diethyl ether (3×100 mL) and ethyl acetate (3×100 mL), and the combined extracts were washed with brine (300 mL), dried over sodium sulfate and concentrated to give 2-allyl-2-ethylpropane-1,3-diol.
Reaction SMILES: [C:1]1([P:7](OCC)[O:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])([CH3:17])([CH3:16])[CH3:15]>>[C:1]1([P:7]([O:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:14]([CH3:17])([CH3:15])[CH3:16])[O:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)c1ccccc1O
Reactant: CCOP(OCC)c1ccccc1
Product: CCOP(Oc1ccccc1C(C)(C)C)c1ccccc1
Temperature: 180 °C
Reaction time: 16 h

Procedure:
99 g (0.5 mol) of diethyl phenylphosphonite and 75 g (0.5 mol) of 2-tert-butylphenol were mixed and heated with stirring at 530mbar to 170° C. Ethanol distilled off during this via a small column. The temperature was then increased stepwise to 180° C., and the vacuum was simultaneously enhanced to 100mbar. After 16 hours, a total of 18 g of ethanol distilled off. The batch was then cooled and distilled. After a first fraction, which contained the unreacted starting materials, 116 g were obtained having a boiling point of 139° C. at 0.1 mbar. The yield was thus for a 78% conversion rate almost 100% of theory.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.Br[CH2:23][C:24]1[C:28]2[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=2[S:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]2[S:26][CH:25]=[C:24]([CH2:23][N:3]3[C:4]4=[N:9][C:8]([N:10]5[CH2:11][CH2:12][O:13][CH2:14][CH2:15]5)=[CH:7][C:6](=[O:16])[N:5]4[CH2:17][C@@:2]3([CH3:1])[C:18]([F:21])([F:19])[F:20])[C:28]=2[CH:29]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1Cc1csc2ccc(Cl)cc12

Procedure:
The product is prepared according to the procedure described in stage k of Example 1, using 100 mg of (2S)-2-methyl-7-morpholin-4-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one (Example 1j) and 103 mg of 3-(bromomethyl)-5-chloro-1-benzothiophene, replacing the sodium hydride with caesium carbonate. After purification by preparative HPLC/MS (method C), 49 mg of (2S)-1-[(5-chloro-1-benzothiophen-3-yl)methyl]-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained in the form of a brown solid, the characteristics of which are the following: