Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][CH2:31][CH2:32]Cl>CN(C=O)C.CCOC(C)=O>[Cl:30][CH2:31][CH2:32][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:11]2[O:10][C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:13][C:12]=2[C:14]([NH2:16])=[O:15])=[CH:22][CH:21]=1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(O)cc1
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCCl)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide (0.100 g, 0.316 mmol) in DMF (5 ml) were added potassium carbonate (0.220 g, 1.58 mmol) and 1,2-dichloroethane (0.50 ml, 6.32 mmol). The reaction was heated to 130° C. via microwave irradiation and held at that temperature for 1 hour. The reaction was then diluted with EtOAc, washed with water and brine and dried over Na2SO4 before being concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using 0-50% EtOAc in hexane as eluant to afford 5-(4-(2-chloroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.11 g, 0.29 mmol, 92%) as a white solid. LCMS (1) 2.25 min; m/z (ES+) 379/381.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[N:21]1([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>ClCCl.CO>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11]([N:30]3[CH2:31][CH2:32][CH2:33][CH:28]([CH2:27][CH2:26][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:29]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: C1CNCC(CCN2CCCC2)C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Solvent: CO
Solvent: ClCCl
Product: O=C1Nc2cccnc2N(C(=O)N2CCCC(CCN3CCCC3)C2)c2cc(Cl)ccc21
Yield: 42 %

Procedure:
Prepared analogously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 3-[2-(1-pyrrolidinyl)ethyl]piperidine in a yield of 42% of theory. Colourless crystals, m.p. 136°-139° C., Rf 0.25 (Merck DC ready made TLC plates, silica gel 60 F254 ; eluant: dichloromethane/methanol/conc. ammonia 90/10/1, v/v/v).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[C:2]1=[O:11].[H-].[Na+].Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>CN(C=O)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3](=[O:10])[C:2]3=[O:11])[CH2:22][CH2:21]2)=[CH:29][CH:28]=1
Reactant: Fc1ccc(CN2CCN(CCCl)CC2)cc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(CCN2CCN(Cc3ccc(F)cc3)CC2)c2ccccc21
Temperature: 80 °C

Procedure:
1H-Indole-2,3-dione (2.9 g) in dry DMF (5 ml) at 0° C. was treated with sodium hydride (80% dispersion in mineral oil, 600 mg). The mixture was warmed to 40° C. and after 45 minutes a solution of 1-(2-chloroethyl)-4-[(4-fluorophenyl)methyl]piperazine (5.1 g) in dry DMF (8 ml) was added. The reaction mixture was heated at 80° C. for 5 hours and then evaporated under reduced pressure. The residue was recrystallised twice to give 1-[2-[4-[(4-fluorophenyl)methyl]-1-piperazinyl]ethyl]-1H-indole-2,3-dione, m.p. 146°-147° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3C=O)=[N:7][O:8][C:4]=2[CH:3]=1.[CH:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])OCC>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:19]([O:23][CH2:24][CH3:25])[O:26][CH2:27][CH3:28])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=Cc1ccccc1-c1noc2cc(Br)ccc12
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(OCC)c1ccccc1-c1noc2cc(Br)ccc12
Temperature: 45 °C
Yield: 101.2 %

Procedure:
To a stirred suspension of 2-(6-bromobenzo[d]isoxazol-3-yl)benzaldehyde (Compound 4a) (10 g) in dry ethanol (100 mL) was added p-toluenesulfonic acid (0.315 g) followed by triethyl orthoformate (11.01 mL, 9.81 g). The suspension was stirred at 45° C. until a clear solution resulted and then maintained at 45° C. for 45 min. The solvent was removed under vacuum and then the mixture was diluted with ethyl acetate and then washed with saturated sodium carbonate solution, brine and then dried over anhydrous sodium sulfate, filtered and evaporated to give the title product (12.6 g).
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:9]2[CH:18]=[CH:19][CH:20]=[C:8]2[C:7]=1[OH:21])=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[S:31]([NH2:34])(=[O:33])=[O:32]>C(O)C>[OH:21][C:7]1[C:8]2[N:9]([CH:18]=[CH:19][CH:20]=2)[N:10]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:11](=[O:12])[C:6]=1[C:4]1[NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[S:31](=[O:32])(=[O:33])[N:34]=1
Reactant: CCOC(=O)c1c(O)c2cccn2n(CCC(C)C)c1=O
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Solvent: CCO
Product: COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccn3n(CCC(C)C)c1=O)N2
Temperature: 180 °C
Yield: 45 %

Procedure:
4-Hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 1f, 0.040 g, 0.14 mmol) was mixed with 2-amino-5-methoxy-benzenesulfonamide (Example 2b, 0.0235 g, 0.14 mmol) and the resulting mixture was heated to 180° C. for 20 min. The resulting crude oil was allowed to cool to 25° C. and ethanol (0.5 mL) was added and sonicated to afford a tan precipitate, which was collected and dried in vacuo. The crude solid was dissolved in 1.0 M aqueous potassium hydroxide solution (0.5 mL) and heated to 110° C. for 12 h. The reaction mixture was allowed to cool to 25° C. and 10% aqueous hydrochloric acid solution (0.5 mL) was added and the resulting white precipitate was collected. The crude solid was washed with methanol and dried in vacuo to afford the desired product, 4-hydroxy-3-(7-methoxy-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (0.027 g, 0.063 mmol, 47% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.07 (6H, d, J=6.4 Hz), 1.69 (1H, m), 1.78 (1H, m), 3.89 (3H, s), 4.39 (2H, t, J=7.6 Hz), 6.60 (1H, dd, J1=4.4 Hz, J2=2.8 Hz), 7.04 (1H, d, J=4.4 Hz), 7.05 (1H, dd, J1=4.8 Hz, J2=2.0 Hz), 7.25 (1H, m), 7.17 (1H, m), 7.39 (1H, d, J=2.0 Hz); LC-MS (ESI) calcd for C19H22N4O5S 430.49. found 431.33 [M+H+].
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[OH:16][C:15](=[C:4]([C:3]#[N:7])[C:5]#[N:6])[CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CCC#N
Reactant: O=C(Cl)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(C#N)=C(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of sodium hydride (12.5 g) in tetrahydrofuran (188 mL) was cooled to 0° C. A solution of malononitrile (10.3 g) in tetrahydrofuran (65 mL) was added dropwise thereto over a period of 1 hour. After stirring the reaction mixture at room temperature for 1 hour, it was again cooled to 0° C., and then a solution of 2-phenylacetyl chloride (24.2 g) in tetrahydrofuran (52 mL) was added dropwise thereto over a period of 80 minutes. After stirring the reaction mixture at room temperature for 49 hours, water (26 mL) was added to the reaction solution. The solvent was distilled off under reduced pressure, diethyl ether (130 mL) and 1 mol/L hydrochloric acid (130 mL) were added to the residue and extraction was performed with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound as a crude product (31.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[Cl:10].[CH3:11][CH:12]1[CH2:17][NH:16][CH:15]([CH3:18])[CH2:14][NH:13]1.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:10][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:8][N:13]1[CH2:14][CH:15]([CH3:18])[NH:16][CH2:17][CH:12]1[CH3:11]
Reactant: CC1CNC(C)CN1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccc(Cl)c(Cl)c2)C(C)CN1

Procedure:
A solution of 1,2-dichloro-4-chloromethyl-benzene (1.1 ml 7.89 mmol) in DMF (5 ml) was added to 2,5-dimethyl-piperazine (1.0 g, 8.77 mmol) dissolved in DMF (25 ml). The reaction was stirred over night, poured into a mixture of EtOAc and sodium carbonate (5%). The water phase was washed twice with EtOAc and the combined organic phase once with brine, and dried over sodium sulfate. After evaporation the crude was dissolved in methanol. The dibensylated piperazine does not dissolve. The filtrate was filtered through a short silica column, using methanol as eluant and evaporated to give the pure product. Yield 812 mg, 38%
Reaction SMILES: [Cl:1][C:2]([Cl:21])([Cl:20])[CH2:3][O:4][C:5](=[O:19])[CH:6](Cl)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][SH:31])=[CH:25][CH:24]=1.COC(=O)C(SCCC1C=CC(F)=CC=1)CC1C=CC(C(C)(C)O[SiH2]C(C)(C)C)=CC=1>>[Cl:1][C:2]([Cl:21])([Cl:20])[CH2:3][O:4][C:5](=[O:19])[CH:6]([S:31][CH2:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cl)Cc1ccc(CCCO)cc1
Reactant: Fc1ccc(CCS)cc1
Agent: COC(=O)C(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)SCCc1ccc(F)cc1
Product: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CCCO)cc1)SCCc1ccc(F)cc1

Procedure:
The title compound was prepared from 2-chloro-3-[4-(3-hydroxy-propyl)-phenyl]-propionic acid 2,2,2-trichloro-ethyl ester (0.74 g, 1.98 mmol) and 2-(4-fluoro-phenyl)-ethanethiol (0.34 g, 2.17 mmol) as described for 3-[4-(tert-butyl-dimethyl-silanyloxy-methyl)-phenyl]-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-propionic acid methyl ester. After repeated purification by flash chromatography with n-heptane/EtOAc 9:1 as the eluent the product was obtained as an oil (94 mg, 9.6%). 1H NMR (300 MHz, CDCl3): δ 7.10-7.11 (m, 6H), 6.94-6.98 (t, 2H), 4.65-4.75 (q, 2H), 3.64-3.68 (t, 2H), 3.58-3.61 (dd, 2H), 3.17-3.23 (dd, 2H), 2.80-2.97 (m, 5H), 2.65-2.70 (t, 2H), 1.86-1.89 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1

Procedure:
1-(4-hydroxy-3-nitro-phenyl)-ethanone was treated with benzyl bromide in the presence of K2CO3 in DMF, and processed as reported in the synthesis of example 20a to obtain the crude product which was purified using flash chromatography (silica gel, 5% CH3CN in chloroform). Yield, 94%; mp, 132° C.; MS (CI): 300 (M++29), 272 (M++1), 91; analysis: C15H13NO4 requires, C, 66.42; H, 4.83; N, 5.16. found; C, 66.58; H, 4.52; N, 5.30%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=O)[CH3:11])([O-])=O.NC1NN=C(C2C=CC(OC3C=CC=CC=3)=CC=2)C=1C#N.NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C#N)=C3N=CC=2)C=CC=1.ClCCC(NC1C=C(C2[N:82]3[N:83]=[C:84]([C:89]4[CH:94]=[CH:93][C:92]([O:95][C:96]5[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=5)=[CH:91][CH:90]=4)[C:85]([C:86]([NH2:88])=[O:87])=[C:81]3[NH:80][CH2:79]C2)C=CC=1)=O>>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[N:82]2[N:83]=[C:84]([C:89]3[CH:94]=[CH:93][C:92]([O:95][C:96]4[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=4)=[CH:91][CH:90]=3)[C:85]([C:86]([NH2:88])=[O:87])=[C:81]2[NH:80][CH2:79][CH2:11]1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Reactant: CC(=O)c1ccccc1[N+](=O)[O-]
Agent: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Agent: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(-c3cccc(N)c3)ccnc12
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1ccccc1N

Procedure:
The desired product was prepared from 1-(2-nitrophenyl)ethanone and 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile according to the procedures similar to those for 7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (step 4 to step 5), compound 2 (step 1 and 2) and compound 68 (step 8) under appropriate conditions recognized by one of ordinary skill in the art. 1H NMR (DMSO-d6) δ 7.48-7.44 (m, 2H), 7.40-7.33 (m, 2H), 7.15-7.09 (m, 1H), 7.05-6.97 (m, 4H), 6.92 (td, J=8.0, 1.2 Hz, 1H), 6.75 (br s, 1H), 6.64 (dd, J=8.0, 1.2 Hz, 1H), 6.46 (td, J=7.6, 1.2 Hz, 1H), 6.23 (dd, J=7.6, 1.2 Hz, 1H), 5.57-5.52 (m, 1H), 5.19 (br s, 2H), 3.27-3.17 (m, 1H), 2.93 (td, J=2.8, 12.0 Hz, 1H), 2.21-2.11 (m, 1H), 2.10-2.05 (m, 1H). MS (ESI) m/e [M+1]+ 426.0.
Reaction SMILES: CS([C:5]1[N:17]=[C:8]2[N:9]=[C:10]([CH2:15][CH3:16])[CH:11]=[C:12]([CH2:13][CH3:14])[N:7]2[N:6]=1)(=O)=O.[O:18]([CH2:25][CH2:26][NH2:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:15]([C:10]1[CH:11]=[C:12]([CH2:13][CH3:14])[N:7]2[N:6]=[C:5]([NH:27][CH2:26][CH2:25][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:17]=[C:8]2[N:9]=1)[CH3:16]
Reactant: NCCOc1ccccc1
Reactant: CCc1cc(CC)n2nc(S(C)(=O)=O)nc2n1
Product: CCc1cc(CC)n2nc(NCCOc3ccccc3)nc2n1
Temperature: 115 °C
Reaction time: 72 h

Procedure:
A mixture of 2-methanesulfonyl-5,7-diethyl-[1,2,4]-triazolo[1,5-a]pyrimidine (4.5 g, 17.7 mmol) and 2-phenoxyethylamine (24.3 g, 177.2 mmol) was added to a 100 mL RBF with a magnetic stirring bar, and the flask was fitted with a condenser. The mixture was allowed to stir at 110-120° C. for 72 hours. Progress of the reaction was monitored by analytical HPLC with UV detection where the title compound eluted with retention time of 5.1 min. The reaction was allowed to cool to room temperature and partitioned between dichloromethane (150 mL) and 2 N HCl (100 mL). The acidic layer was extracted with dichloromethane (100 mL), and the combined organic layers were washed with saturated aqueous NaCl (75 mL). The NaCl layer was extracted with dichloromethane (75 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was added to chloroform (25 mL) and methanol (0.5 mL), and a precipitate was removed by filtration. The material in the organic layer was purified by silica gel chromatography with a gradient elution of 0.75-3.0% ethanol in chloroform. Fractions were pooled and concentrated under reduced pressure, and the solid material was crystallized from hot ethanol (35 mL) to afford the title compound as an off white solid (3.26 g, 59% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.27 (m, 2H), 7.03 (t, 1H), 6.96 (m, 3H), 6.85 (s, 1H), 4.13 (t, 2H), 3.61 (q, 2H), 2.96 (q, 2H), 2.75 (q, 2H), 1.31 (t, 3H), 1.24 (t, 3H). EM (calc.): 311.2; MS (ESI) m/e: 312.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([C:13]([CH3:17])([CH3:16])[CH:14]=[O:15])=[CH:6][C:5]2=[O:18].I[CH2:20][CH2:21][CH2:22][CH3:23]>CC#N.[Ag]>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([C:13]([CH3:16])([CH3:17])[CH:14]=[O:15])=[CH:6][C:5]2=[O:18])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCI
Reactant: CC(C)(C=O)C1=CC(=O)c2cc(O)ccc2C1=O
Agent: [Ag]
Solvent: CC#N
Product: CCCCOc1ccc2c(c1)C(=O)C=C(C(C)(C)C=O)C2=O
Temperature: 25 °C

Procedure:
A mixture of 2-(6-Hydroxy-1,4-dioxo-1,4-dihydro-2-naphthalenyl)-2-methylpropanal (compound 3 prepared in step II above) (125 mg, 0.52 mmol) and freshly prepared Ag2O (240 mg, 1.04 mmol) in CH3CN was ultrasonicated for 2 min to disperse the silver salt. Iodobutane (120 μL, 1.05 mmol) was added and the mixture was stirred over night at room temperature. The mixture was filtered on Celite and was washed with EtOAc. The crude product was purified on silica gel with hexane:EtOAc 4:1 but failed to yield pure material. The product was further purified on RP-HPLC. Yield: 53 mg (34%). 1H NMR (400 MHz, CDCl3) δ 0.99 (tr., 3H), 1.40 (s, 6 H), 1.52 (sext., 2 H), 1.82 (quint., 2 H), 4.11 (tr., 2H), 6.87 (s, 1 H), 7.18 (dd, 1 H), 7.48 (d, 1 H), 8.00 (dd, 1 H), 9.72 (s, 1 H).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]2[CH2:9][CH2:10][N:11]=[C:7]2[CH:6]=[C:5]([Cl:12])[N:4]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>>[ClH:12].[CH3:2][C:3]1[N:8]2[CH2:9][CH2:10][N:11]=[C:7]2[CH:6]=[C:5]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:4]=1
Reactant: CC1=NC(Cl)=CC2=NCCN12
Reactant: C1CCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1=NC(N2CCCC2)=CC2=NCCN12
Reaction time: 3 h

Procedure:
A reaction mixture was prepared from 2.0 g. of 5-methyl-7-chloro-2,3-dihydroimidazo[1,2-c]pyrimidine hydrochloride and 0.7 g. of pyrrolidine in a saturated aqueous sodium bicarbonate solution. The reaction mixture was allowed to remain at ambient temperature for about three hours, after which time the solvent was removed in vacuo. The resulting residue was heated in ethanol. Solids were separated by filtration and dilute aqueous hydrochloric acid was added to the ethanolic filtrate. The solvent was removed from the filtrate in vacuo to yield 5-methyl-7-pyrrolidino-2,3-dihydroimidazo[1,2-c]pyrimidine hydrochloride formed in the above reaction which decomposed above 245° C. after recrystallization from an ethanol-ethyl acetate solvent mixture.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)=[C:8]([C@H:17]([OH:31])[C@@H:18]2[O:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2)[CH:7]=[CH:6][CH:5]=1.BrC[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>C1COCC1>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][O:31][C@@H:17]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([F:3])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1)[C@@H:18]1[O:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19]1)[CH3:39]
Reactant: Cc1cccc(-c2c(F)cccc2[C@H](O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Reactant: CCOC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CO[C@@H](c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
To a slurry of 60% NaH in oil (0.75 g, 18.7 mmol) in THF (30 mL) was added a solution of (R)-tert-butyl 2-((S)-(6-fluoro-3′-methylbiphenyl-2-yl)(hydroxy)methyl)morpholine-4-carboxylate (2.5 g, 6.23 mmol) in THF (20 mL) dropwise at and then the reaction mixture was stirred for about 1 h at rt. A solution of ethyl 3-bromopropionate (1.55 g, 9.35 mmol) in THF (20 mL) was added dropwise while the temperature was maintained at −15 to −5° C. The mixture was allowed to warm slowly to rt and stirred for ˜2 h until the reaction was complete by tlc analysis. The reaction was cooled in an ice bath, quenched with satd aq NH4Cl (120 mL) and extracted with EtOAc. The combined organic extracts were washed with brine, dried over NaSO4, concentrated and purified by flash chromatography to afford (R)-tert-butyl 2-((S)-(2-ethoxy-2-oxoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (570 mg, 19%). MS (E/Z): 488 (M+H+)
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)(O)[O-].[Na+].[C:15](OC([O-])=O)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C(OCC)(=O)C>[C:18]([O:17][C:15]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)CC1
Yield: 85.2 %

Procedure:
4-Piperidone monohydrate hydrochloride (5 g, 0.033 mol) was added to 50 mL distilled water and stirred until dissolved. To this solution was added solid sodium bicarbonate (3 g, 0.035 mol) followed by tert-butyl dicarbonate (7.2 g, 0.033 mol), and the resulting clear solution was stirred for 20 hours at room temperature. The slurry was treated with 100 mL of ethyl acetate and stirred until all solids dissolved. The layers were separated, and the organic layer was washed with 30 mL of 1N H3PO4 and 30 mL of 10% NaCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 5.6 g (86%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 3.75-3.68 (t, 4H), 2.47-2.40 (t, 4H), 1.5 (s, 9H). MS (DCl/NH3) m/e 200 (M+H)+, 217 (M+H+NH3)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH:17](Br)([CH3:19])[CH3:18]>CN(C)C=O.CC(C)=O>[CH:17]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([CH3:19])[CH3:18]
Reactant: CC(C)Br
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC(C)Oc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A solution of 2-nitrophenol (10 g, 71.9 mmol) and potassium carbonate (21.85 g, 158.1 mmol) in N,N-dimethylformamide:acetone (1:2, 150 mL) was heated under reflux and isopropyl bromide (14.8 mL, 158 mmol) was added dropwise (in 30 minutes) during reflux and stirred overnight. The reaction was cooled to room temperature and partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% ethyl acetate:hexanes) to provide the title compound as a golden yellow oil (11.5 g, 88%). 1H NMR (300 MHz, CDCl3) δ 1.4 (d, 6H, J=6 Hz), 4.7 (septet, 1H, J=6 Hz), 6.98 (m, 1H), 7.09 (d, 1H, J=9 Hz), 7.45 (m, 1H), 7.78 (dd, 1H, 3 Hz); MS (DCI/NH3) m/e 182 (M+H)+.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[NH2:16][OH:17]>C(O)C>[OH:17][NH:16][C:1](=[NH:2])[N:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:7][CH2:8]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Temperature: 0 °C
Yield: 83.8 %

Procedure:
1,1-Dimethylethyl 4-cyanopiperazine-1-carboxylate (10 g, 47.1 mmol) was taken into ethanol (100 mL) and the resulting solution was cooled to 0° C. Hydroxylamine (50% aqueous solution, 3.5 mL, 56.5 mmol) was added and the mixture was allowed to warm to room temperature then stirred an additional hour. The mixture was then concentrated in vacuo to a paste and suspended in 1:1 ethyl ether/hexane (100 mL) and the solid product collected by filtration. The solid was washed with an additional portion of ethyl ether/hexane then dried to give 1,1-dimethylethyl 4-[(hydroxyamino)(imino)methyl]piperazine-1-carboxylate (9.64 g, 83% yield) as a white solid. 1H-NMR (400 MHz, DMSO-d6): 8.34 (s, 1H), 5.19 (s, 2H), 3.30 (tr, 4H), 2.91 (tr, 4H), 1.39 (s, 9H).