Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]1[C:12]2[O:13][C:14]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH:1](=[C:8]1[C:12]2[O:13][C:14]3[CH:21]=[C:20]([O:22][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCN1CCOCC1
Reactant: O=c1c2c(oc3cc(O)ccc13)C(=Cc1ccccc1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c2c(oc3cc(OCCN4CCOCC4)ccc13)C(=Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
3-Benzylidene-6-hydroxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one (1.2 g) was reacted with 4-(2-chloro-ethyl)-morpholine (1.15 g) in dimethylformamide (50 ml), in the presence of anhydrous K2CO3 (1.7 g), under stirring for 4 hours at room temperature and then for 1 hour at 70° C. The reaction mixture was diluted with ice water containing NaH2PO4 and the precipitated product was filtered and washed with water. Crystallization from CH2Cl2 /isopropyl alcohol gave 0.9 g of 3-benzylidene-6-(2-morpholino-ethoxy)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one, m.p. 167°-169° C.
Reaction SMILES: [OH:1][C@H:2]([C@H:12]([OH:21])[C@H:13]([OH:20])[C:14]#[C:15][C:16]#[C:17][C:18]#[CH:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:22](OCC)(=O)C>C(OCC)C>[OH:1][C@H:2]([C@H:12]([OH:21])[C@H:13]([OH:20])[C:14]#[C:15][C:16]#[C:17][C:18]#[CH:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:22])=[O:10]
Reactant: C#CC#CC#C[C@@H](O)[C@@H](O)[C@@H](O)CCCCCCC(=O)O
Reactant: CCOC(C)=O
Solvent: CCOCC
Product: C#CC#CC#C[C@@H](O)[C@@H](O)[C@@H](O)CCCCCCC(=O)OC
Reaction time: 0.17 h

Procedure:
A quantity of a 1 mg/ml solution in ethyl acetate of 8(S),9(S),10(R)-trihydroxy-11,13,15-hexadecatriynoic acid (10 ml, 34.2 μmols) was stirred at ambient temperature in a flask equipped with a vacuum adapter. A solution of CH2N2 in diethyl ether (1 ml) was added and the progress of the reaction followed by thin layer chromatography. After 10 minutes, vacuum was applied and the excess CH2N2 was removed. The mixture was partially concentrated to 0.2 ml and applied to a short silica gel column. The desired material was eluted with diethyl ether. After partial concentration, the solvent was replaced by repeated removal of CDCl3 under reduced pressure and the reaction quantized by nmr spectroscopy (using an internal standard) to establish recovery of the title compound (6.8 mg, 65%). Structure assignment was supported by the nmr spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:37][C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)CBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(O)c3)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
100 mg of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol (described later, produced in Intermediate Production Example 2) was dissolved in 1 ml of N,N-dimethylformamide, and to this was added 34 mg of anhydrous potassium carbonate, and 37 mg of methyl bromoacetate was added with stirring at room temperature, then, the mixtures was stirred for 1 hours at 60° C. The reaction solution was cooled to room temperature, then, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 110 mg of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate [Compound 2-11 of the present invention].
Reaction SMILES: CC1(C)CCCC(C)(C)N1.O1CCCC1.C([Li])CCC.[F:21][C:22]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].[I:31]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[F:21][C:22]1[C:29]([I:31])=[C:28]([CH3:30])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: Cc1ccc(C#N)c(F)c1
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C#N)c(F)c1I
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a mixture of 2,2,6,6-tetramethyl-piperidine (4.50 mL, 26.6 mmol) and tetrahydrofuran (40 mL, 500 mmol) at −78° C. was slowly added n-butyllithium (2.5 mol/L in hexane, 11.5 mL, 28.8 mmol). The reaction vessel was transferred to a 0° C. ice bath for 60 minutes and then recooled at −78° C. 2-fluoro-4-methylbenzonitrile (3.1095 g, 23.010 mmol) as a solution in tetrahydrofuran (20 mL, 200 mmol) was then slowly added. The reaction mixture was stirred at −78° C. for 2 hours, and then a solution of iodine (7.33 g, 28.9 mmol) in tetrahydrofuran (10 mL, 100 mmol) was slowly added and then the reaction mixture was allowed to warm to room temperature. After 1.5 hours the reaction mixture was poured into a solution of sodium thiosulfate (20 g) in water (40 mL) and stirred at room temperature for 15 minutes. The layers were separated, and the aqueous layer extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (80 g silica, solvent gradient 0-10% ethyl acetate in heptanes) to yield a mixture of regioisomeric products, with the desired product as the major component (3.9385 g, 76% pure). LCMS (ESI): M+H=262.1; 1H NMR (400 MHz, CDCl3) δ 7.51-7.44 (m, 1H), 7.14 (d, J=7.9 Hz, 1H), 2.56 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[CH3:22]O>S(=O)(=O)(O)O>[CH3:22][O:11][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:8]=1[O:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=1
Reactant: COc1ccc(Oc2ccc([N+](=O)[O-])cc2C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccc(OC)cc1
Reaction time: 16 h

Procedure:
2-(4-Methoxy-phenoxy)-5-nitro-benzoic acid (2.5 g), (DE 2058295) in methanol (75 ml) containing conc. sulfuric acid (3 drops) was boiled for 16 h. Solvent was removed at reduced pressure, the residue dissolved in ethyl acetate and washed with aqueous sodium hydrogen carbonate. The organic phase was dried (Na2SO4) and solvent removed at reduced pressure to give 2-(4-methoxy-phenoxy)-5-nitro-benzoic acid methyl ester (2.50 g). m/z (API+): 304 (MH+).
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[C:17]#[CH:18]>CN(C)C=O.CCOC(C)=O.O>[Br:9][C:6]1[CH:7]=[CH:8][N:3]2[N:2]=[CH:18][C:17]([C:16]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]2[CH:5]=1
Reactant: C#CC(=O)OCC
Reactant: N[n+]1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cnn2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.5 %

Procedure:
Into a 250-mL three neck round-bottom flask, was placed a solution of 1-amino-4-bromopyridin-1-ium iodide (compound 64.2, 15 g, ˜50% purity, 24.9 mmol) in N,N-dimethylformamide (80 mL). Potassium carbonate (10.6 g, 76.7 mmol) was added portion-wise followed by the addition of ethyl propiolate (11.7 mL, 115 mmol) drop-wise over 10 min. The resulting mixture was stirred overnight at room temperature, then diluted with EtOAc (300 mL) and water (100 mL). The solids were removed by filtration and the organic layer was washed with brine (3×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:10) as the eluent to yield the title compound as a brown solid (300 mg, 6%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH2:20][OH:21])[CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)#[N:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH:20]=[O:21])[CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)#[N:2]
Reactant: COC(=O)c1ccc(CCC(CO)CCCCC#N)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCC(C=O)CCCCC#N)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 2.23 g (7.71 mmol) of methyl 4-(7-cyano-3-hydroxymethylheptyl)benzoate in 100 ml of dichloromethane is mixed with 1.99 g (9.26 mmol) of pyridinium chlorochromate (PCC) and stirred at room temperature for 6 hours. After conversion is complete, the solvent is concentrated to dryness in vacuo. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). 1.50 g (9.09 mmol, 68% of theory) of an oil are obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[C:10]([Cl:18])[C:11]([Cl:17])=[C:12]([OH:16])[CH:13]=2)[C:8]1=[O:19])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].Cl>CN(C)C=O.O>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[C:10]([Cl:18])[C:11]([Cl:17])=[C:12]([O:16][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:13]=2)[C:8]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC1Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CCOC(C)=O)C2
Temperature: 60 °C
Yield: 96.3 %

Procedure:
2-(Acetoxyethyl)-6,7-dichloro-2,3-dihydro-5-hydroxy-1H-inden-1-one (5.8 gm, 0.0191 mole), potassium carbonate (3.97 gm, 0.0287 mole), methyl bromoacetate (3.52 gm, 0.023 mole) in dry N,N-dimethylformamide (35 ml) were stirred and heated at 60° C. for 3 hours. The mixture was cooled and poured into a mixture of water and ice containing hydrochloric acid. The resulting mixture was extracted with a mixture of ether and tetrahydrofuran then methylene chloride. The combined organic extracts were washed with water, then with brine and finally dried over MgSO4. Evaporation of the solvent gave 6.9 gm of residue which was purified by column chromatography using silica (300 gm) and eluting with a 50/1 mixture of methylene chloride and tetrahydrofuran. Combining the appropriate fractions and evaporating the solvent gave 3.3 gm of product, m.p. 111°-113° C.
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][C:32](O)([C:35]#[C:36][C:37]([O:39][CH3:40])=[O:38])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])O.[Na+]>ClCCl>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH:31]=[C:32]([C:35]#[C:36][C:37]([O:39][CH3:40])=[O:38])[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)C#CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C#CC1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
Pyridine (1.12 ml) and trifluoromethanesulfonic anhydride (875 μl) were added dropwise to a solution of 1-(tert-butoxycarbonyl)-4-hydroxy-4-(methoxycarbonyl-ethynyl)piperidine (490 mg) in dichloromethane (15 ml) at −78° C. After heating the mixture to room temperature in 1 hour, a saturated aqueous solution (50 ml) of sodium hydrogencarbonate and dichloromethane (10 ml) were added to the reaction mixture to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1→2:1) to obtain the title compound (249 mg) as a pale yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]([C:13]#[N:14])=[CH:6][C:7]([CH3:12])([CH3:11])[CH2:8][CH:9]=[CH2:10])C.[H][H].[ClH:18]>C(O)C.O=[Pt]=O>[ClH:18].[NH2:14][CH2:13][CH:5]([CH2:6][C:7]([CH3:11])([CH3:12])[CH2:8][CH2:9][CH3:10])[C:4]([OH:15])=[O:3]
Reactant: C=CCC(C)(C)C=C(C#N)C(=O)OCC
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CCCC(C)(C)CC(CN)C(=O)O

Procedure:
2-Cyano-4,4-dimethyl-hepta-2,6-dienoic acid ethyl ester (5.88 g, 28 mmol) was dissolved in the mixture of 91 mL of ethanol and 6 mL of HCl and treated with 0.4 g of PtO2. The reaction was carried out under 100 psi of hydrogen pressure at room temperature for 15 hours. The catalyst was filtered and filtrate was concentrated to give 3.8 g of the desired product 2-aminomethyl-4,4-dimethyl-heptanoic acid ethyl ester as an oil. MS (APCI): 216.2 (M+1)+. This oil was refluxed in 75 mL of 6N HCl for 18 hours. While the reaction was cooled, a precipitate formed. The solid was filtered, washed with additional HCl solution and triturated with ether to give the clean title compound. MS (APCI): 188.1 (M+1)+. 186.1 (M−1)+. 1H NMR (400 MHz; CD3OD): 0.91 (9H, m), 1.30 (5H, m), 1.81 (dd, 1H, J=7.2 Hz, 14.4 Hz), 2.72 (1H, m), 3.04 (2H, m); Anal. Calc'd for C10H21NO2.HCl: C: 53.68, H: 9.91, N: 6.26, Cl: 15.85; Found: C: 53.83, H: 10.15, N: 6.22, Cl: 15.40. MP: 229.5–231.0° C.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][CH3:9])([CH2:6][OH:7])[CH2:4][OH:5])[CH3:2].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([N+]([O-])=O)[C:14]=1[C:15]#[N:16])([O-:12])=[O:11]>>[CH2:1]([C:3]([CH2:6][OH:7])([CH2:8][CH3:9])[CH2:4][O:5][C:17]1[CH:18]=[CH:19][CH:20]=[C:13]([N+:10]([O-:12])=[O:11])[C:14]=1[C:15]#[N:16])[CH3:2]
Reactant: CCC(CC)(CO)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CCC(CC)(CO)COc1cccc([N+](=O)[O-])c1C#N
Yield: 86 %

Procedure:
Prepared as in Example 215c from 2,2-diethylpropane-1,3-diol and 2,6-dinitrobenzonitrile in 86% yield. 1H NMR (400 MHz, DMSO-d6) δ 0.80 (t, J=7.6 Hz, 6H), 1.34 (q, J=7.6 Hz, 4H), 3.33 (d, J=5.6 Hz, 2H), 3.96 (s, 2H), 4.57 (t, J=5.2 Hz, 1H), 7.74-7.76 (m, 1H), 7.84-7.90 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:3]=1.[CH2:12]([O:19][CH2:20][C:21](Cl)=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>CC(C)=O.O>[NH2:11][S:8]([C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[CH2:20][O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:9])=[O:10]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(Cl)COCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NS(=O)(=O)c1cccc(NC(=O)COCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
A suspension of 1-aminobenzene-3-sulfonamide (1 g; 5.8 mmol; 1 eq) in a mixture of acetone (10 mL) and water (10 mL) is stirred at room temperature until complete dissolution. Benzyloxyacetyl chloride (1.4 mL; 8.7 mmol; 1.5 eq) is added at 0° C. followed by the addition of NaHCO3 (1.4 g) over 15 min. After 30 min, the reaction mixture is allowed to stir at room temperature for 2 h. The reaction mixture is then filtered off and the solid residue is washed with MeOH and ACN. The filtrate is concentrated to dryness, affording 1.8 g (97%) of the title compound as a brown foam. 1H NMR (DMSO-d6) δ 8.25 (br s, 1H), 7.81-7.75 (m, 1H), 7.55-7.48 (m, 2H), 7.42-7.28 (m, 8H), 4.62 (s, 2H), 4.13 (s, 2H). HPLC (max plot) 91%; Rt 2.53 min. UPLC/MS: (ES+) 321.2; (ES−) 319.2.
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+].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][NH:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Fc1cccc2c1CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(F)cccc21
Yield: 69.5 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 274 mg of 4-fluoro-2,3-dihydro-1H-indole, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of N,N-dimethylformamide. 249 mg of 2-[2-(4-fluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: I.[N:2]([C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([C:15]([F:18])([F:17])[F:16])[N:8]=[CH:7][CH:6]=1)=[N+]=[N-]>ClCCl>[NH2:2][C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([C:15]([F:18])([F:16])[F:17])[N:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1c(N=[N+]=[N-])ccnc1C(F)(F)F
Agent: I
Solvent: ClCCl
Product: COC(=O)c1c(N)ccnc1C(F)(F)F
Yield: 50.9 %

Procedure:
Cold (0° C. ice bath) concentrated hydriodic acid (182 mL of a 57% aqueous solution) is added to methyl 4-azido-2-(trifluoromethyl)nicotinate (7.50 g, 30.5 mmol) in a flask. The mixture is stirred at 0° C. until TLC (ethyl acetate-hexanes, 75:25) shows complete consumption of starting material. The mixture is poured over an ice cold solution of potassium hydroxide (95 g of solid KOH dissolved in 300 mL of water). The mixture is extracted with diethyl ether. The ethereal layer is washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a yellow solid. The solid is dissolved in a minimal amount of dichloromethane and passed through a silica gel plug, eluting with ethyl acetate-hexanes (10:90). The eluant is concentrated to afford 3.42 g (51%) of methyl 4-amino-2-(trifluoromethyl)nicotinate as an off-white solid. 1HNMR (400 MHz, CD3OD), 8.11 (d, 1H), 6.93 (d, 1H), 3.878 (s, 3H). LC/MS (M+1)=221.2
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:11]=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=1>C(N(CC)CC)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][O:16][C:14]1[CH:13]=[N:12][CH:11]=[C:10]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=1
Reactant: C#Cc1ccccc1
Reactant: COc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccccc2)c1
Temperature: 80 °C
Yield: 65.6 %

Procedure:
Add phenylacetylene (0.180 mL, 1.6 mmol), copper (I) iodide (0.029 g, 0.15 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.053 g, 0.08 mmol) to a solution of 3-bromo-5-methoxypyridine (0.282 g, 1.5 mmol) in degassed triethylamine (8 mL) and heat at 80° C. for 16 h. Cool the reaction mixture to room temperature, filter through diatomaceous earth, wash with ethyl acetate, and concentrate. Purify the residue by silica gel chromatography, eluting with 50:50 to 0:100 hexanes:ethyl acetate to give the title compound (0.206 g, 66%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][C:18]2[CH:20]=[CH:21][C:22]([F:23])=[C:16]([F:15])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)c(F)c2)CC1

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and 3,4-difluoroaniline (3.09 g) was treated in the same manner as described in Preparation Example 37 to give light brown prism crystal of the title compound.
Reaction SMILES: Br.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[CH:12](OCC)=[O:13].C(N(CC)CC)C.O>C(OCC)(=O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][CH:12]=[O:13])=[CH:5][CH:4]=1
Reactant: CCOC=O
Reactant: NCCc1ccc(Br)cc1
Agent: Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=CNCCc1ccc(Br)cc1
Yield: 93.1 %

Procedure:
500 g (1.78 mol) of 2-(4-Bromo-phenyl)ethylamine hydrobromide, 1 liter (12.4 mol) of ethyl formate and 248 mL (1.78 mol) of triethylamine were combined and heated to reflux for 3 hrs. The reaction was treated with 1 liter each of deionized water and ethyl acetate. The organic layer was separated and washed with 1 liter each of water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to yield 378 g of a solid.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([O:10][CH3:11])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].O.O[Li].O>C(#N)C>[C:15]([O:14][C:12]([N:6]1[CH2:7][C@H:8]([O:10][CH3:11])[CH2:9][C@@H:5]1[C:3]([OH:4])=[O:2])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)[C@H]1C[C@@H](OC)CN1C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: CC#N
Solvent: O
Product: CO[C@@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
Into a solution of 5 (2.54 g, 9.80 mmol) in acetonitrile (20 mL) was added water (20 mL) and LiOH.H2O (1.64 g, 39.2 mmol). The mixture was stirred at RT for 28 h before removing the acetonitrile under reduced pressure. EtOAc was added to the residue that was then washed with 1N HCl. The aqueous layer was extracted with additional EtOAc and the combined organic layers were washed with brine and dried over MgSO4. The solution was concentrated under reduced pressure to reveal 6 (2.16 g, 90%) as a white solid. MS: APCI (AP−): 244.1 (M)−.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:10][C:9]([C:11]2[S:12][C:13]([Sn](CCCC)(CCCC)CCCC)=[CH:14][CH:15]=2)=[CH:8][CH:7]=1)CCC.Br[C:38]1[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[CH:40][CH:39]=1>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:44]([C:41]1[CH:42]=[CH:43][C:38]([C:13]2[S:12][C:11]([C:9]3[S:10][C:6]([C:38]4[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[CH:40][CH:39]=4)=[CH:7][CH:8]=3)=[CH:15][CH:14]=2)=[CH:39][CH:40]=1)([CH3:46])[CH3:45]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2ccc([Sn](CCCC)(CCCC)CCCC)s2)s1
Reactant: CC(C)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)c1ccc(-c2ccc(-c3ccc(-c4ccc(C(C)C)cc4)s3)s2)cc1
Yield: 61.6 %

Procedure:
A solution of 1.8 g of 5,5′-bis(tributylstannyl)-2,2′-bithiophene, 1.3 g of 1-bromo-4-isopropylbenzene, and 80 mg of Pd(PPh3)4 in 35 milliliters (“mL”) of N,N-dimethylformamide was heated at 70° C. for 2 days under nitrogen. After cooling, 0.6 g of yellow-green solid was obtained after washing with methanol and ether, verified pure by nuclear magnetic resonance spectroscopy (“NMR”), and used directly for film and crystal studies.