Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.Cl.[NH2:26][OH:27]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2=[N:20][C:19](/[C:22](=[N:26]/[OH:27])/[CH3:23])=[CH:18][N:17]=[C:16]2[N:15]=[N:14]1
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Reactant: NO
Agent: Cl
Product: C/C(=N\O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 65 %

Procedure:
The title compound (68.0 mg, 62%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (100.0 mg, 0.31 mmol) and hydroxylamine hydrochloride (43.1 mg, 0.62 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.49 (bs, 1H), 9.31 (s, 1H), 8.92 (d, 1H), 8.40 (d, 1H), 8.18 (d, 1H), 7.82 (d, 1H), 7.54 (d, 1H), 6.22 (s, 2H), 2.23 (s, 3H). LCMS (method A): [MH]+=338, tR=5.15 min.
Reaction SMILES: C([Al](CC(C)C)CC(C)C)C(C)C.[OH:14][CH2:15]/[CH:16]=[C:17](/[CH3:24])\[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22].C(=O)C1OC=CC=1>C1(C)C=CC=CC=1>[CH3:23][C:21](=[CH:20][CH2:19][CH2:18][C:17](=[CH:16][CH:15]=[O:14])[CH3:24])[CH3:22]
Reactant: CC(C)=CCC/C(C)=C\CO
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: Cc1ccccc1
Solvent: O=Cc1ccco1
Product: CC(C)=CCCC(C)=CC=O

Procedure:
This example illustrates the use of triisobutylaluminum to generate the aluminum alkoxide catalyst. A flask was charged with 80 grams of nerol and 10 ml of a 25% solution of triisobutylaluminum in toluene. To the solution was added 39 grams (0.75 equivalents) of furfural and the solution was allowed to react at ambient temperature for 18 hours. Analysis by glpc showed that 69% of the nerol had been consumed to give citral in 98+% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[CH2:11](Br)[CH3:12]>>[CH2:11]([O:4][CH2:3][C:2]([CH3:10])([CH3:1])[CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7])[CH3:12]
Reactant: CC(C)C(O)C(C)(C)CO
Reactant: CCBr
Product: CCOCC(C)(C)C(O)C(C)C
Yield: 90 %

Procedure:
Treatment of 2,2,4-trimethylpentan-1,3-diol with ethyl bromide employing the alkylation reaction conditions described above provided 1-ethoxy-2,2,4-trimethylpentan-3-ol in 90.0% yield (313.2 g, b.p.=79–80 C./3.2 mmHg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][C:10]([OH:12])=[O:11].Cl>C1COCC1.O>[N:1]1([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)CBr
Reactant: c1c[nH]cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1ccnc1
Reaction time: 8 h
Yield: 31.3 %

Procedure:
Imidazole (3.7 g, 54 mmol) was added to a suspension of sodium hydride (2.6 g of a 60% dispersion in oil, 60 mmol) in 50 ml dry THF. Bromoacetic acid (3.4 g, 24 mmol) was then added and the mixture stirred overnight. Water (1 ml) was then added and the solvent removed under reduced pressure. The residue was taken up in water (50 ml, pH>10), extracted with ether and the organic layer discarded. The aqueous layer was acidified to pH 1 with concentrated HCl and extracted again with ether. The aqueous layer was evaporated to dryness. The oily residue was dissolved in absolute ethanol (EtOH) to precipitate NaCl, and recrystallized from acetone/methanol to give 1.22 g (7.5 mmol, 30%) pure product as the hydrochloride. 1H NMR: (DMSO-d6, 200 MHz) δ 9.20 (s, H2), 7.76 (d, J=1.5 Hz), 7.69 (d, J=1.5 Hz), 5.20 (s, CH2).0
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].C(N(C(C)C)CC)(C)C.[CH3:49][N:50]([CH3:54])[CH2:51][CH2:52][NH2:53]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:53][CH2:52][CH2:51][N:50]([CH3:54])[CH3:49])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CN(C)CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 42.1 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (300 mg, 0.54 mmol) in CH2Cl2 (30 mL) were added diisopropyl ethyl amine (0.2 mL, 1.14 mmol), N,N-dimethyl-ethylenediamine (0.3 mL, 2.7 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (131 mg, 42%). LC-MS m/z 576 (M+H)+; 1H-NMR (MeOD) δ 2.19 (s, 6H), 2.35 (s, 3H), 2.42 (m, br, 2H), 3.24 (m, br, 2H), 4.16 (s, 2H), 7.12 (m, 4H), 7.52 (m, 2H), 7.72 (m, 2H), 7.83 (s, 1H), 7.99 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][C:11]1[N:12]=[N:13][C:14]([NH:17][NH2:18])=[CH:15][CH:16]=1.[CH:19](=O)[C:20]([CH3:23])([CH3:22])[CH3:21].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[C:20]([C:23]1[N:13]2[N:12]=[C:11]([C:10]#[C:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH:16]=[CH:15][C:14]2=[N:17][N:18]=1)([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C)C=O
Reactant: NNc1ccc(C#Cc2ccc(F)cc2F)nn1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CC(C)(C)c1nnc2ccc(C#Cc3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
A mixture of 3-((2,4-difluorophenyl)ethynyl)-6-hydrazinylpyridazine (0.60 g, 2.4 mmol) and pivalaldehyde (0.31 g, 3.7 mmol) were dissolved in DCM (8 mL) and were stirred at ambient temperature for about 2 h. Iodobenzene diacetate (0.86 g, 2.7 mmol) was added and was stirred for about 2 h at ambient temperature. The reaction mixture was concentrated in vacuo and was purified by silica gel chromatography using DCM/MeOH (gradient, 0-2% MeOH) to afford the title compound (0.49 g, 64%): LC/MS (Table 1, Method a) Rt=2.50 min; MS m/z: 313.2 (M+H)+.
Reaction SMILES: C(O[C@H]1C[C@@H](C2C=CC=CN=2)OC2(CCNCC2)C1)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH:35]([O:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][C:40]=1[CH3:48])([CH3:37])[CH3:36]>ClCCl.O>[CH:35]([O:38][C:39]1[CH:47]=[CH:46][C:42]([CH:43]=[O:44])=[CH:41][C:40]=1[CH3:48])([CH3:37])[CH3:36]
Reactant: Cc1cc(C(=O)Cl)ccc1OC(C)C
Agent: CCO[C@H]1C[C@@H](c2ccccn2)OC2(CCNCC2)C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C=O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
To a solution of cis-8-ethoxy-10-(2-pyridyl)-11-oxa-3-azaspiro[5.5]undecane; 2,2,2-trifluoroacetic acid (42 mg, 0.11 mmol) in dichloromethane (1 mL) was added triethylamine (75 μL, 0.54 mmol). 4-isopropoxy-3-methyl-benzoyl chloride (46 mg, 0.21 mmol) (˜50% pure) was added. The mixture was stirred at rt for 15 min. Water was added. The aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (40-60% ethyl acetate-hex) to provide cis-8-ethoxy-10-(2-pyridyl)-11-oxa-3-azaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (37 mg). ESI-MS m/z calc. 452.27, found 453.3 (M+1)+; Retention time: 1.38 minutes (3 min run).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[CH:11][N:12]1[CH2:16][CH2:15][NH:14][C:13]1=[N:17][N+:18]([O-:20])=[O:19])[CH2:2][CH3:3].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:14]2[CH2:15][CH2:16][N:12]([CH:11]=[N:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH2:1][CH2:2][CH3:3])[C:13]2=[N:17][N+:18]([O-:20])=[O:19])=[CH:24][N:23]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCCc1ccccc1N=CN1CCNC1=N[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1ccccc1N=CN1CCN(Cc2ccc(Cl)nc2)C1=N[N+](=O)[O-]
Yield: 30.8 %

Procedure:
A mixture of 0.8 g of 1-(2-n-propylphenyliminomethyl)-nitroiminoimidazolidine, 0.42 g of 2-chloro-5-chloromethylpyridine, 0.36 g of potassium carbonate and 8 ml of acetonitrile were refluxed under heating conditions for 4 hours. The reaction mixture was evaporated and purified by column chromatography [silica gel, eluent: hexane-ethyl acetate (1:2)] to give 0.32 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(2-propylphenyliminomethyl)imidazolidine.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:27])[CH2:15][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:17]=2[F:26])[CH2:10][CH2:9]1)C1C=CC=CC=1>ClCCCl.ClC(OC(Cl)C)=O>[F:26][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([F:24])([F:25])[F:23])[C:16]=1[CH2:15][C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:27]
Reactant: O=C(Cc1c(F)cccc1C(F)(F)F)C1CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: O=C(Cc1c(F)cccc1C(F)(F)F)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.4 %

Procedure:
After dissolving 136 mg of 1-(1-benzylpiperidin-4-yl)-2-[2-fluoro-6-(trifluoromethyl)phenyl]ethanone in 3 ml of 1,2-dichloroethane, 0.06 ml of 1-chloroethyl chloroformate was added and the mixture was stirred at room temperature for 5 minutes and then heated to reflux for 45 minutes. The solvent was distilled off under reduced pressure, 10 ml of methanol was added to the residue and heating to reflux was continued for 30 minutes. The solvent was distilled off under reduced pressure, ammonia water was added to the residue and extraction was performed with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: ethyl acetate/methanol) to obtain the title compound (45 mg, 43% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20]I>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH3:20])[C:6]=2[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1COc2ccc(Br)c(Oc3ccccc3)c2N1
Reactant: CI
Product: CN1C(=O)COc2ccc(Br)c(Oc3ccccc3)c21

Procedure:
This compound was synthesized according to the procedure of Example 83, Step 1, using 6-bromo-5-phenoxy-2H-1,4-benzoxazin-3(4H)-one and methyl iodide as the starting materials. LCMS calculated for C18H13BrNO3 (M+H)+: m/z=334.0, 336.0. found: 333.9, 335.9.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:20])=[C:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)=O.[N+:21]([CH3:24])([O-:23])=[O:22].C([O-])(=O)C.[NH4+].C(O)(=O)C>>[CH3:20][C:4]1[C:3](/[CH:1]=[CH:24]/[N+:21]([O-:23])=[O:22])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(C=O)cccc1NC(=O)OCc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1c(/C=C/[N+](=O)[O-])cccc1NC(=O)OCc1ccccc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
A mixture of benzyl 3-formyl-2-methylphenylcarbamate (4.968 g, 18.45 mmol), nitromethane (2.478 mL, 46.1 mmol), and ammonium acetate (3.56 g, 46.1 mmol) in acetic acid (70 mL, 1223 mmol) was heated at 90° C. for 4.5 hr. The acetic acid was removed under vacuum. To the residue was added water (100 mL), and the mixture was stirred at room temperature for 30 min. The insoluble material was collected with suction filtration. The filter cake was mixed with water (100 mL) and the aqueous mixture was adjusted to pH 9 with saturated NaHCO3 solution and stirred at room temperature for 30 min. The insoluble product (4.13 g, 88% purity, 13.22 mmol, 71.7% yield) was collected as a yellow solid with suction filtration and dried over Drierite under vacuum.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[CH2:7]([O:6][C:5]([NH:4][CH2:3][CH2:2][O:1][N:16]1[C:17](=[O:26])[C:18]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]2[C:20]1=[O:21])=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(NCCO)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCON1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a solution of benzyl N-(2-hydroxyethyl)carbamate (5.9 g, 30 mmol), N-hydroxyphthalimide (4.9 g, 30 mmol), and triphenylphosphine (7.9 g, 30 mmol) in tetrahydrofuran (100 mL) was added diethyl azodicarboxylate (5.2 g, 30 mmol). The reaction mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added, the solution washed with saturated NaHCO3 (2×100 mL) and brine (100 mL), and dried over Na2SO4. After evaporating the solvent, the residue was purified by flash column chromatography (methylene chloride to 4% ethyl acetate in methylene chloride) to give the title compound as a white solid (9.3 g, 91%). 1H-NMR (300 MHz, CDCl3) δ7.84 (m, 2H), 7.78 (m, 2H), 7.37 (m, SH), 5.97 (br s, 1H), 5.14 (s, 2H), 4.27 (t, J=4.9 Hz, 2H), 3.51 (q, J=5.2 Hz, 2H).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:26]([O:30][C:31]([C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[CH:37][CH:38]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14]([NH:39][C:36]3[N:35]=[CH:34][C:33]([C:31]([O:30][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:32])=[CH:38][CH:37]=3)=[O:15])=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1ccc(N)nc1
Reactant: O=C(O)C(Nc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(Nc2ccc(F)cc2F)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Yield: 14 %

Procedure:
The compound of example A8 was obtained by similar method described in example A1 using 2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluoroanilino)acetic acid (Preparation 3, 0.150 g, 0.408 mmol), 6-aminopyridine-3-carboxylic acid tert-butyl ester (preparation 54, 0.095 g, 0.49 mmol), HOBT (0.082 g, 0.612 mmol), and EDCl (0.116 g, 0.612 mmol), N-methyl morpholine (0.103 g, 1.02 mmom) in DCM (4 mL) to provide the title compound (0.031 g).
Reaction SMILES: [CH3:1][C:2]([CH:6]1[CH:15]2[CH2:16][CH:17]=[CH:18][CH:14]2[C:13]2[CH:12]=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=[CH:9][C:8]=2[NH:7]1)([CH3:5])[CH2:3][NH2:4].[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>CN(C)C=O.O.C(OCC)(=O)C>[CH:22]([NH:25][C:26]([NH:4][CH2:3][C:2]([CH3:1])([CH:6]1[CH:15]2[CH2:16][CH:17]=[CH:18][CH:14]2[C:13]2[CH:12]=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=[CH:9][C:8]=2[NH:7]1)[CH3:5])=[O:27])([CH3:24])[CH3:23]
Reactant: CC(C)N=C=O
Reactant: CC(C)(CN)C1Nc2ccc([N+](=O)[O-])cc2C2C=CCC21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)NCC(C)(C)C1Nc2ccc([N+](=O)[O-])cc2C2C=CCC21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound of Example 49 (57 mg) was dissolved in 2 ml of dimethylformamide, and 0.03 ml of isopropyl isocyanate was added. After 30 minutes stirring at room temperature, the reaction mixture was diluted with water and ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:1) to obtain 62 mg of the captioned compound. Its physical properties are shown below.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1)(=[O:3])[CH3:2].[CH2:18]1COC[CH2:19]1>>[CH2:7]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[CH2:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:19][CH:18]=1.[C:1]([O:4][CH2:5][CH2:6][C:7]1([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH2:12]1)(=[O:3])[CH3:2]
Reactant: C1CCOC1
Agent: CC(=O)OCCC1(c2ccsc2)C=CC=CC1
Product: c1ccc(CCc2ccsc2)cc1
Reaction time: 0.5 h
Yield: 34 %

Procedure:
1-(3-thienyl)phenethyl acetate dissolved in THF (20 ml) was added carefully to dry liquid ammonia (300 ml). Lithium metal was added in small portions until the blue color persisted. The resulting reaction mixture was stirred for 30 min and the reaction was quenched by addition of solid ammonium chloride. The residue, after the complete evaporation of liquid ammonia, was dissolved in water (100 ml) and was extracted with methylene chloride (4×50 ml). The combined organic layer was dried over MgSO4 and filtered. Removal of the solvent gave a crude product, which was purified by column chromatography using hexane followed by mixture of ethyl acetate in hexane as eluent to give 3-phenethylthiophene (3.2 g, 34% yield) and 1-(3-thienyl)phenethyl acetate (starting material, 7 g).
Reaction SMILES: C=CC=C.[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[CH2:6].O1[C:17](=[O:18])[CH:16]=CC1=O.CC(C)=C.C(OCC1CO1)C(OCC1CO1)COCC1CO1>>[O:18]1[CH:17]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:7][CH:5]=[CH2:6])[CH2:16]1
Reactant: O=C1C=CC(=O)O1
Reactant: C=Cc1ccccc1
Agent: C(OCC1CO1)C(COCC1CO1)OCC1CO1
Agent: C=C(C)C
Agent: C=CC=C
Product: C=CCCCCCCC1CO1

Procedure:
2-Butenedioic acid (2Z)-sodium salt, polymer with 1,3-butadiene, ethenylbenzene, 2,5-furandione, 2-methyl-1-propene and 2,2′,2″-[1,2,3-propanethyltris(oxymethylene)]tris[oxirane], block (9Cl)
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][C:15]3[CH:30]=[CH:29][C:18]([C:19]([O:21]CC4C=CC=CC=4)=[O:20])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C:2]1([CH3:31])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][C:15]3[CH:30]=[CH:29][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2ccc(C(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)cc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CCSc2ccc(C(=O)Oc3ccc(C(=O)O)cc3)cc21

Procedure:
To a stirred solution of 580 mg (1.34) of benzyl 4-(4,4-dimethyl-6-thiochromanoyloxy)benzoate in 12 ml of methylene chloride at -10° C. under nitrogen was added slowly 1.24 ml of a 1.0 M (1.24 mmol) solution of boron tribromide in methylene chloride. The reaction mixture was stirred at -10° C. for a further 2h and then was quenched by the addition of ice. The organic layer was separated and the aqueous layer extracted with 2×25 ml methylene chloride. The organic extracts were combined and then washed with water and dried (MgSO4). The solution was then filtered and the solvent removed in-vacuo. The resultant residue was purified by flash chromatography (silica; 20% ethyl acetate in hexane followed by 100% ethyl acetate) and then recrystallization from a mixture of ethyl acetate and ethanol to give the title compound as a white solid. PMR (CDCl3): 6 1.39 (6H, s), 2.10 (2H, m), 3.10 (2H, m), 7.21 (1H, d, J~8.4 Hz), 7.28 (2H, d, J~8.7 Hz), 7.82 (1H, dd, J~8.4, 2.1 Hz), 8.14 (2H, d, J~8.7 Hz), 8.16 (1H, d, J~2.1 Hz).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:24]1([C:30]2[CH:31]=[N:32][C:33]([NH2:36])=[CH:34][CH:35]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:36][C:33]4[N:32]=[CH:31][C:30]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:35][CH:34]=4)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: Nc1ccc(N2CCCCC2)cn1
Solvent: Cc1ccccc1
Product: CCOCc1cc2cnc(Nc3ccc(N4CCCCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 15.2 %

Procedure:
8-Cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.60 g, 1.79 mmol) and 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamine (0.438 g, 2.47 mmol) were heated to reflux in toluene (6 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was filtered off and washed with toluene (2×4 mL) to give 8-cyclopentyl-6-ethoxymethyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (0.122 g, 15.2%). MS (APCl) Calc'd for M+1: 449.3. Found: 449.3. Anal. Calc'd for C25H32N6O2: C, 66.94; H, 7.19; N, 18.74. Found: C, 66.72; H, 7.13; N, 18.57.
Reaction SMILES: [CH3:1][C:2]1[O:6][CH2:5][C:4](=[O:7])[CH:3]=1.[Cl-].[Ca+2].[Cl-].[CH:11](=O)[C:12]1[CH:22]=[C:19]([O:20][CH3:21])[C:17]([OH:18])=[C:14]([O:15][CH3:16])[CH:13]=1.B(OC(CC)C)(OC(CC)C)OC(CC)C>ClCCl.C(N)CCC.C(OCC)(=O)C.O.C(O)(=O)C>[OH:18][C:17]1[C:19]([O:20][CH3:21])=[CH:22][C:12]([CH:11]=[C:5]2[C:4](=[O:7])[CH:3]=[C:2]([CH3:1])[O:6]2)=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: CC1=CC(=O)CO1
Agent: CCC(C)OB(OC(C)CC)OC(C)CC
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CCCCN
Solvent: O
Product: COc1cc(C=C2OC(C)=CC2=O)cc(OC)c1O
Temperature: 2.5 °C
Yield: 43.8 %

Procedure:
5-methyl-furan-3-one (2, 6.0 g g, 0.061 mol) was dissolved in dichloromethane (40 mL) and taken in a 3-necked 250 mL round bottomed flask fitted with a mechanical agitator and calcium chloride guard tube. Syringaldehyde (3c, 13.3 g, 0.073 mol) dissolved in dichloromethane (40 mL) was added. The mixture was cooled to 0-5° C. with stirring. Tri-sec-butyl borate (14.0 g, 0.061 mol) was added and stirred for 2 h. n-Butyl amine (4 drops) was added, the reaction mixture allowed to warm to room temp. on its own with stirring and stirred at room temp. overnight. The orange yellow color reaction mixture was poured into 5% aq. acetic acid solution (120 mL) preheated to 60° C. with stirring. This was stirred for 30 min., and then allowed to settle down. The dichloromethane layer was isolated and concentrated under reduced pressure to get an orange yellow color thick liquid. Water (20 mL), followed by ethyl acetate (100 mL) were added to this thick gummy material and the mixture concentrated under reduced pressure in a rotary evaporator until the product crystallized out. This was filtered, dried in vacuo at 110° C. to get pure 2-(4-Hydroxy-3,5-dimethoxy-benzylidene)-5-methyl-furan-3-one (4c) (7.0 g, 44% yield) as an orange yellow powder, m.p. 187.9-189.6° C.