Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)=O.CC(C)=O.[H-].[Na+].[C:32](N1C=CN=C1)(N1C=CN=C1)=[S:33]>O1CCCC1>[S:33]=[C:32]1[N:12]2[C:13]3[N:14]([C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH3:2])[CH:4]=4)=[CH:10][CH2:11]2)[N:15]=[CH:16][C:17]=3[C:18](=[O:19])[NH:20]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cc1cccc(C2=CCn3c(=S)[nH]c(=O)c4cnn2c43)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1.00 g of 4,5-dihydro-7-(3-methyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (prepared as described in Example 4) in dry tetrahydrofuran cooled to -78° C. (dry ice-acetone) is added sodium hydride (60% dispersion in mineral oil). The reaction mixture is stirred at -78° C. for 30 minutes then 1,1'-thiocarbonyldiimidazole is added. The mixture is allowed to slowly warm to room temperature and is stirred for 36 hours. Then reaction mixture is quenched with water, neutralized with 5% aqueous hydrochloric acid and extracted with chloroform. Evaporation of the solvent in vacuo gives 4,5-dihydro-5-thioxo-8-(3-methylphenyl)-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)(Cl)=O.C1COCC1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>O>[CH2:23]([N:25]([CH2:26][CH3:27])[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)[CH3:24]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CCNCC
Solvent: C1CCOC1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 4-methyl-3-nitrobenzoic acid (1.97 g) and thionyl chloride (6 mL) was heated under reflux for 18 hours. The reaction liquid was concentrated under reduced pressure, followed by an azeotropic process with toluene to give a red-brown oil. To a mixture of the red-brown oil and THF (25 mL), diethylamine (2.6 mL) was added under ice cooling and stirred at room temperature for 5 hours. The reaction liquid was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give N,N-diethyl-4-methyl-3-nitrobenzamide (2.61 g) as a brown oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13](=[O:20])[C:14](=[N+:18]=[N-:19])[C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH3:21]>C(#N)C>[NH2:21][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13](=[O:20])[C:14](=[N+:18]=[N-:19])[C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(=O)C(=[N+]=[N-])C(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: N
Solvent: CC#N
Product: CC(=O)C(=[N+]=[N-])C(=O)CCc1ccc(S(N)(=O)=O)cc1
Reaction time: 6 h

Procedure:
To a solution of 6-(4-chlorosulfonylphenyl)-3-diazo-2,4-hexanedione (1.0 g, 3.2 mmol) obtained in Example 3, (3) in acetonitrile (5 ml), 28% aqueous ammonia (2 g) was added dropwise at 5°-10° C., and stirring was continued for 6 h at room temperature. Then the mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel (Wako Gel C-200; manufactured by Wako Pure Chemical Industries, Ltd.) with n-hexane/ethyl acetate (from 5:1 to 2:1) as eluent to give the title compound as a white amorphous solid; yield: 800 mg; mp 109.5°-111.5° C.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([Br:13])=[CH:15][CH:16]=1)=[O:4]
Reactant: Nc1ccc(Br)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: Nc1ccccc1C(=O)Nc1ccc(Br)cc1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
1H-Benzo[d][1,3]oxazine-2,4-dione (A) (3.26 g, 20.0 mmol) and 4-bromo-aniline (H) (3.23 g, 18.8 mmol) were mixed together as a neat mixture (both solids), and the reaction mixture was stirred at 130° C. for 4 hours, and then cooled to room temperature. The crude compound was purified by the Simpliflash system (20% ethyl acetate in hexanes as eluent) to give 2-amino-N-(4-bromo-phenyl)-benzamide (J) as white solid. Yield: 4.35 g (75%).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])C.[OH-].[Na+]>C(O)C>[C:19]1([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([OH:27])=[O:3])=[CH:18][CH:17]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1
Reactant: CCCCCCC(Oc1ccc(C2=CCCCCCC2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(Oc1ccc(C2=CCCCCCC2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 34 g of α-[p-(1-cyclooctenyl)-phenoxy]-octanoic acid ethyl ester in 120 ml of ethanol are added 120 ml of 2N sodium hydroxide solution and the mixture is stirred for 11/2hours at room temperature. The reaction mixture is then evaporated to dryness in vacuo and the residue partitioned between N-hydrochloric acid and ether. The organic phase is washed until neutral, dried over sodium sulphate and evaporated to dryness in vacuo. The residue is distilled at 0.07 mm/205°-210° C. The distillate is crystallised from pentane at 0° C to yield the α-[p-(1-cyclooctenyl)-phenoxy]-octanoic acid of the formula ##STR10## which melts at 55°-57° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([O:12]CC=C)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].O1CCCC1.[C:33]([O:37][CH2:38][CH:39]=[CH2:40])(=[O:36])[CH:34]=[CH2:35]>O1CCCC1>[O:12]=[C:10]1[CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:35][CH:34]1[C:33]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36]
Reactant: C=CCOC(=O)CNC(=O)OC(C)(C)C
Reactant: C=CCOC(=O)C=C
Agent: C[Si](C)(C)[NH-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC1=O
Temperature: 3 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
An ice-cooled (3° C.) stirred solution of N-boc-glycine, allyl ester (6.46 g, 30 mmol) in anhydrous tetrahydrofuran (60 mL) under nitrogen was treated with 1N lithium bis(trimethylsilylamide)/tetrahydrofuran (33 mL, 33 mmol) at a rate to keep pot temperature below 10° C., then stirred at 3° C. for 15 min and cooled (−40° C.). A solution of allyl acrylate (4.45 mL, 35 mmol) in anhydrous tetrahydrofuran (25 mL) was added dropwise, and the mixture allowed to reach room temperature, stirred 1 h, and refluxed for 2 h. The mixture was cooled to room temperature, quenched with glacial acetic acid (2.5 mL), and concentrated. The residual oil was dissolved in methylene chloride (300 mL) and the solution washed with water and saturated sodium bicarbonate (150 mL each), dried (Na2SO4), and concentrated. The residue was dissolved in minimum methylene chloride and loaded onto a silica gel column (350 mL volume) and eluted with 55:30:15 heptane/methylene chloride/ethyl acetate to afford 3-allyl 1-tert-butyl 4-oxopyrrolidine-1,3-dicarboxylate (5.07 g, 63%) as a colorless oil. NMR (CDCl3): δ 5.85-6.00 (m, 1 H), 5.20-5.40 (m, 2 H), 4.60-4.75 (m, 2 H), 4.20 (m, 1 H), 3.95-4.10 (m, 1 H), 3.87 (d J=6.5 Hz, 1 H), 3.62 (t, J=8 Hz, 1 H), 1.48 (s, 9 H). MS (m+1): 270.4; MS (m−bu+1): 214.2.
Reaction SMILES: S(O[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])(=O)(=O)C.C(O[CH2:29][CH3:30])(=O)C>>[N:9]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:30][CH2:29][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: CCOC(C)=O
Product: CC(CN1CCCCCC1)N1c2ccccc2Sc2ccc(C#N)cc21

Procedure:
A solution of 2-(2-cyano-10-phenothiazinyl)propyl mesylate (9.05 g) in hexamethylenimine (28.2 cc) is brought to 90° C. for 16 hours. After cooling, the mixture is diluted with ethyl acetate (200 cc) and washed with distilled water (4×150 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is purified by chromatography on a column of 0.06-0.2 mm silica gel (height: 44 cm; diameter: 3.8 cm), eluting with mixture of cyclohexane and ethyl acetate in proportions (by volume) of 80:20 (500 cc) and 70:30 (1500 cc) and collecting 125-cc fractions. Fractions 7 to 15 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-[(2RS)-1-(perhydro-1-azepinyl)-2-propyl]-2-phenothiazinecarbonitrile (5.27 g) in the form of a yellow product of honey-like consistency.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[S:24][C:25]#N)[CH2:21][CH2:20][S:19]3)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].CI.[OH-].[K+]>CO.O>[C:12]([C:9]1[CH:8]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[S:24][CH3:25])[CH2:21][CH2:20][S:19]3)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(-c2nc3n(c2SC#N)CCS3)cc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CI
Product: CSc1c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)nc2n1CCS2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
In 10 ml of methanol was dissolved 1.3 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-thiocyanato-2,3-dihydroimidazo[2,1-b]thiazole and after cooling the solution to 0° C., 0.65 g of methyl iodide was added dropwise to the solution with stirring and further a solution of 0.2 g of potassium hydroxide dissolved in a mixture of 2 ml of water and 2 ml of methanol was added dropwise to the solution. After 30 minutes, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography using chloroform as the eluent and further recrystallized from ethanol to provide 0.18 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methylthio-2,3-dihydroimidazo[2,1-b]thiazole.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[Mg+2].[Cl-].[Cl-].CC(C)([O-])C.[K+].[C:21]([NH:28][C@@H:29](C(O)=O)[CH3:30])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].Cl>C1COCC1.C(N1C=CN=C1)(N1C=CN=C1)=O.CCOCC>[C:24]([O:23][C:21]([NH:28][C@H:29]([CH3:30])[C:3](=[O:5])[CH2:2][C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)CC(=O)OC(C)(C)C
Yield: 74.8 %

Procedure:
Flask A: To a clear solution of mono-tert-butyl malonate (29.3 mL, 190 mmol) and magnesium chloride anhydrous (Aldrich; 18.12 g, 190 mmol) in 400 mL THF in a 3 neck 3000 mL RBF with temperature probe and mechanical stirrer at 2° C. was added potassium tert-butoxide (1.0 M solution in THF, Aldrich; 190 mL, 190 mmol) slowly dropwise via addition funnel such that the temperature did not exceed 10° C. The reaction became cloudy over the addition and was easy to stir. the ice bath was removed, and the reaction was stirred at RT for 3 h. Flask B: To a clear solution of Boc-D-alanine (Chem Impex Intl.; 30.0 g, 159 mmol) in 300 mL THF at RT under N2 (fitted with N2 inlet and gas outlet to bubbler) was added 1,1′-carbonyldiimidazole (Aldrich; 0.926 g, 5.71 mmol) in three portions separated by 5 min. Gas evolution observed. The reaction was stirred 3 h. Then the contents in Flask B were added via funnel to Flask A and the cloudy white reaction was stirred 39 h at RT. The resulting white suspension was cooled in an ice bath and 500 mL 1 N HCl was added at a rate such that the internal temperature did not exceed 20° C. 0.8 L Et2O was added and the mixture transferred to a separatory funnel. The layers were separated and the organic layer was washed sequentially with 1×200 mL 1 N HCl, 1×200 mL water, 2×200 mL sat'd aq. NaHCO3, 1×200 mL brine, and was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting clear/colorless oil was treated with small crystals of the desired product and was further concentrated on the rotovap to give a white solid. The material was dried in vacuo for 2 h to give (R)-tert-butyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (34.3 g, 119 mmol, 75% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 5.15 (1H, br. s.), 4.30-4.51 (1H, m), 3.38-3.58 (2H, m), 1.48 (9H, s), 1.46 (9H, s), 1.37 (3H, d, J=7.2 Hz). m/z (ESI, +ve) 310.1 (M+Na)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)[CH3:8].[O:16]=[C:17]1[N:21]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[NH:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCl.C(O)(=O)C.ClCCCl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]([N:9]1[CH2:14][CH2:13][CH:12]([N:25]2[CH2:24][CH2:23][CH:22]([N:21]3[C:20]4[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=4[NH:18][C:17]3=[O:16])[CH2:27][CH2:26]2)[CH2:11][CH2:10]1)[CH3:8]
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CC(c1cnccn1)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(c1cnccn1)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.8 %

Procedure:
A mixture of 1-(1-(2-pyrazinyl)-ethyl)-4-oxopiperidine (37 mg), 4-(2-oxo-1-benzimidazolinyl)piperidine (41 mg), 1,2-dichloroethane (0.75 mL), glacial acetic acid (0.011 mL) and sodium triacetoxyborohydride (60 mg) was stirred at room temperature for 48 h. The reaction mixture was poured into dichloromethane (5 mL) and saturated aqueous Na2CO3 (3 mL) and the layers separated. The aqueous layer was extracted with dichloromethane (2×5 mL) and the combined organic layers dried over Na2SO4 and concentrated under reduced pressure. Purification by preparative TLC, eluting with chloroform; 10% methanol; 1% NH4OH, followed by trituration with diethyl ether gave 35 mg of (±)-1,3-dihydro-1-(1-{1-[1-(2-pyrazinyl)-1-ethyl]piperidin-4-yl}piperidin-4-yl)-2H-benzimidazol-2-one as a colorless solid: 1H NMR (400 MHz, CDCl3) 9.77 (br s, 1H), 8.69 (d, 1H), 8.54 (dd, 1H), 8.46 (d, 1H), 7.35 (m, 1H), 7.11-7.03 (m, 3H), 4.39 (m, 1H), 3.73 (q, 1H), 3.11 (m, 3H), 2.90 (m, 1H), 2.35-2.55 (m, 5H), 2.11 (m, 2H), 1.92-1.61 (m, 6H), 1.44 (d, 3H). Analysis calculated for C23H30N6O.0.1 H2O.0.3 CHCl3 : C: 63.01, H: 6.92, N: 18.92 found C: 63.07, H: 6.96, N: 18.76.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1.CO>CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:40]([NH:39][C:36]2[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)=[O:41])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: COc1ccc(N=C=O)cc1
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(NC(=O)Nc2nc3nc(NCCCN4CCN(C)CC4)ncc3cc2-c2c(Cl)cccc2Cl)cc1
Yield: 87 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 4-methoxyphenyl isocyanate (0.334 g) according to the general procedure of Example 37 to give 1.16 g of 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-(4-methoxy-phenyl)-urea, ESMS (20/80 MeOH/CH3CM+0.1% AcOH): M+ +H=595; mp 93.5°-100.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[S:8][C:7]=2[CH:25]=1.[Al+3].[Cl-].[Cl-].[Cl-].[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>ClCCCl>[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([C:10]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][C:7]=3[S:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:16]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc2cc(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc2c(C(=O)c3ccc(F)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To 671.4 mg of 6-methoxy-2-[4-[2-(1-pyrrolidinyl)-ethoxy]phenyl]benzo[b]thiophene (Example 1, Part B) in 10 mL of 1,2-dichloroethane was added 1.114 g of AlCl3 at 0° C., followed by dropwise addition of 0.30 mL of 4-fluorobenzoyl chloride. The deep red solution was stirred at 0° C. for 1 h and then at 0 to 15° C. for 19 h. The reaction was quenched by pouring the reaction mixture into 50 mL of ice-cold 2.0 N NaOH solution. The mixture was then extracted with 3×100 mL of EtOAc which was washed with 50 mL of H2O and brine. Combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography with 5 v/v % (10% conc NH4OH in MeOH) in CH2Cl2 to give 826.4 mg (92%) of the product ketone as viscous oil.
Reaction SMILES: CO[C:3](=[O:36])[CH:4]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:5][C:6]1[C:7]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:8][C:9]([NH:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[N:10][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([CH:4]2[C:3](=[O:36])[N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=4)[N:10]=[CH:11][C:6]=3[CH2:5]2)=[CH:29][CH:30]=1
Reactant: COC(=O)C(Cc1cnc(Nc2ccc(OC)nc2)nc1Nc1ccccc1)c1ccc(OC)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(C2Cc3cnc(Nc4ccc(OC)nc4)nc3N(c3ccccc3)C2=O)cc1
Temperature: 80 °C

Procedure:
To a solution of 3-[2-(6-methoxy-pyridin-3-ylamino)-4-phenylamino-pyrimidin-5-yl]-2-(4-methoxy-phenyl)-propionic acid methyl ester (45.0 mg, 0.09 mmol) (from Example 12c supra) in glacial acetic acid (1 mL) was added concentrated sulfuric acid (0.1 mL) in one portion. After heating at 80° C. for 3 hours, the reaction mixture was diluted with ethyl acetate (50 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by preparative thin layer chromatography to give 6-(4-methoxy-phenyl)-2-(6-methoxy-pyridin-3-ylamino)-8-phenyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidine-7-one as brown powder. (Yield 5.2 mg, 12.4%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1.[CH2:17]([C:21]1[CH:26]=[CH:25][C:24](Cl)=[CH:23][CH:22]=1)[CH2:18][CH2:19][CH3:20]>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].CC1C=CC(C(C2C=CC(C)=CC=2)C(=O)C(C)C)=CC=1.CC(O)(C)C>[CH2:17]([C:21]1[CH:26]=[CH:25][C:24]([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)=[CH:23][CH:22]=1)[CH2:18][CH2:19][CH3:20]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: CCCCc1ccc(Cl)cc1
Agent: [Pd]
Agent: Cc1ccc(C(C(=O)C(C)C)c2ccc(C)cc2)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: CCCCc1ccc(Nc2ccc(C(N)=O)cc2)cc1
Temperature: 110 °C
Yield: 87.6 %

Procedure:
An oven-dried resealable Schlenk flask was evacuated and backfilled with argon. The flask was charged with Pd2(dba)3 (4.6 mg, 0.005 mmol, 1 mol % Pd), Ligand 1 (9.4 mg, 0.02 mmol, 2 mol %), ground K2CO3 (193 mg, 1.4 mmol), and 4-amino-benzamide (163 mg, 1.2 mmol). The flask was evacuated and backfilled with argon (3×) and then capped with a rubber septum. To the flask was added t-BuOH (1.5 mL), 4-n-butyl-chlorobenzene (168 mg, 1.0 mmol) and t-BuOH (0.5 mL). The septum was replaced with a Teflon screwcap, the flask was sealed, and the mixture was heated to 110° C. with stirring until the starting aryl chloride was consumed by GC analysis (19 h). The reaction was cooled to room temperature, diluted with ethyl acetate, filtered through Celite, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (eluting with EtOAc/hexanes, 8:2) to give the desired product as a white solid (235 mg, 88%).
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH:7]=[CH:8][C:9]([CH3:12])(O)[CH3:10])=[CH:3][CH2:4][OH:5].[OH:13]C/C=C(/C)\CCC=C(C)C>>[OH:5][CH2:4][CH:3]1[O:13][C:2]1([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:12])[CH3:10]
Reactant: CC(=CCO)CC=CC(C)(C)O
Reactant: CC(C)=CCC/C(C)=C\CO
Product: CC(C)=CCCC1(C)OC1CO

Procedure:
Ohloff prepared the intermediate 3,7-dimethyl-octa-2,5-dien-1,7-diol from nerol by its photosensitized air oxidation followed by reduction and cyclisation with an acid to obtain racemic nerol oxide [G. Ohloff, K. H. Schulte-Elite & B. Willhalm Helv. Chim. Acta. 47, 602, 1964]. In another publication nerol was first subjected to epoxidation at C6–C7 double bond and the epoxy derivative so obtained was heated in dimethyl amine at 150° to give 3,7-dimethyl-6-dimethyl amino-2-octen-1,7-diol which on oxidation with hydrogen peroxide and pyrolysis at 180° C. gave a diol intermediate that on acid catalysed cyclisation led to the formation of nerol oxide [G. Ohloff & B. Lienhard Helv. Chim. Acta. 48, 182, 1965].
Reaction SMILES: [O-]CC.[Na+].C(=O)(O)O.[NH2:9][C:10]([NH2:12])=[NH:11].[C:13]1([NH:19][C:20]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:32][C:31](=O)[C:30](=[CH:34]N(C)C)[CH2:29]3)[CH:25]=[CH:24][N:23]=2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(O)C>[C:13]1([NH:19][C:20]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:29][C:30]4[CH:34]=[N:9][C:10]([NH2:12])=[N:11][C:31]=4[CH2:32]3)[CH:25]=[CH:24][N:23]=2)=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(C)C=C1CN(c2ccnc(C(=O)Nc3ccccc3)c2)CC1=O
Reactant: N=C(N)N
Agent: CC[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ncc2c(n1)CN(c1ccnc(C(=O)Nc3ccccc3)c1)C2
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 46.4 %

Procedure:
To a solution of sodium ethoxide (0.18 mL, 0.56 mmol, 3M) in ethanol (10 mL) was added guanidine carbonate (50 mg, 0.56 mmol). The suspension was stirred for 45 minutes, then added to a suspension of 4-(3-((Dimethylamino)methylene)-4-oxopyrrolidin-1-yl)-pyridine-2-carboxylic acid phenylamide (95 mg, 0.28 mmol) in ethanol (10 mL). The reaction mixture was heated at 80° C. for 18 hours. Water (20 mL) was added and the mixture stirred for 1 hour. The solid was isolated by filtration and vacuum dried at 50° C. for 115 h and gave the title compound (44 mg, 0.13 mmol, 47%).