Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:15]=1.[OH:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][NH:38][C:39]([C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](O)=[O:45])=[O:40].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[OH:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][NH:38][C:39](=[O:40])[C:41]1[CH:49]=[CH:48][CH:47]=[C:43]([C:44]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)=[CH:4][C:3]=2[C:14]2[CH:15]=[C:16]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[N:17]=[CH:18][N:19]=2)=[O:45])[CH:42]=1
Reactant: O=C(O)c1cccc(C(=O)NCCOCCO)c1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCOCCO)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 6-(2-amino-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-4-amine (300 mg, 0.70 mmol, 1.00 equiv) in N,N-dimethylformamide (6 mL). This was followed by the addition of 3-(2-(2-hydroxyethoxy)ethylcarbamoyl)benzoic acid (302.2 mg, 1.19 mmol, 1.70 equiv) at room temperature. To this was added triethylamine (156 mg, 1.54 mmol, 2.20 equiv). To the mixture was added EDC.HCl (148.2 mg, 0.78 mmol, 1.10 equiv) at room temperature, followed by HOBT (104.4 mg, 0.77 mmol, 1.10 equiv) at room temperature. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 83.6 mg (15%) of a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.76 (s, 1H), 8.40 (s, 1H), 8.039 (t, J=8.1 Hz, 2H), 7.74 (s, 1H), 7.63˜7.57 (m, 3H), 7.53˜7.50 (m, 2H), 7.47˜7.40 (m, 2H), 6.93 (s, 1H), 4.81 (s, 2H), 3.71˜3.58 (m, 8H), 3.43˜3.39 (m, 4H), 1.84˜1.81 (m, 6H). MS (ES, m/z): 663 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:12]2[F:19])=[C:4](N)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:23]>O>[F:19][C@@H:12]1[C@H:13]([OH:14])[C@@H:15]([CH2:17][OH:18])[O:16][C@H:11]1[N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:23])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3F)c2n1
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Temperature: 4 °C
Reaction time: 96 h

Procedure:
2,6-Diamino-9-(2-deoxy-2-fluoro-β-D-ribofuranosyl)-9H-purine (0.20 g, 0.64 mmole), prepared as in Example 6, was dissolved in 15 ml of water. Calf intestinal adenosine deaminase (4 I.U., Boehringer Mannheim) was added and the solution incubated at 37° for 4 days. The solution was cooled to 4° C. After 3 hrs, the suspension was filtered to remove the first batch of product crystals. The volume of the filtrate was reduced under vacuum and the suspension cooled to 4° C. The suspension was filtered to remove the second batch of product crystals. The batches of product crystals were combined, suspended in water and lyophilized to obtain title compound that analyzed as a 1.3 hydrate.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Reactant: CN1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCN(C)CC1
Temperature: 60 °C
Yield: 8.3 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 79A (225 mg, 0.426 mmol) in DMF (3 mL) was added N-methyl piperazine (0.141 mL, 1.278 mmol) followed by diisopropyl ethylamine (0.222 mL, 1.278 mmol) and tetrabutyl ammonium iodide (157.35 mg, 0.426 mmol). The reaction mixture was heated at 60° C. for 24 h. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (using phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea (21 mg, 8.3%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.60-7.25 (m, 5H), 6.45 (s, 1H), 4.35 (m, 2H), 4.00 (m, 3H), 2.80-2.25 (m, 10H), 2.15 (s, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 592 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:14]Br)[C:5](=[O:13])[N:6]([CH2:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.[C-:16]#[N:17].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:14][C:16]#[N:17])[C:5](=[O:13])[N:6]([CH2:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1
Reactant: [C-]#N
Reactant: O=c1c(CBr)cc(Br)cn1CC(F)(F)F
Agent: [Na+]
Solvent: CO
Product: N#CCc1cc(Br)cn(CC(F)(F)F)c1=O
Reaction time: 1 h
Yield: 62.5 %

Procedure:
5-Bromo-3-(bromomethyl)-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one (1.40 g, 4.01 mmol) was added in portions over 15 min to a solution of sodium cyanide (1.48 g, 30.1 mmol) in methanol (15 mL). After 1 h, the reaction was concentrated to dryness, diluted with water, extracted with dichloromethane (3×), and the combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane >5% methanol/dichloromethane) gave the title compound (0.740 g). MS 296.9 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4]O.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[N:14]=[C:15]=[S:16]>O1CCCC1>[CH3:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH3:6])[C:8]=1[NH:14][C:15]1[S:16][CH2:4][CH2:3][CH2:2][N:1]=1
Reactant: Cc1cccc(C)c1N=C=S
Reactant: NCCCO
Solvent: C1CCOC1
Product: Cc1cccc(C)c1NC1=NCCCS1
Temperature: 50 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
380 ml (373 grams, 4.97 moles) of 3-amino-1-propanol and 450 ml of tetrahydrofuran ("THF") were added to a 5-L flask fitted with a mechanical stirrer, teflon clad thermol-couple and an addition funnel. Then with rapid stirring, 749 grams (4.59 moles) of the 2,6-dimethylphenylisothiocyanate were added dropwise over a 2 hour period. The temperature was kept below 45° C. by controlling the rate of addition and by the use of a cooling bath. The cooling bath was removed, and replaced with a heating mantle. The temperature was raised to 50° C. followed by the addition of 435 ml. concentrated hydrochloric acid. The addition funnel was removed and a distillation head was placed on the flask. Heating was continued with the distillation of THF and water until the internal temperature had reached 95° C., which took about 2 hours. The reaction mixture was then diluted with 2 liters of water and the stirred solution was allowed to cool to room temperature. The aqueous solution was filtered through a 0.2 microfilter. The reaction mixture was made basic by the careful addition of 10% sodium hydroxide. The addition was continued until the pH of the solution was greater than or equal to 12. A solid was collected by filtration, washed with water and partially dryed in the funnel. The solid was then transferred into a flask fitted with a mechanical stirrer and 1 liter of acetone was added. The slurry was stirred for 1 hour using an ice bath to chill the mixture. The product was isolated by filtration, and air dryed to give 750 grams of crude xylazine. The product had a purity of 99% by GC analysis and gave a IR spectrum that was virtually identical to that of a standard sample of xylazine. The 80 MHz 1HNMR spectrum (CDCl3) produced the following results: delta 7.15 (bs, 3, ArH), 4.5 (t, 2, CH2), 3.15 (t, 2, CH2), 2.9-2.0 (m, 8, CH2 and CH3) was in complete agreement with a spectrum of a standard xylazine sample. Furthermore, the mixed melting point of the xylazine sample and a standard showed no depression.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][CH2:14]O)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[Cl:18][CH2:14][CH2:13][CH2:12][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: O=S(Cl)Cl
Reactant: OCCCOc1cccc2cccnc12
Solvent: c1ccccc1
Product: ClCCCOc1cccc2cccnc12
Temperature: 25 °C

Procedure:
A solution of 3-(8-quinolinyloxy)-1-propanol (32.0 g, 0.158 mole) and thionyl chloride (24.0 g, 0.203 mole) was heated at reflux for 5 hours in 300 ml of dry benzene (dried over 4 A molecular sieves). The reaction mixture was cooled to room temperature and then stripped to dryness. The residue was treated with potassium carbonate solution (30 g in 500 ml of water). The gummy residue was dissolved in chloroform and extracted with the potassium carbonate solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give a dark mass which crystallized. The mass was treated with 500 ml of boiling hexane. The hexane layer was decanted off from insoluble oil. A white solid crystallized on cooling, the hexane layer was filtered off. The solid was dried in vacuo at room temperature overnight to give 26.69 g (76.2%) of white cyrstalline solid, m.p. 69°-71° C.
Reaction SMILES: [BrH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([F:11])[CH:10]=1)[CH2:6]O>S(=O)(=O)(O)O>[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([F:11])[CH:10]=1)[CH2:6][Br:1]
Reactant: Br
Reactant: OCc1cc(F)cc(F)c1
Agent: O=S(=O)(O)O
Product: Fc1cc(F)cc(CBr)c1
Reaction time: 3 h

Procedure:
A 120 ml portion of 48% hydrobromic acid was added to 120 g of 3,5-difluorobenzyl alcohol. At room temperature, 120 ml of sulfuric acid was added dropwise thereto, and the mixture after the dropwise addition was stirred for 3 hours. The reaction solution was poured onto crashed ice, extracted with 600 ml of hexane, washed with water and saturated brine in that order and then dried with anhydrous sodium sulfate. By evaporating the solvent, 176 g of 3,5-difluorobenzyl bromide was obtained.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][CH2:17][CH2:18][S:19]([NH2:22])(=[O:21])=[O:20].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[S:19]([CH2:18][CH2:17][NH:16][C:13]([C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][CH:11]=1)=[O:14])(=[O:21])(=[O:20])[NH2:22]
Reactant: NCCS(N)(=O)=O
Reactant: O=C(Cl)c1cnc(-c2ccccc2)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)CCNC(=O)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenyl-pyrimidine-5-carboxylic acid chloride (1.51 mmol) and 2-amino-ethanesulfonic acid amide (1.51 mmol) in DCM (15 mL) is added diisopropylethylamine (4.53 mmol). The mixture is stirred at room temperature overnight. The mixture is concentrated in vacuo. The residue is washed with water and DCM to afford 2-phenyl-pyrimidine-5-carboxylic acid (2-sulfamoyl-ethyl)-amide as a solid. MS: 307 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 3.25 (q, 2H), 3.67 (m, 2H), 6.93 (s, N—H), 7.47-7.60 (m, 3H), 8.36-8.48 (m, 2H), 8.92-9.15 (m, N—H), 9.16-9.36 (m, 2H); IC50=55 nM.
Reaction SMILES: O[CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]1[C:9]([C:10]#[N:11])=[CH:8][N:7]=[CH:6][CH:5]=1.[OH-:18].[K+]>O>[CH:3]([C:4]1[C:9]([C:10]([NH2:11])=[O:18])=[CH:8][N:7]=[CH:6][CH:5]=1)=[CH:2][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1cnccc1CC(O)c1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: NC(=O)c1cnccc1C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
4(2-hydroxy-2-phenyl-ethyl)-nicotinonitrile (2.0 g, 8.92 mmol) was dissolved in KOH (1M solution in MeOH, 36 mL, 35.67 mmol) and then stirred at room temperature for about 4 hours under the nitrogen atmosphere. The mixture was added with 100 mL of distilled water and extracted twice with 150 mL of methylene chloride. The resulting organic layer was dried with anhydrous sodium sulfate, filetered, and then concentrated. A silica gel column chromatography (10% MeOH/MC) was performed on the resulting residue and obtained 1.66 g (83%) of 4-styryl-nicotinamide in white solid.
Reaction SMILES: C(OC(OC1C=C[C:12]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20](OCCC)=[CH:19][CH:18]=2)=CC=1)=O)(C)(C)C.[CH2:27](OC1C=CC(C#C)=CC=1)[CH2:28]C>>[CH2:16]([C:17]1[CH:18]=[CH:19][C:20]([C:27]#[CH:28])=[CH:21][CH:22]=1)[CH2:15][CH3:12]
Reactant: CCCOc1ccc(C#Cc2ccc(OC(=O)OC(C)(C)C)cc2)cc1
Reactant: C#Cc1ccc(OCCC)cc1
Product: C#Cc1ccc(CCC)cc1

Procedure:
1-[4-(tert-butoxycarbonyloxy)phenyl]-2-(4-n-propyloxyphenyl)acetylene was gained in the same manner as in the step (iii) of the Example 31, except for using 4-(n-propyloxy)phenylacetylene obtained in the step (iii) instead of 4-n-propylphenylacetylene.
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([CH3:21])[CH:4]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([CH3:21])[CH:4]=1
Reactant: COC(=O)Cc1ccccc1Oc1ccc(C=O)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccccc1Oc1ccc(CO)cc1C
Yield: 65.5 %

Procedure:
A stirred solution of 1.00 g (3.52 mmol) of the product of Step A dissolved in 14 mL of methanol was treated with 0.067 g (1.8 mmol) of sodium borohydride at room temperature. After 15 minutes the reaction mixture was partitioned between ethyl acetate and 1N hydrochloric acid, and the organic layer was separated. The product was washed with water, brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 30% ethyl acetate/hexane to afford 0.660 g (66%) of the title compound.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:41])[CH2:21][NH:22][C:23]2([CH2:26][CH2:27][N:28]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[C:31]([CH3:39])([CH3:38])[O:30][C:29]3=[O:40])[CH2:25][CH2:24]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:41][CH:20]([C:12]1[C:13]2[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=2[C:9]([OH:8])=[CH:10][CH:11]=1)[CH2:21][NH:22][C:23]1([CH2:26][CH2:27][N:28]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]([CH3:39])([CH3:38])[O:30][C:29]2=[O:40])[CH2:24][CH2:25]1
Reactant: CC1(C)OC(=O)N(CCC2(NCC(O)c3ccc(OCc4ccccc4)c4c3OCC(=O)N4)CC2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC(=O)N(CCC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)c2ccccc21

Procedure:
650 mg (1.17 mmol) 1-(2-{1-[2-(5-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-cyclopropyl}-ethyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one are dissolved in 30 mL methanol, combined with palladium on charcoal (10%) and hydrogenated at ambient temperature and 3 bar hydrogen pressure.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([Cl:34])[CH:33]=1)[NH:30][C:29](=[O:35])[CH:28]=[C:27]2[OH:36].Cl>O>[C:1]([C:28]1[C:29](=[O:35])[NH:30][C:31]2[C:26]([C:27]=1[OH:36])=[CH:25][C:24]([Cl:23])=[CH:33][C:32]=2[Cl:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1cc(O)c2cc(Cl)cc(Cl)c2[nH]1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1ccccc1)c1c(O)c2cc(Cl)cc(Cl)c2[nH]c1=O
Temperature: 25 °C
Yield: 65.6 %

Procedure:
Benzoyl chloride (0.93 gram) is added to a mixture of 1.5 grams of anhydrous aluminum chloride and 10 ml of nitrobenzene, the mixture is stirred at room temperature until it becomes uniform, stirred at 105° to 110° C. for eight hours with 1.26 grams of 6,8-dichloro-4-hydroxy-2-quinolone, decomposed with concentrated hydrochloric acid, small amount of water is added thereto, and crystals separated out therefrom are collected by filtration. The crystals are washed with water and then washed with methanol and ether to give 1.2 grams of 3-benzoyl-6,8-dichloro-4-hydroxy-2-quinolone, pale yellow powder, melting point 258° to 259° C.
Reaction SMILES: CS([C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[N:9]=1)=O.[CH2:21]([NH2:23])[CH3:22]>>[CH2:21]([NH:23][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[N:9]=1)[CH3:22]
Reactant: CS(=O)c1ncc2ccc(=O)n(-c3ccccc3)c2n1
Reactant: CCN
Product: CCNc1ncc2ccc(=O)n(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
A mixture of 2-methanesulfinyl-8-phenyl-8H-pyrido[2,3-d]pyrimidin-7-one (81 mg, 0.28 mmol) and 1.5 mL of aqueous ethyl amine was stirred at room temperature for 10 minutes then partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 54 mg (72%) of 2-ethylamino-8-phenyl-8H-pyrido[2,3-d]pyrimidin-7-one, mp 193-195° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH:7]=[N:8][C@H:9]([C:13]([O-:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[CH:5][CH:4]=1.[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>>[CH2:23]([O:22][C:20]([N:8]1[C@@H:9]([CH:10]([CH3:12])[CH3:11])[C:13](=[O:15])[O:14][C@H:7]1[C:6]1[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(C=N[C@H](C(=O)[O-])C(C)C)cc1
Agent: [Na+]
Product: COc1ccc([C@@H]2OC(=O)[C@H](C(C)C)N2C(=O)OCc2ccccc2)cc1

Procedure:
(2S,4S)-N-Benzyloxycarbonyl4-isopropyl-2-(4'-methoxyphenyl)-1,3-oxazolidin-5-one (22) was prepared from sodium N-(para-methoxybenzylidene)-(L)-valinate (2.57 g, 10.0 mM) and benzyl chloroformate (1.43 mL, 10.0 mM) following general procedure C and obtained as a colourless oil after purification by flash column chromatography, using 25% ethyl acetate/petrol as eluant (2.54 g, 69% mixture of 2 rotamers in a ratio of 2:1, NMR data for major isomer only reported): IR (CHCl3): 1795, 1715 cm-1 ; 1H NMR (200 MHz, CDCl3): δ 6.92-7.41 (m, 9H), 6.87 (s, 1H), 5.24 (s, 2H), 4.26 (d, J=5 Hz, 1H), 3.82 (s, 3H), 1.10-1.35 (m, 1H), 0.94 (d, J=5 Hz, 3H), 0.98 (d, J=5 Hz, 3H); 13C NMR (50.3 MHz, CDCl3): δ 171.2, 160.2, 155.1, 135.3, 129.5, 128.6, 128.0, 127.3, 113.8, 88.4, 68.3, 61.6, 55.3, 31.5, 19.1, 18.4; LRMS (Scan AP+): 370 (MH+); HRMS: calcd for C21H24NO5 (MH+): 370.1654; found: 370.1654.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[CH2:22][CH2:21]1)[C:15](=[O:36])[N:14]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=1)[C:13]2=[O:48].CCN(CC)CC>C(Cl)Cl>[C:1]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:22][CH2:21]1)[C:15](=[O:36])[N:14]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=1)[C:13]2=[O:48])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(Cn2c(=O)c3cc(CN)ccc3n(C3CCN(C(=O)OCc4ccccc4)CC3)c2=O)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)c3cc(CNC(C)=O)ccc3n(C3CCN(C(=O)OCc4ccccc4)CC3)c2=O)cc1OC
Reaction time: 1 h
Yield: 107.5 %

Procedure:
0.049 g of acetic anhydride is added to a solution of 0.09 g of benzyl 4-[6-(aminomethyl)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carboxylate obtained in stage 5.5 and 0.09 ml of NEt3 in 3 ml of DCM and the mixture is stirred at AT for 1 h 00. DCM is added and the solution is washed with a saturated NH4Cl solution, then with a 1N HCl solution, then with a 2N NaOH solution and then with water. The organic phase is dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure to give 0.104 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[N+:6]([O-])[CH:7]=1.C[Si]([C:14]#[N:15])(C)C.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:7]([C:14]#[N:15])=[N:6][C:5]([CH3:9])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: Cc1ccc(Br)c[n+]1[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(Br)c(C#N)n1
Temperature: 100 °C

Procedure:
To the solution of 5-bromo-2-methylpyridine 1-oxide (8.935 g, 47.52 mmol) in acetonitrile (240 mL) was added trimethylsilyl cyanide (TMSCN) (25 mL, 190 mmol) and triethylamine (20 mL, 142.56 mmol). The reaction was heated at 100° C. for 16 h. The mixture was cooled to rt and concentrated in vacuo. The crude was purified by silica gel chromatography using 0-50% EtOAc in hexane to obtain the title compound.
Reaction SMILES: [CH2:1]([C:5]12[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:10]([CH3:16])=[C:9]1[C:8]1[CH:17]=[CH:18][C:19]([O:21]COC)=[CH:20][C:7]=1[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl.C([O-])(O)=O.[Na+]>CO.ClCCl>[CH2:1]([C:5]12[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:10]([CH3:16])=[C:9]1[C:8]1[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:7]=1[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCCC(=O)C(C)=C1c1ccc(OCOC)cc1C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCCC12CCCC(=O)C(C)=C1c1ccc(O)cc1C2
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A solution of 9a-butyl-2-(methoxymethoxy)-5-methyl-8,9,9a,10-tetrahydrobenzo[a]azulen-6(7H)-one(5 mg) in methanol (1 mL) was treated with aqueous 2N HCl (0.1 mL, 0.2 mmol). After stirring at 65° C. for two hours, the mixture was diluted with dichloromethane(2 mL), treated with solid NaHCO3, and purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 20% EtOAc in hexane. The UV visible product band was eluted with EtOAc and the eluant was evaporated under vacuum to provide 9a-butyl-2-hydroxy-5-methyl-8,9,9a,10-tetrahydrobenzo[a]azulen-6(7H)-one as a foam.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:25]=[CH:24][S:23][C:22]=1[C:26](O)=[O:27]>>[NH2:20][C:21]1[CH:25]=[CH:24][S:23][C:22]=1[C:26]([NH:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][O:14][C:10]1[CH:9]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=[CH:12][N:11]=1)=[O:27]
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Nc1ccsc1C(=O)O
Product: Nc1ccsc1C(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 40 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 3-amino-2-thiophenecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as colorless needles, melting at 138°-140° C., in a 40% yield.