Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH:12]3[CH2:13][CH2:14][CH:9]([CH2:10][CH2:11]3)[N:8]2C(OCC)=O)[CH:2]=1>[OH-].[Na+].C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH:12]3[CH2:13][CH2:14][CH:9]([CH2:10][CH2:11]3)[NH:8]2)[CH:2]=1
Reactant: CCOC(=O)N1C2CCC(CC2)C1c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1cncc(C2NC3CCC2CC3)c1
Yield: 83 %

Procedure:
(±)-3-(3-pyridyl)-2-carboethoxy-2-azabicyclo[2.2.2]octane (XII) (500 mg, 1.92 mmol) was dissolved in a solution of 20% (w/v) NaOH in absolute ethanol (10 mL) and refluxed for 24 h. The organic solvent was evaporated on a rotary evaporator. The pH of the basic residue was adjusted to 9 by addition of a solution of 2N HCl in water and was extracted with ethyl acetate (4×10 mL). The organic extracts were dried over anhydrous K2CO3, and concentrated. The resulting oily residue was purified by distillation under reduced pressure (108°-110° C./0.4 mm Hg) to afford 300mg (83%) of compound (XIII).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)[CH2:2][CH3:3].Cl.[NH2:18][OH:19]>>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=[N:18][OH:19])[CH2:12][CH2:11]1)[CH2:2][CH3:3]
Reactant: CCCOCCCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: CCCOCCCCCN1CCC(=NO)CC1

Procedure:
1-(5-Propoxypentyl)-4-piperidone oxime is prepared from 1-(5-propoxypentyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([N:13]2[C:21]3[CH2:20][CH2:19][CH2:18][CH:17]([CH2:22][CH2:23]O)[C:16]=3[CH:15]=[N:14]2)[CH:9]=[CH:10][C:11]=1[Cl:12]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:3][CH2:23][CH2:22][CH:17]1[CH2:18][CH2:19][CH2:20][C:21]2[N:13]([C:8]3[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([Cl:5])[CH:7]=3)[N:14]=[CH:15][C:16]1=2
Reactant: O=S(Cl)Cl
Reactant: OCCC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: ClCCC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Yield: 85 %

Procedure:
Thionyl chloride (4 mL) is slowly added at room temperature over a solution of 2-(1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethanol (512 mg, 1.65 mmol) in 20 mL of toluene. The reaction mixture is heated at 90° C. during 2 hours. The solvent is eliminated at reduced pressure. The crude is diluted in ethyl acetate and washed twice with a NaHCO3 solution. The solvent is next evaporated at reduced pressure to obtain 4-(2-chloroethyl)-4,5,6,7-tetrahydro-1-(3,4-dichlorophenyl)-1H-indazole (462 mg, 1.40 mmol, 85%, oil).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][C:14]([O-:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17](O)[CH3:18]>[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: O=C([O-])CCC=CCCCc1ccccc1
Agent: [Pd]
Product: CCOC(=O)CCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
First, 831 mg of et - 8-phenyl-4-octenoate was dissolved in 17 ml of absolute ethanol, and after adding 83 mg of 5% palladium on carbon, the mixture was stirred under a hydrogen gas flow at a room temperature for 80 minutes. After filtering off the catalyst, the filtrate was evaporated to obtain 795 mg of ethyl 8-phenyloctanoate as a colorless liquid.
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]3[NH:19][C:18]4[C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH3:23])[C:15](=[O:24])[N:14]([CH2:25][CH2:26][CH3:27])[C:13]=4[N:12]=3)([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:24]=[C:15]1[N:14]([CH2:25][CH2:26][CH3:27])[C:13]2[N:12]=[C:11]([C:6]34[CH2:7][CH2:8][C:3]([CH:2]=[O:1])([CH2:10][CH2:9]3)[CH2:4][CH2:5]4)[NH:19][C:18]=2[C:17](=[O:20])[N:16]1[CH2:21][CH2:22][CH3:23]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CO)(CC3)CC4)nc2n(CCC)c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C34CCC(C=O)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Yield: 62.2 %

Procedure:
To a solution of 0.092 g (0.246 mmol) of 8-(4-Hydroxymethyl-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 15) in 5 ml of CH2Cl2 was added 0.125 g (0.295 mmol) Dess-Martin periodinane. The reaction mixture was stirred at rt until the oxidation was complete. The reaction solution was filtered through a plug of basic alumina, washed with sat'd NaHCO3, brine, and dried over Na2SO4. The CH2Cl2 solution was conc'd in vacuo to give 0.057 g (62% yield) of an off-white solid. (MH+=373.30)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].C([O-])(=O)C.[NH4+:23]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:23])=[O:13]
Reactant: [NH4+]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Agent: CC(=O)[O-]
Product: NC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 8 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 16 mmol of. ammonium acetate. LC/MS [7.27 min; 358 (M+1)].
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH2:32][CH:33]2[CH2:34][CH2:35]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([NH:30][C:36](=[O:39])[CH2:37][CH3:38])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)=O)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-N-(trans-4-aminocyclohexyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f56) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br.I.O>C(O)(=O)C>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(-c2ncc(-c3ccc(OC)cc3)s2)cc1
Agent: Br
Agent: I
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 22.8 %

Procedure:
In a 200 ml-round-bottomed flask, 8.20 g (21.6 mM) of 2-(4-octylphenyl)-5-(4-methoxyphenyl)thiazole, 80 ml of a solution of 25%-hydrogen bromide in acetic acid and 3 ml of 57%-hydroiodic acid were placed, followed by heat-stirring for 20 hours at 100° C. After the reaction, the reaction mixture was poured into 200 ml of water, followed by extraction with chloroform. The organic layer was washed with water and dried with anhydrous sodium sulfate, followed by distilling-off of the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=20/1) to obtain 1.80 g of 2-(4-octylphenyl)-5-(4-hydroxyphenyl)thiazole (Yield: 22.8%).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:8][S:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH2:20])(=[O:19])=[O:18])=[O:10].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C>[CH2:1]([NH:5][C:6]([NH:20][S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[S:9]([CH3:8])=[O:10])(=[O:19])=[O:18])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C=O
Reactant: CS(=O)c1ccccc1S(N)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCNC(=O)NS(=O)(=O)c1ccccc1S(C)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
10.2 g of n-Butyl isocyanate (0.10 mol) were added dropwise at 25° C. to a suspension of 20.1 g of 2-(methylsulfinyl)benzenesulfonamide (0.09 mol) in 250 ml of acetonitrile. 13.9 g of potassium carbonate (0.10 mol) were added, after which the refluxing mixture was stirred for 4 hours. After cooling to 0° C., the mixture was poured onto 400 ml ice/water, brought to a pH of 1 by adding concentrated hydrochloric acid and extracted with methylene chloride. The organic extracts were washed neutral with water and dried. After removal of the solvent, 25 g of the title compound (85% of theory) were obtained as a pale brown oil.
Reaction SMILES: [Mg+2].[Cl-].[Cl-].[CH3:4][CH:5]([CH3:12])[CH2:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10].[CH:13](=O)[CH2:14][CH3:15].OP(O)(O)=O>O.C(OCC)(=O)C>[CH3:4][CH:5]([CH3:12])[CH2:6][CH2:7]/[C:8](=[CH:13]\[CH2:14][CH3:15])/[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)CCCC(C)C
Reactant: CCC=O
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: O
Product: CC/C=C(\CCC(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 22.2 %

Procedure:
Anhydrous MgCl2 (27.0 g, 284 mmol) was charged into a 1 liter, 4-necked round bottom flask, and ethyl acetate (150 ml) was added. The suspension was stirred at room temperature, and a solution of TiCl3(OiPr) (34% in ethyl acetate; 21.50 g, 34.3 mmol) was added dropwise over 1.5 hour. The reaction mixture was stirred overnight at room temperature, and after that heated to 70° C. 6-Methyl 2-heptanone (110.0 g, 858 mmol) was added over 2.5 hours, followed by a slow addition of propanal (105.0 g, 1716 mmol) over 6 hours. Stirring at 70° C. was continued for 22 hours. After cooling at room temperature, the black reaction mixture was poured onto a mixture of ice (100 g), water (300 ml) and 25% aqueous H3PO4 (100 ml). The aqueous phase was discarded and the organic phase washed with 25% aq. potassium citrate, then twice with 10% aqueous K2CO3 and twice with brine. Drying over Na2SO4 and evaporation of the solvent afforded the crude product. Fractional distillation though a Vigreux column followed by a second distillation through a Fischer column afforded the desired ketone (32.0 g, 22.2% yield).
Reaction SMILES: BrN1C(=O)CCC1=O.[S-:9][C:10]#[N:11].[K+].[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>CO>[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[S:9][C:10]#[N:11])[NH2:17]
Reactant: Nc1cccc(F)c1
Reactant: N#C[S-]
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: CO
Product: N#CSc1ccc(N)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-Bromosuccinimide (1.76 g, 9.89 mmol) and potassium thiocyanate (1.75 g, 18.0 mmol) in methanol (30 ml) were stirred for 15 minutes at room temperature. The reaction mixture was cooled to 0° C., and 3-fluoroaniline (1.00 g, 9.0 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 h. Solvent was removed under vacuum, and the residue was washed with dichloromethane. The mixture was filtered to remove succinimide by-product, and the solution was washed with water, brine, and dried (MgSO4). Solvent was removed under vacuum to afford the desired product as a colorless oil. Yield 1.45 g (96%). 1H NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1>C(O)(=O)C.C(O)(C)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[C:7]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[OH:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COc1ccc(C(O)(c2ccccc2)C(O)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 99.3 %

Procedure:
0.04 g of acetic acid was added to 35.98 g of isopropyl alcohol, and 4.02 g of 4-methoxybenzophenone was dissolved therein. To this solution, ultraviolet rays were irradiated by a high pressure mercury lamp (UVL-100HA, manufactured by Riko Kagaku Sangyo K.K.) to carry out the reaction for 4 hours. After the reaction, the solvent was distilled off to obtain 4.01 g of 1,2-bis(p-methoxyphenyl)-1,2-diphenyl-1,2-ethanediol (compound (C2)).
Reaction SMILES: [CH3:1][S:2](NC1C=CC=CC=1N1CCN(C(OC(C)(C)C)=O)CC1)(=[O:4])=[O:3].[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N:42]1[CH2:47][CH2:46][N:45]([C:48](=[O:78])[C@H:49]([NH:58][C:59]([C@@H:61]2[CH2:70][C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[CH2:63][N:62]2[C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])=[O:60])[CH2:50][C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=2)[CH2:44][CH2:43]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CS(Cl)(=O)=O.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)CCl>[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][N:35]([S:2]([CH3:1])(=[O:4])=[O:3])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N:42]1[CH2:43][CH2:44][N:45]([C:48](=[O:78])[C@H:49]([NH:58][C:59]([C@@H:61]2[CH2:70][C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[CH2:63][N:62]2[C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])=[O:60])[CH2:50][C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=2)[CH2:46][CH2:47]1)=[O:31])([CH3:27])([CH3:28])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCNc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCN(c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1)S(C)(=O)=O

Procedure:
tert-Butyl 3-[N-((1R)-2-{4-[2-({2-[(tert-butoxy)carbonylamino]ethyl}(methylsulfonyl)amino)phenyl]piperazinyl}-1-[(4-chlorophenyl)methyl]-2-oxoethyl)-carbamoyl](3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared according to the procedure for Preparation III using tert-butyl 3-[N-((1R)-2-{4-[2-({2-[(tert-butoxy)carbonylamino]ethyl}amino)phenyl]piperazinyl}-1-[(4-chlorophenyl)methyl]-2-oxoethyl)carbamoyl](3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step 1) (370 mg, 0.45 mmol), methanesulfonyl chloride (41 μl, 0.530 mmol), pyridine (40 μl, 0.495 mmol), DMAP (cat.), and ClCH2CH2Cl (15 mL). The crude material was purified by flash chromatography, (SiO2, 1:1 hexane:EtOAc) to afford the desired material (155 mg). MS (ESI, pos. ion) m/z: 839 (M+H), (ESI, neg. ion) m/z: 837 (M−H). Calc'd for C42H55ClN6O8S: 839.44.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=1)=O>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=3)[N:8]=2)[N:7]=1
Reactant: CCc1ccc(C(=O)CBr)cc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)nn1
Solvent: O
Solvent: CC#N
Product: CCc1ccc(-c2cn3nc(Cl)ccc3n2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A solution of 6-chloropyridazin-3-amine (4.76 g, 0.037 mol) and 2-bromo-1-(4-ethyl-3-nitrophenyl)ethanone (10.0 g, 0.037 mol) in acetonitrile (100 mL) is heated at reflux for 18 hr. The reaction mixture is diluted with water (500 mL), stirred at room temperature for 1 hour and solids are collected by filtration to give the title compound (6.9 g, 62% yield). LCMS m/z=303.3, 305.4 [M+H]+, tR=2.90 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.Br[CH2:11][C:12]([C:14]1[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([OH:24])=[CH:16][CH:15]=1)=[O:13]>C(N(CC)CC)C.C(O)C>[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:11][C:12]([C:14]2[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([OH:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=1
Reactant: COC(=O)c1cc(C(=O)CBr)ccc1O
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(=O)Cn2cc(Cl)cnc2=O)ccc1O

Procedure:
A solution of 5-chloropyrimidin-2-one hydrochloride (508 mg) and methyl 5-bromoacetylsalicylate (827 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 13/4 hours, by which time a precipitate had formed. This suspension was chilled in ice, and the collected solid was crystallised from chloroform-ethanol to give the title pyrimidinone: yield 442 mg: m.p. 203°-204° dec: λmaxEtOH 228.5 nm (ε 40720), 269.5 nm (ε 16930), 312.5 nm (ε 6320).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][N:20]([CH2:28][CH2:29][CH3:30])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1>>[CH3:19][N:20]([CH2:28][CH2:29][CH3:30])[C:21]1[N:22]=[CH:23][C:24]([NH:27][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:25][CH:26]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CCCN(C)c1ccc(N)cn1
Product: CCCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(methyl-propyl-amino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-methyl-N2-propyl-pyridine-2,5-diamine. LCMS calcd for C20H19F3N4O2 (m/e) 404, obsd 405 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8](O)=[O:9])[N:3]=1.[Cl:14]C(OC(Cl)(Cl)Cl)=O.CN(C)C=O>O1CCCC1>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([Cl:14])=[O:9])[N:3]=1
Reactant: CO/N=C(\C(=O)O)c1nsc(N)n1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 30.0 ml of tetrahydrofuran (THF), 10.0 g of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetic acid were stirred at -20° C., followed by the dropwise addition of a chlorinating reagent, which had been prepared beforehand by gradually adding 5.43 g of trichloromethyl chloroformate at 5° C. to a mixture of 80 ml of THF and 4.0 g of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. After they were reacted for 5 minutes, the reaction mixture was poured into 200 ml of ice water to precipitate crystals. The crystals were collected by filtration, washed with 100 ml of ice water, collected by filtration, and then stirred for 30 minutes in 100 ml of n-hexane. After filtration, the resulting crystals were dried under reduced pressure, whereby the title compound was obtained. Yield: 9.2 g (84.3%). Purity: 96.5%.
Reaction SMILES: [C:1]([C:12]1[CH:20]=[C:16]([C:17]([OH:19])=O)[C:15]([OH:21])=[CH:14][CH:13]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].P(Cl)(Cl)Cl.[N+:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)([O-:28])=[O:27]>ClC1C=CC=CC=1>[C:1]([C:12]1[CH:20]=[C:16]([C:17]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=2)=[O:19])[C:15]([OH:21])=[CH:14][CH:13]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Solvent: Clc1ccccc1
Solvent: ClP(Cl)Cl
Product: CCCCCCCCCC(=O)c1ccc(O)c(C(=O)Nc2ccc([N+](=O)[O-])cc2)c1
Temperature: 60 °C
Yield: 23.2 %

Procedure:
In a 100 ml round-bottom flask fitted with a condenser and drying tube is placed 5-n-decanoylsalicylic acid (1.85 g., 6.7 mmoles), dry chlorobenzene (50 ml), and phosphorous trichloride (0.47 g., 3.4 mmoles). The mixture is then stirred by means of a magnetic stirring bar while the mixture is heated to 60° C. for three hours. The resulting solution is cooled to room temperature and 0.93 g. (6.7 mmoles) of p-nitroaniline is added. The mixture is then heated to 60° C. for three hours, with stirring, and then refluxed for 24 hours. The solvent is removed by vacuum vaporization and the residue is recrystallized from ethanol-water. The crystalline product is triturated with concentrated hydrochloric acid, collected and washed with water. Recrystallization from ethanol-water gives 0.64 grams of 5-n-decanoyl-4'-nitrosalicylanilide, mp 142°-143° C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:48])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([O:38]CC)=[O:37])=[CH:32][CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]Br)C>CCCCCC.C(OCC)(=O)C>[C:36]([C:33]1[CH:32]=[CH:31][C:30]([C:28]([C:26]2[CH:25]=[CH:24][C:23]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:48])=[O:18])[CH:27]=2)=[O:29])=[CH:35][CH:34]=1)([OH:38])=[O:37]
Reactant: CCOC(=O)CCc1cc(C(=O)c2ccc(C(=O)OCC)cc2)ccc1OCCCCCBr
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCOc2ccc(C(=O)c3ccc(C(=O)O)cc3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 54.4 %

Procedure:
Starting with 0.157 g (0.76 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.391 g (0.75 mmol) of 2-[(5-bromopentyl)oxy]-5-[[4-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound (0.240 g; 63.6% overall yield) was obtained as a white solid, mp 175°-177° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[N:7]=[N:8][C:4]=2[CH:3]=1.C([Li])CCC.[F:23][C:24]([F:38])([F:37])[C:25]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH3:36])[CH:28]=1)=[O:26]>C1COCC1>[F:38][C:24]([F:23])([F:37])[C:25]([C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[N:7]=[N:8][C:4]=2[CH:3]=1)([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH3:36])[CH:28]=1)[OH:26]
Reactant: Fc1ccc(-n2nnc3cc(Br)ccc32)cc1
Reactant: Cn1cc(C(=O)C(F)(F)F)c2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(C(O)(c2ccc3c(c2)nnn3-c2ccc(F)cc2)C(F)(F)F)c2ccccc21
Reaction time: 0.25 h
Yield: 18.2 %

Procedure:
To a chilled (−78° C.) solution of 5-bromo-1-(4-fluorophenyl)-1H-benzotriazole (145 mg, 0.5 mmol) in anhydrous THF (3 mL) was added n-butyllithium (0.25 mL of a 2.5 M solution in hexanes, 0.625 mmol) over a 1 minute period followed by a chilled (−78° C.) solution of 2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethanone (170 mg, 0.75 mmol) in 1 mL of THF. After 15 minutes, the mixture quenched with brine (50 mL) and extracted with three 50 mL portions of methylene chloride. The combined organic layers were washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a yellow oil. The residue was purified by column chromatography over silica gel eluting with 0-50% ethyl acetate in hexanes to afford 40 mg of the title compound as a light yellow solid. MS m/z 441 (MH+).
Reaction SMILES: [C:1](O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Br.[NH2:36][CH:37]1[CH2:46][CH2:45][CH2:44][C:43]2[C:42]([OH:47])=[CH:41][CH:40]=[CH:39][C:38]1=2.C(N(CC)CC)C>O1CCCC1>[C:1]([NH:36][CH:37]1[CH2:46][CH2:45][CH2:44][C:43]2[C:42]([OH:47])=[CH:41][CH:40]=[CH:39][C:38]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: NC1CCCc2c(O)cccc21
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CCCc2c(O)cccc21)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
50 mmol of benzoic acid and 50 mmol of 1-hydroxybenzotriazole (HOBT) are taken in 200 ml of absolute tetrahydrofuran at 0° C. 55 mmol of dicyclohexylcarbodiimide (DCC) are added under N2 and the mixture is stirred at 0° C. for 1 hour and then at room temperature for 1 hour. 50 mmol of 5-amino-1-hydroxy-5,6,7,8-tetrahydro-naphthalene hydrobromide and 50 mmol of triethylamine are added to this solution and the mixture is stirred at room temperature for 6 hours.