Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C(N(CC)CC)C.CN(C=O)C.Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27]>C1COCC1>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:5]1[CH:4]=[C:3]([F:12])[C:2]([Cl:1])=[CH:7][C:6]=1[N+:8]([O-:10])=[O:9])[CH3:27]
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1cc(F)c(Cl)cc1[N+](=O)[O-]
Yield: 7.3 %

Procedure:
By using 6.32 g of 5-chloro-2,4-difluoronitrobenzene, 9.91 g of triethylamine, 60 ml of DMF, 60 ml of THF and 4.56 g of glycine ethyl ester hydrochloride, 0.66 g (7%) of N-(4-chloro-5-fluoro-2-nitrophenyl)glycine ethyl ester was obtained.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C@@H:8]1[CH2:7][CH2:6][C:5]2=[O:23].C(O)(=O)C>C(O)C>[CH3:3][C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:23]
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Yield: 44.7 %

Procedure:
Add sodium borohydride (0.5 g.) in ethanol (60 cc.) with stirring to 13-methyl-3-methoxygona-1,3,5(10), 8-tetraen-17-one (2.0 g.) in ethanol (150 cc.) at 14°-15°. Leave the mixture at room temperature for 1 hour, acidify with glacial acetic acid and evaporate to dryness under reduced pressure. Treat the residue with water, ether-extract and wash and dry. Evaporate the extracts. Recrystallize the residue from a mixture of methanol (15 cc.) and water (3 cc.) to obtain the title product (0.90 g.), m.p. 110°-2°. A sample sublimes at 110°/10-4 mm. and has an ultra-violet absorption peak at 277 mβ (ε 14,500).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH3:17])[C@H:12]1[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[O:10].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41]([C:43]([O:45]C(C)(C)C)=[O:44])[CH:42]=2)O1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1.O>[CH3:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:9]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[C:38]2[CH:39]=[N:40][NH:41][CH:42]=2)=[O:10])[C@@H:12]1[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.[C:43]([OH:45])([C:26]([F:29])([F:28])[F:27])=[O:44]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc(Br)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cn[nH]c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: O=C(O)C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of (2-bromo-5-methylphenyl)((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)methanone (0.045 g, 0.097 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.034 g, 0.116 mmol), Pd(PPh3)4 (0.017 g, 0.015 mmol), K2CO3 (0.4 g, 0.291 mmol) and dioxane/H2O (4:1, 3 mL) was degassed for 5 min and heated overnight at 100° C. The completion of the reaction was monitored by anal. HPLC. The mixture was cooled and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3 and dried over Na2SO4. The solvent was removed in vacuo to obtain the crude, which was purified by preparative-HPLC to obtain the title compound as TFA salt. ESI-MS (m/z): 458 [M+1]+.
Reaction SMILES: [F:1][CH2:2][CH:3]([C:5]1[C:6]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4].[C:19](OC(=O)C)(=[O:21])[CH3:20].O.OS(O)(=O)=O>C1COCC1>[C:19]([O:4][CH:3]([C:5]1[C:6]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][F:1])(=[O:21])[CH3:20]
Reactant: OC(CF)c1cccnc1SCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OC(CF)c1cccnc1SCc1ccccc1
Yield: 92.7 %

Procedure:
A solution of 3-(2-fluoro-1-hydroxyethyl)-2-(phenylmethylthio)pyridine (16 g) in dry THF and acetic anhydride (7.4 g) is stirred with a catality amount of4-dimethylaminopyridine at room temperature for 12 hours. The reaction mixture is then poured into water and neutralized with dilute H2SO4. The mixture is extracted three times with methylene chloride, the combined extracts are dried (MgSO4), evaporated to obtain the desired product (oil, 17.2 g, Yield: 93%).
Reaction SMILES: Cl[CH2:2][C:3](=[O:17])[C:4]([CH3:16])([CH3:15])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH:28]=[N:27][CH:26]=[N:25]1>CC(C)=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][C:4]([CH3:16])([CH3:15])[C:3](=[O:17])[CH2:2][N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)=[CH:9][CH:10]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(CCOc1ccc(Cl)cc1)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CCOc1ccc(Cl)cc1)C(=O)Cn1cncn1
Temperature: 20 °C
Reaction time: 3 h
Yield: 49.4 %

Procedure:
A solution of 55 g (0.2 mol) of 1-chloro-5-(4-chlorophenoxy)-3,3-dimethyl-2-pentanone in 50 ml of acetone is added dropwise to a mixture of 27.6 g (0.2 mol) of potassium carbonate and 27.6 g (0.4 mol) of 1,2,4-triazole in 400 ml of boiling acetone. The mixture is boiled for a further 3 hours, cooled down to 20° C., filtered and the filtrate is evaporated in vacuo. The oily residue is taken up in 250 ml of ethyl acetate and washed three times with 100 ml of water each time. After drying the organic phase over anhydrous sodium sulphate, it is evaporated in vacupo. the residual crude product (61 g) is dissolved in 250 ml of acetone, and a solution of 57.6 g of naphthalene-1,5-disulphonic acid in 250 ml of acetone is added. The salt which has crystallized out (45.4 g; melting point 188°-190° C.) is suspended in a mixture of 150 ml each of dichloromethane and water and is made alkaline by the addition of 10% strength sodium carbonate solution. The organic phase is separated off, and the aqueous phase is extracted once more with 100 ml of dichloromethane and the combined organic phases are evaporated in vacuo. 30.4 g (49.4% of theory) of 5-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-pentanone are obtained as a pale yellowish liquid of refractive index nD20 =1.5457.
Reaction SMILES: O[C:2]1([CH3:10])CS[C:5]([OH:9])([CH3:8])[CH2:4][S:3]1.O1CCCC1.N1CCCCC1.[C:22]([O:26][CH3:27])(=[O:25])C=C>O>[CH2:4]([S:3][CH2:2][CH2:10][C:22]([O:26][CH3:27])=[O:25])[C:5]([CH3:8])=[O:9]
Reactant: C=CC(=O)OC
Reactant: CC1(O)CSC(C)(O)CS1
Solvent: O
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: COC(=O)CCSCC(C)=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
90.1 g (0.5 mol) of 2,5-dihydroxy-2,5-dimethyl-1,4-dithiane are initially introduced into 100 ml of absolute tetrahydrofuran. 1.0 g of piperidine is then added, and 94.7 g (0.945 mol) of methyl acrylate are added dropwise at 10°-15° C, during which process another two portions of 0.5 g of piperidine are added at the same time. The mixture is subsequently stirred for 60 minutes at 60° C. It is allowed to cool and introduced into 500 ml of water.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[C:16](C(OC)(OC)OC)[N:15]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])OC(C)(C)C)[C:14]=3[CH:36]=2)=[O:9])[CH:2]=1.Cl.C(N(CC)CC)C>CO.C(Cl)Cl>[O:35]=[C:29]1[C:16]2=[N:17][C:13]3[CH:12]=[CH:11][C:10]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:9])=[CH:36][C:14]=3[N:15]2[CH2:25][CH2:26][CH2:27][NH:28]1
Reactant: COC(OC)(OC)c1nc2ccc(C(=O)Nc3cccnc3)cc2n1CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)c1ccc2nc3n(c2c1)CCCNC3=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.8 %

Procedure:
To a solution of tert-butyl {3-[6-(pyridin-3-ylcarbamoyl)-2-(trimethoxymethyl)-1H-benzimidazol-1-yl]propyl}carbamate (85 mg, 0.17 mmol) in methanol (2 mL) was added concentrated HCl (1 mL). The solution is stirred at room temperature for 2 h and is evaporated to dryness. The residue is dissolved in methanol (5 mL), triethylamine (0.14 mL, 1.0 mmol) added, and the solution heated at reflux for 2 h. The cooled solution was diluted with CH2Cl2, and washed with Na2CO3. The organic layer was dried (MgSO4) and evaporated. The crude product was purified via preparative HPLC. The major peak was collected by passing the HPLC fractions, without concentrating, directly through an SCX cartridge (Silicycle tosic acid, 1 g). The cartridge was washed with methanol, then CH2Cl2/methanol (50:50). Finally, the product was eluted with CH2Cl2/methanol containing 1% NH4OH. The solution containing product was evaporated to afford the title compound (13 mg, 22%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:25][CH2:24]2)=[CH:4][C:5]([N:20]([CH3:22])[CH3:21])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].[CH:36]1([C:39]2[O:40][CH:41]=[C:42]([C:44](O)=[O:45])[N:43]=2)[CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[CH3:21][N:20]([CH3:22])[C:5]1[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:19][C:2]([NH:1][C:44]([C:42]2[N:43]=[C:39]([CH:36]3[CH2:38][CH2:37]3)[O:40][CH:41]=2)=[O:45])=[C:3]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:27][CH2:28]2)[CH:4]=1
Reactant: Cc1ccccc1N1CCN(c2cc(N(C)C)c(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Reactant: O=C(O)c1coc(C2CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(c2cc(N(C)C)c(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2coc(C3CC3)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
5-Amino-2-dimethylamino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 7c (111.4 mg, 0.23 mmol, 100 mol %), 2-cyclopropyl-oxazole-4-carboxylic acid 1h (53.5 mg, 0.35 mmol, 150 mol %) and N,N-diisopropylethylamine (0.12 ml, 0.70 mmol, 300 mol %) were combined in N,N-dimethylformamide (2.0 ml) and HATU (132.7 mg, 0.35 mmol, mol %) was added and the reaction was stirred at room temperature for 16 h. The reaction was then diluted with water and extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate and then concentrated to a residue that was purified by column chromatography (dichloromethane to 10% methanol/dichloromethane) to afford 2-cyclopropyl-oxazole-4-carboxylic acid [4-dimethylamino-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 7e (100.0 mg; 0.16 mmol, 70.0%) as a white solid.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][C:29]([O:32][C:33](ON=C(C1C=CC=CC=1)C#N)=[O:34])([CH3:31])[CH3:30]>O.CC(C)=O>[C:33]([NH:14][C@H:13]([C:15]([OH:17])=[O:16])[CH2:12][C:11]1[CH:18]=[CH:19][CH:20]=[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)([O:32][C:29]([CH3:31])([CH3:30])[CH3:28])=[O:34]
Reactant: N[C@@H](Cc1cccc(C(=O)c2ccccc2)c1)C(=O)O
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C(=O)c2ccccc2)c1)C(=O)O
Reaction time: 3 h

Procedure:
A suspension of 2.175 g of m-benzoyl-L-phenylalanine in 25 ml of water and 1.15 g of triethylamine was treated with 3.35 g of BOC-ON in 40 ml of acetone. After 3 h, acetone was removed and the aqueous residue was extracted three times with ether (discarded). The aqueous solution was acidified to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried (MgSO4) and stripped. The residue was triturated for 7 days with petroleum ether. The waxy insoluble solid was triturated for 14 days with an additional portion of petroleum ether and finally for 7 days with a third portion. The resulting white solid weighed 1.786 g after vacuum drying, [α]D25 +22.2±0.9°, C=0.86 g/100 ml ethanol. Anal.: Calcd. for C21H23NO5 :C, 68.28; H, 6.28; N, 3.79. Found: C, 68.01; H, 6.49; N, 3.68.
Reaction SMILES: II.Br[CH:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:15]([O:18]CC(=O)C)(=[O:17])[CH3:16].[C:23]1(C)C=CC=CC=1>[Zn]>[C:15]([O:18][C:9]1([CH3:23])[CH2:8][O:7][C:5](=[O:6])[CH:4]1[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:17])[CH3:16]
Reactant: CC(=O)COC(C)=O
Reactant: CCCCCC(Br)C(=O)OCC
Reactant: Cc1ccccc1
Agent: II
Agent: [Zn]
Product: CCCCCC1C(=O)OCC1(C)OC(C)=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 43.5 %

Procedure:
Zinc powder (65.37 g, 1 mol) and 3.27 g (50 mmol) of iodine are placed in 400 ml of toluene. This violet suspension is heated to 80° C. in an oil bath while stirring and treated within 80 minutes with a solution of 118.55 g (500 mmol) of ethyl 2-bromoheptanoate and 87.08 g (750 mmol) of acetoxyacetone in 100 ml of toluene. The exothermic reaction which sets in immediately can be held at 80°-90° C. by removing the oil bath. After a further 90 minutes at 80° C. the reaction mixture, cooled to room temperature, is treated with 400 ml of ice-water and then with 120 ml of 20% HCl and stirred for 30 minutes. Then, it is extracted three times with 500 ml of ether in a separating funnel. The ether phases are washed with 500 ml of sat. NaHCO3 solution and with 500 ml of sat. NaCl solution, dried over MgSO4 and concentrated on a rotary evaporator. The crude product distills at 110°-112° C./0.06 mbar and gives 49.64 g (43.5%) of 4-acetoxy-4-methyl-3-pentyl-tetrahydrofuran-2-one.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[S:5](Cl)([Cl:8])(=[O:7])=[O:6].[CH2:10](N(CC)CC)C.Cl>C(Cl)Cl.O1CCOCC1.[Pd]>[ClH:8].[S:5]([O:2][CH2:1][CH2:3][NH2:4])([CH3:10])(=[O:7])=[O:6]
Reactant: NCCO
Reactant: O=S(=O)(Cl)Cl
Reactant: CCN(CC)CC
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)OCCN
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Sulfonyloxy-ethylamine hydrochlorides can be prepared by converting ethanolamine to its N-CBZ derivative, purifying by column chromatography with purity confirmed by TLC, reaction with one equivalent of the appropriate sulfonyl chloride in methylene chloride at 0° C. followed by dropwise addition of one equivalent of triethylamine, stirring one hour at 0° C. and one hour at room temperature, washing with water, drying over sodium sulfate, and evaporation to dryness to yield a syrup, which is purified by column chromatography or preparative TLC. The purified product is characterized by TLC and mass and NMR analysis. The resulting N-CBZ derivative in dioxane in the presence of one equivalent of concentrated hydrochloric acid and 10% Pd/C catalyst is hydrogenated in Parr shaker apparatus for one hour at 15 psig pressure, and the mixture is filtered. The filtration residue (catalyst and ppt.) is washed with MeOH and filtered. Evaporation of the combined dioxane-methanol filtrate to dryness in vacuo yields the 2-mesyloxyethylamine hydrochloride in sufficient purity and yield for use as described above.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([O:14][CH3:15])=[C:8]([CH3:16])[C:4]=1[CH2:5][Mg]Br.C1[O:22][CH:18]1[C:19](=[CH2:21])[CH3:20].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([O:14][CH3:15])=[C:8]([CH3:16])[C:4]=1[CH2:5][CH:20]=[C:19]([CH3:21])[CH2:18][OH:22]
Reactant: C=C(C)C1CO1
Reactant: COc1c(C)c(C)c(OC)c(C[Mg]Br)c1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(CC=C(C)CO)c1C
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 68.4 %

Procedure:
26.7 mmol of 2,5-dimethoxy-3,4,6-trimethylbenzylmagnesium bromide were treated at -78° C. with 3.6 g of lithium tetrachlorocuprate (Li2CuCl4) as a 0.1 molar solution in tetrahydrofuran. 2.2 g (26 mmol) of isoprene oxide were subsequently added. The mixture was thereupon stirred at -78° C. for 1 hour and at room temperature for 3-4 hours. 10 ml of saturated ammonium chloride were then added at 0° C. and the mixture was extracted with ether. After drying the ether extract over sodium sulphate, concentration and crystallization from ethyl ether at -20° C., there were obtained 4.7 g (75%) of 4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-2-butenol with a melting point of 85°-86° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][C:9]2[C:10]([Cl:23])=[N:11][CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=O)=[C:4]([F:26])[CH:3]=1>O=P(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:23][C:10]1[N:11]=[CH:12][N:13]=[C:14]2[C:9]=1[N:8]=[C:6]([C:5]1[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=1[F:26])[N:15]2[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1
Reactant: O=C(Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1)c1ccc(Cl)cc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Fc1cc(Cl)ccc1-c1nc2c(Cl)ncnc2n1-c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A suspension of 4-chloro-N-[4-chloro-6-(4-chlorophenylamino)-pyrimidin-5-yl]-2-fluorobenzamide I-(7A-91)a (8.3 g, 20 mmol) in POCl3 (100 ml) was heated to reflux. The light brown reaction became homogeneous over 2 hours. After refluxing 3 hours, the reaction mixture was cooled and concentrated under reduced pressure to give a viscous oil. The residue was diluted with ethyl acetate and poured over ice/aqueous sodium bicarbonate. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated. Crystallization from diethyl ether afforded product I-(7A-91)b (5.8 g, 73%) as an off-white solid: +ESI MS (M+1) 393.0; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.72 (t, J=8.1 Hz, 1H), 7.60–7.55 (m, 3H), 7.50–7.42 (m, 3H).
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10](=[O:41])[C:11]([NH:32][NH:33]C(OC(C)(C)C)=O)([CH3:31])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]([O:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:14]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.Cl>C(Cl)Cl.O1CCOCC1>[C:6]([CH2:8][O:9][C:10](=[O:41])[C:11]([NH:32][NH2:33])([CH3:31])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]([O:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:14]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)Oc1ccc(CC(C)(NNC(=O)OC(C)(C)C)C(=O)OCC(=O)OC(C)(C)C)cc1OC(=O)OCC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)Oc1ccc(CC(C)(NN)C(=O)OCC(=O)O)cc1OC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 155 was dissolved in 2 mL CH2Cl2 and treated with 1 mL trifluoroacetic acid at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was cooled to 0° C. again and a solution (1 mL) of 4 N HCl in dioxane was added. After stirring at room temperature for 2 h, the solvent was removed in vacuo. The crude residue was purified by reverse phase LC/MS to afford 103 mg (24% overall yield) of the title compound. 1H-NMR (400 MHz, CD3OD): δ 7.14–7.22 (m, 3H), 4.49–4.69 (Abq, J=62.8, 14.8, 2H), 4.24–4.29 (m, 4H), 3.03–3.13 (q, J=13.6 Hz), 1.33 (t, J=6.0 Hz, 6H). MS (ESI) m/z 429.2 (M+H+).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:19]=[C:20]1[NH:29][C:28](=S)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1>CN(C)C=O>[O:19]=[C:20]1[N:29]=[C:28]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1
Reactant: O=c1[nH]c(=S)c2ccccc2[nH]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CN(C)C=O
Product: O=c1nc(NCCCOc2cccc(CN3CCCCC3)c2)c2ccccc2[nH]1

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.98 g) and 2-oxo-4-thiono-1,2,3,4-tetrahydroquinazoline (1.78 g) (J. Heterocyclic Chem. 11 (5) p749 (1974)) were stirred in dimethylformamide (5 ml) for 5 days. The reaction mixture was filtered, washing through with cold dimethylformamide and diethyl ether. The filtrate was slowly evaporated to yield the title product as a white crystalline solid (1.38 g), m.p. 219°-221° C. (recrystallised from isopropanol).
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:4]=1[C:5]([NH2:7])=[NH:6].[Cl:13][C:14]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:15]=1[CH:16]=O.[C:23]([O:29][CH3:30])(=[O:28])[CH2:24][C:25]([CH3:27])=O.C([O-])(=O)C.[Na+]>C(O)C>[F:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:4]=1[C:5]1[NH:7][C:25]([CH3:27])=[C:24]([C:23]([O:29][CH3:30])=[O:28])[CH:16]([C:15]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:14]=2[Cl:13])[N:6]=1
Reactant: N=C(N)c1c(F)cccc1F
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: COC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C1=C(C)NC(c2c(F)cccc2F)=NC1c1ccc(F)cc1Cl
Yield: 26.6 %

Procedure:
2 mmol 2,6-Difluorobenzamidine hydrochloride (Boere, R. J., Oakley, R. T., Read, R. V., J. Organometal. Chem. 1987, 331:161-167), 2 mmol 2-chloro-4-fluorobenzaldehyde, 2 mmol methyl acetoacetate and 2.2 mmol sodium acetate were reacted under reflux in 10 ml anhydrous ethanol for 20 hr, concentrated, and then ethyl acetate and water were added to separate the layers. The ethyl acetate layer was dried over anhydrous sodium sulfate, and separated by a column chromatography to obtain 0.21 g of a colorless fine needle crystal with mp 126-128° C.; 1H-NMR (400 MHz, DMSO-d6) δ 2.87 (3H, s); 3.45 (3H, s); 5.92 (1H, s); 7.10-7.38 (6H, m); 9.87 (1H, s); MS (EI) 394.0 (M+).
Reaction SMILES: [CH3:1][O-].[Na+].C(OCC)(=O)[CH2:5][C:6](C)=[O:7].[Cl:13][C:14]1[C:24]([Cl:25])=[C:23]([C:26](=O)[C:27](=[CH2:30])[CH2:28][CH3:29])[CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18]([OH:20])=[O:19]>C(O)C>[Cl:13][C:14]1[C:24]([Cl:25])=[C:23]([C:26]2[CH:27]([CH2:30][CH3:1])[CH2:28][CH2:29][C:6](=[O:7])[CH:5]=2)[CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)CC(C)=O
Reactant: C[O-]
Reactant: C=C(CC)C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Agent: [Na+]
Solvent: CCO
Product: CCC1CCC(=O)C=C1c1ccc(OCC(=O)O)c(Cl)c1Cl
Yield: 99.1 %

Procedure:
To a stirred solution of sodium methoxide (24.3 g, 0.45 mole) in ethanol (700 ml) and ethyl acetoacetate (58.6 g, 0.45 mole) was added [2,3-dichloro-4-(2-methylene-1-oxobutyl)phenoxy]acetic acid (60.6 g, 0.20 mole). The reaction mixture was heated at reflux for 21/2 hours, then the solvent was distilled at reduced pressure. The residue was dissolved in water, acidified with hydrochloric acid, extracted into ether, washed with water, extracted into sodium bicarbonate, acidified, extracted into ether, dried over magnesium sulfate, filtered and evaporated in vacuo to give 68 g of [2,3-dichloro-4-(6-ethyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid which melts at 170°-172° after recrystallization from nitromethane.