Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[C:6]([O:10][C:11]([NH:13][OH:14])=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:1]([O:14][NH:13][C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])(=[O:4])[CH2:2][CH3:3]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CCC(=O)Cl
Product: CCC(=O)ONC(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino propanoate is prepared from propionyl chloride and N-tert-butoxycarbonyl hydroxylamine according to Scheme 1 described by Carpino et al. J. Am. Chem. Soc. 1959, 955-957. (3.4 g, 48%), 1H NMR (250 MHz, DMSO-d6) δ ppm 10.57 (1H, br. s.), 2.40 (2H, q, 7.5 Hz), 1.40 (9H, s), 1.07 (3H, t, 7.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:23])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[CH2:24]([Mg]Cl)[CH2:25][CH3:26]>ClCCl.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:16]([OH:23])([CH2:24][CH2:25][CH3:26])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: O=C(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reactant: CCC[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCC(O)(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36 %

Procedure:
MgBr diethyl etherate (10.5 g, 40.2 mmol) was added to a solution of the above-mentioned ethanone (6.0 g, 16.8 mmol) in dichloromethane (DCM, 65 ml) and the mixture stirred at room temperature for about 90 min. This mixture was then cooled to about 0° C. and n-propylmagnesium chloride (22.8 ml of a 2 M solution in THF, 45.6 mmol) was added dropwise. After stirring for about two hours, the mixture was allowed to warm to room temperature and was then quenched by addition of a saturated ammonium chloride solution. The organic components were extracted three times with DCM, the organic phases combined, washed again with saturated ammonium chloride solution, dried and the solvents evaporated. Addition of diisopropyl ether resulted in precipitation of the unreacted starting material, which was filtered off. The filtrate was then purified using reverse phase chromatography, to give the product as a light brown colored solid (2.5 g, 36%, HPLC2 Rt=1.26 min, masse=392).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C.C1COCC1>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCNCC1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Yield: 89.4 %

Procedure:
To a mixed solution of a commercially available product of 1-(diphenylmethyl)azetidin-3-one (1.00 g, 4.21 mmol), THF (20 mL) and acetic acid (1.00 mL) was added methylpiperazine (561 μL, 5.05 mmol) at room temperature. The resultant mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added sodium triacetoxyborohydride (1.79 g, 8.42 mmol) at room temperature, and the resultant mixture was stirred at room temperature for 2 hours and 15 minutes. Sodium hydrogen carbonate and water were added to the reaction mixture, and the resultant mixture was extracted with ethyl acetate. An organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by silica gel column chromatography (ethyl acetate-methanol) and then further purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to give the title compound (1.21 g, yield: 89%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][CH:6]([C:15]([OH:17])=[O:16])[C:5]2=1.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][CH:6]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[C:5]2=1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(C(=O)O)CCC3
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]c3c(c2c1)C(C(=O)OCc1ccccc1)CCC3

Procedure:
Following a procedure similar to that of 34C but using 8.2 g. of 6-methyl-1,2,3,4-tetrahydrocarbazole-4-carboxylic acid, 4.6 g. of benzyl chloride and 4 g. of sodium carbonate in 50 ml. dry dimethylformamide there was obtained 9.1 g. of the title compound; m.p. 115°-117°C. (ethyl alcohol-pentane).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23].[C:25](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:18]([O:19][CH2:20][CH:21]([CH2:22][O:23][C:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[OH:24])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
51.69 Grams (150 mmol) of batylalcohol and 62.73 g (225 mmol) freshly recrystallized tritylchloride are dissolved at 35° C. in 350 ml methylene chloride. (Note: It is recommended that the tritylchloride be freshly recrystallized from halpasol, trademark for a petroleum ether fraction, b.p. 100°-120° C.). During 15 minutes, 22.77 g (225 mmol; 31.38 ml) triethylamine is added dropwise to the stirred solution at 30°-35° C. (cooling with a water bath). The reaction is continued for six hours at ambient temperature. (Note: It is recommended that a control TLC be done to make sure that the reaction is complete). The solution is then washed with 300 ml of a NaHCO3 solution (1%), dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The oily residue (155 g) is dissolved in 660 ml acetonitrile by warming up to 70° C. with stirring. After cooling to room temperature the title product crystallizes (preferentially after adding a few seed crystals). Crystallization is completed by standing overnight at ambient temperature. The crystallizate is filtered off to yield 82.5 g (93.7%) of crude product (m.p. 53°-55° C.) which can be used for the following step without purification. Recrystallization from halpasol (310 ml) yields 71 g (80%) of pure tritylbatylalcohol. B. In a similar way, introduction of the 3-O-trityl function is accomplished for each 1-O-R-glycerol of Example 2-B.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([NH2:16])=[CH:14][N:13]=[C:12]([NH:17][C@H:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH3:19])[CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[C:27](O)(=O)C.C(N)=N.C([O-])(O)=O.[Na+].CCOC(C)=O>CCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:10]4[CH:11]=[C:12]([NH:17][C@H:18]([C:20]5[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=5)[CH3:19])[N:13]=[CH:14][C:15]=4[N:16]=[CH:27]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c(N)cn1)c1ccc(F)cc1
Reactant: CC(=O)O
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H](Nc1cc2c(cn1)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 59 %

Procedure:
A mixture of (S)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,4,5-triamine (Method 88, 0.15 g, 0.43 mmol) and formamidine acetate (0.089 g, 0.85 mmol) in EtOH (5 ml) was heated at reflux for 2 hours. After cooling to 25° C., the reaction mixture was treated with saturated NaHCO3 solution (10 ml) and EtOAc (30 ml). The organic layer was separated, washed with brine (10 ml), and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc-MeOH=40:1) to give the title compound as an off-white solid (0.092 g, 60%). 1H NMR (400 MHz) 12.75 (s, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 7.42 (m, 2H), 7.08 (m, 2H), 6.90 (s, 1H), 6.89 (d, J=2.8 Hz, 1H), 6.26 (d, J=1.6 Hz, 1H), 5.00 (m, 1H), 1.96 (m, 1H), 1.42 (d, J=6.8 Hz, 3H), 1.02 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 362; Found: [M+H]+ 363.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:11][N:10](C(OCC3C=CC=CC=3)=O)[CH2:9]2)[CH2:4][CH2:3]1>CO.[Pd]>[NH:10]1[CH2:11][CH:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH2:9]1
Reactant: CN1CCN(C2CN(C(=O)OCc3ccccc3)C2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C2CNC2)CC1
Yield: 100.2 %

Procedure:
A mixture of benzyl 3-(4-methylpiperazin-1-yl)azetidine-1-carboxylate (1.45 g, 5.01 mmol) and Pd/C (0.320 g, 0.150 mmol) in methanol (30 mL) was hydrogenated at 30 psi over the weekend. The reaction mixture was filtered through celite and the filtrate was concentrated. The crude product 1-(azetidin-3-yl)-4-methylpiperazine (0.78 g, 5.02 mmol, 100% yield) was obtained as a colorless oil and used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:23]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][N:26]=[C:25]2[N:34]([CH3:38])[N:35]=[C:36]([CH3:37])[C:24]=12.O>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:23]2[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][N:26]=[C:25]3[N:34]([CH3:38])[N:35]=[C:36]([CH3:37])[C:24]=23)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1Cl
Reactant: COc1ccc(S(=O)(=O)NCc2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1cnc2c(c(C)nn2C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
To a solution of 1.39 g (5 mmol) of (4-methoxybenzenesulfonyl)(3-pyridinylmethyl) amine in 4 ml of anhydrous 1-methyl-2-pyrrolidinone was added 0.2 g (5 mmol) of sodium hydride (60% in oil) and the mixture stirred at room temperature until gas evolution ceased. To this mixture was added 1.15 g (4.54 mmol) of ethyl 4-chloro-1,3-dimethylpyrazolo[3,4-b]pyridine-5-carboxylate and 2 ml of anhydrous 1-methyl-2- pyrrolidinone. The mixture was stirred in a sealed tube under nitrogen in an oil bath at 90° C. for 3 days. The mixture was cooled, poured into water and extracted with ethyl acetate. The extract was washed with H2O, brine and dried (Na2SO4). The solution was filtered through a thin pad of hydrous magnesuim silicate and the filter pad washed with ethyl acetate. The filtrate was concentrated to dryness under vacuum to give 1.3 g of solid. Chromatography on silica gel with ethyl acetate as solvent gave 0.35 g of product as a solid, mp 152-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](O)([CH2:11][CH2:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][C:24]([CH3:27])=[N:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C[Si]([N:35]=[N+:36]=[N-:37])(C)C.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:10])[N:35]3[N:36]=[N:37][C:15]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH:26]=[N:25][C:24]([CH3:27])=[N:23]5)=[C:18]([O:28][CH3:29])[CH:17]=4)=[C:14]3[CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C#CCCCC(C)(O)c2ccc(Cl)c(Cl)c2)ccc1-n1cnc(C)n1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(-c2nnn3c2CCCC3(C)c2ccc(Cl)c(Cl)c2)ccc1-n1cnc(C)n1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
Boron trifluoride-diethyl ether complex (75.3 μL) was added to a mixture of 2-(3,4-dichlorophenyl)-7-[3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]hept-6-yn-2-ol (88.0 mg), trimethylsilylazide (105 μL) and toluene (4 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 min, at 70° C. for 15 min and at 110° C. for 6 hr, and allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (15.7 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]#N.Cl.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.C([O:27]CC)C>[Cl-].[Cl-].[Zn+2]>[Cl:1][CH2:2][C:3]([C:15]1[N:14]([CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[F:6])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=1)=[O:27]
Reactant: N#CCCl
Reactant: CCOCC
Reactant: Fc1ccccc1C(c1ccccc1)n1cccc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C(CCl)c1cccn1C(c1ccccc1)c1ccccc1F
Temperature: 95 °C
Reaction time: 6 h

Procedure:
A cooled mixture of chloroacetonitrile (11.3 g) and ZnCl2 (10.2 g) in 10 ml of diethyl ether was saturated with gaseous hydrochloric acid. A solution of 1-[(2-fluorophenyl)phenylmethyl]pyrrole (18.8 g) in 200 ml of ethyl ether was added and this was stirred for 6 hours. The resulting solid was collected, added to water and heated at 95° C. for 2 hours. This was then cooled and extracted with ethyl ether and the organics were dried (saturated NaCl, MgSO4) and concentrated to give 20.4 g of a yellow oil, a portion of which was crystallized to give a white solid, mp 86°-91° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:24])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1

Procedure:
After repetition of the reaction so described, a mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (20.3 g), thionyl chloride (440 ml) and DMF (1.75 ml) was heated to reflux for4 hours. The thionyl chloride was evaporated under vacuum and the residue was azeotroped with toluene three times to give 7-benzyloxy-4-chloro-6-methoxyquinazoline.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:7][O:6][CH2:5][CH2:4]1.CO[C:10](=[O:13])[O:11][CH3:12].COC1C=[C:18]2[C:22](=[CH:23]C=1)[C:21](=[O:25])[CH2:20][CH2:19]2>C(OCC)(=O)C>[CH3:12][O:11][C:10]([CH:20]1[CH2:19][C:18]2[C:22](=[CH:23][C:7]([O:6][CH3:5])=[CH:3][CH:4]=2)[C:21]1=[O:25])=[O:13]
Reactant: COC(=O)OC
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)C1Cc2ccc(OC)cc2C1=O
Reaction time: 12 h
Yield: 67 %

Procedure:
Combine NaH (5.4 g, 122.1 mmol), THF anhydrous (150 mL), and dimethylcarbonate (6.6 mL, 81.3 mmol). While refluxing the reaction under a nitrogen atmosphere, add dropwise 5-Methoxyindanone (3.46 g, 21.33 mmol) over one hour. After the reaction mixture refluxes for 12 hours, quench using Acetic acid and then add Ethyl acetate to the reaction mixture in a separatory funnel. Wash the organic layer several times with water and dry the organic layer over Na2SO4 followed by concentration under reduced pressure. Flash Chromatograph using 1:1 Hexanes:Ethyl acetate to afford 3.14 g, 14.3 mmol (67% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 3.3-3.4 (1H, dd), 3.5-3.6 (1H, dd), 3.7-3.8 (1H, m), 3.8 (3H, s), 3.9 (3H, s), 6.8-7.0 (2H, m), 7.7-7.8 (1H, m); TLC 2:1 Hexanes:Ethyl acetate Rf:=0.4.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br:10][C:11]1[C:16]([OH:17])=[C:15]([F:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:12]=1.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29]Cl.O>ClCCl>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:15]([F:18])[C:16]=1[O:17][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29]
Reactant: CCCCOc1ccc(Br)c(O)c1F
Reactant: COCCOCCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1ccc(Br)c(OCOCCOC)c1F
Reaction time: 8 h
Yield: 99.8 %

Procedure:
60.4 ml (0.355 mol) of ethyldiisopropylamine were added with ice-cooling to 77.4 g (0.294 mol) of 6-bromo-3-butoxy-2-fluorophenol dissolved in 500 ml of dichloromethane, 40.3 ml (0.355 mol) of 2-methoxyethoxymethyl chloride were added dropwise, and the mixture was left to stirr overnight at room temperature. The batch was hydrolysed using water, extracted with dichloromethane and evaporated, and the crude product was filtered through silica gel with n-heptane/MTB ether (3:1), giving 103 g (99%) of 1-bromo-4-butoxy-3-fluoro-2-(2-methoxyethoxymethoxy)benzene as a yellow oil.
Reaction SMILES: [CH:1]1([CH:7]([CH2:19][C:20]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=O)[CH2:8][C:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[OH:18])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O.C[N:32](C)C=O>>[CH:1]1([C:7]2[CH:19]=[C:20]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)[N:32]=[C:9]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[OH:18])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CC(CC(=O)c1cc(F)ccc1O)C1CCCCC1)c1ccco1
Reactant: CN(C)C=O
Solvent: CC(=O)O
Product: Oc1ccc(F)cc1-c1cc(C2CCCCC2)cc(-c2ccco2)n1
Temperature: 100 °C

Procedure:
A mixture of 3-cyclohexyl-1-(2-hydroxy-5-fluorophenyl)-5-(furan-2-yl)-1,5-pentanedione on Wang resin (3.2 g, 1.9 mmol), NH4OAc (1.8 g), and AcOH (1.8 mL) in dimethylformamide (45 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 2-(4-cyclohexyl-6-furan-2-yl-pyridin-2-yl)-4-fluoro-phenol; 1H NMR (DMSO-d6) d 1.35 (m, 4H), 1.61 (m, 2H), 1.76 (m, 4H), 2.68 (m, 1H), 6.74 (dd, J=3.4, 1.8 Hz, 1H), 6.94 (dd, J=9.0, 5.1 Hz, 1H), 7.18 (m, 1H), 7.26 (d, J=3.4 Hz, 1H), 7.72 (s, 1H), 7.94 (s, 1H), 8.04 (m, 2H), 14.22 (s, 1H); IR (KBr) 1617 cm−1; MS [M+H]+ m/z=338. Anal. calcd for C21H20FNO2.0.2MCF3CO2H: C, 71.29; H, 5.61; N, 3.89; Found: C, 71.24; H, 5.74; N, 3.76.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([CH3:20])[CH3:19].[H-].[Na+].ClC(Cl)(Cl)[C:25]([N:27]=C=O)=[O:26]>CN(C=O)C.C(Cl)Cl>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:25]([NH2:27])=[O:26])[C:13](=[O:18])[C:12]2([CH3:19])[CH3:20]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
1.45 g (5 mmol) 5-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (Example 3) in 30 ml DMF were cooled to 0° C. 0.12 g (5 mmol) sodium hydride from a 55% dispension in mineral oil was added and the mixture was stirred for 0.5 hr at 0° C. then 0.5 hr at 20° C. After cooling to 0° C. a solution of 1 g trichloroacetyl isocyanate in 5 ml dry methylene chloride was added dropwise. The reactional mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum, the residue taken up in 50 ml ethyl acetate and 40 g neutral aluminum oxide was added. The compound was then extracted from the aluminum oxide on a column with ethyl acetate. The solvent was evaporated and the residue was purified by chromatography on silica (eluent:methylene chloride/ethyl acetate: 2/1) to yield 0.37 g (22%) of the desired compound.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]([F:32])([O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])[CH:21]([F:23])[F:22].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[C:25]([O:24][C:20]([F:19])([F:32])[CH:21]([F:22])[F:23])[CH:26]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc(OC(F)(F)C(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(OC(F)(F)C(F)F)c1
Yield: 72.8 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 300 mg of 3-(1,1,2,2-tetrafluoroethoxy)aniline, and 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of N,N-dimethylformamide. 300 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.[C:28]1(=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCCCC1
Product: COc1ccc2c(c1)CCN(C1CCCCC1)C2Cc1ccc(OCc2ccccc2)cc1
Yield: 52.8 %

Procedure:
The title compound was prepared as described in Example 14.C, using 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.5 g, 1.39 mmol) and cyclohexanone (0.588 g. 6.0 mmol) to provide the title compound (0.324 g, 53% yield): ES-MS (m/z) 442 [M+H]+.
Reaction SMILES: Cl[C:2]1([F:11])[C:7](F)([F:8])[CH2:6][C:5]([CH3:10])=[CH:4][CH2:3]1.ClC1(F)CC(C)=CCC1(F)F.ClC(F)=C(F)F.C=CC(=C)C>>[F:8][C:7]1[CH:6]=[C:5]([CH3:10])[CH:4]=[CH:3][C:2]=1[F:11]
Reactant: CC1=CCC(F)(Cl)C(F)(F)C1
Agent: CC1=CCC(F)(F)C(F)(Cl)C1
Agent: FC(F)=C(F)Cl
Solvent: C=CC(=C)C
Product: Cc1ccc(F)c(F)c1

Procedure:
As shown in the above reaction, a mixture of 4-chloro-1-methyl-4,5,5-trifluorocyclohexene (IIIa) and 5-chloro-1-methyl-4,4,5-trifluorocyclohexene (IIIb) is prepared by reacting chlorotrifluoroethylene (CTFE) (I) and isoprene (II) at temperature range of 390 to 480° C. through continuous vapor phase condensation in a flow reactor and distilling the resultant. The mixture is dehydrohalogenated in the presence of alkali metal hydroxide and a phase transition catalyst to form 3,4-difluorotoluene (IV). The 3,4-difluorotoluene is reacted with chlorine gas in the presence of catalysts consisting of ferro-shaving and ferric chloride at temperature range of -10 to 40° C. without using any organic solvent to form 2-chloro-4,5-difluorotoluene (V). The 2-chloro-4,5-difluorotoluene is photo-reacted with chlorine gas under a lighting mercury lamp at temperature range of 80 to 140° C. without using any organic solvent to form 2-chloro-4,5-difluorobenzotrichloride (VI). The 2-chloro-4,5-difluorobenzotrichloride is reacted with aqueous acid solution at temperature range of 35 to 80° C. without using any organic solvent to give 2-chloro-4,5-difluorobenzoic acid (VII). The 2-chloro-4,5-difluorobenzoyl chloride (VIII) according to the present invention is prepared by reacting 2-chloro-4,5-difluorobenzotrichloride (VI) with zinc oxide.