Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:13][CH:12]=[C:11]([CH:23]=[O:24])[C:10]2=[O:25])=[O:5])[CH3:2].S(=O)(=O)([OH:28])N.Cl([O-])=O.[Na+]>ClCCl.O>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:13][CH:12]=[C:11]([C:23]([OH:28])=[O:24])[C:10]2=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)Oc1cc2occ(C=O)c(=O)c2cc1OC(=O)OCC
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(=O)OCC

Procedure:
The compound (1.05 g) obtained in (2) was dissolved in of dichloromethane (31.5 ml) and a solution of 1.05 g of sulfamic acid in water (18.9 ml) was added at 10° C. with stirring. Then, a solution of sodium chlorite (525.6 mg) in water (1.2 ml) was added. The solution was stirred at the same temperature for 1 hour, and allowed to separate. The dichloromethane layer was washed with water (once) and then with a saturated aqueous solution of sodium chloride (twice), and dried over magnesium sulfate. The solvent was distilled off, and ethyl ether was added to the residue to triturate it. The triturated product was collected by filtration, and dried to afford the desired product (950 mg).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1.Cl.N([O-])=O.[Na+].B(O)(O)O.[FH:30]>O>[F:30][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2N)cc1
Reactant: F
Agent: Cl
Agent: O=N[O-]
Agent: OB(O)O
Solvent: O
Product: CCOC(=O)C(O)c1ccc(-c2ccccc2F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 44.2 g. (0.15 moles) of ethyl 2'-amino-4-biphenylylglycolate is added at 0°C 44 ml. of 1.5 moles of concentrated hydrochloric acid. The reaction mixture is maintained at 0°C and the diazonium salt is prepared with23.2 g. (0.32 moles) of 95% sodium nitrite in 80 ml. of water. To this mixutre is rapidly added a solution of 10.4 g. (0.17 moles) of boric acid dissolved in 22 g. (0.66 moles) of 60% hydrofluoric acid. The reaction mixture is then stirred for 1/2 hour and filtered, washed with 3 × 25 ml. of water, 2 × 25 ml. of methanol and 25 ml. of ether. The residual cake is then treated in vacuo. The treated cake is then placed in a distilling flask and heated to permit spontaneous decomposition. After the decomposition, the residue is then fractionally distilled to obtain ethyl 2'-fluoro-4-biphenylylglycolate.
Reaction SMILES: [CH3:1][C:2](=[N:6][OH:7])[C:3](=[O:5])[CH3:4].[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O>C(O)(=O)C>[Br:8][C:9]1[CH:10]=[C:11]([C:12]2[O:5][C:3]([CH3:4])=[C:2]([CH3:1])[N+:6]=2[O-:7])[CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CC(=O)C(C)=NO
Solvent: CC(=O)O
Product: Cc1oc(-c2cccc(Br)c2)[n+]([O-])c1C
Yield: 74.1 %

Procedure:
A solution of 2,3-butanedione monooxime (50 g, 0.49 mol) and 3-bromobenzaldehyde (101 g, 0.54 mol) in acetic acid (500 mL) was cooled to 0° C. and then gaseous HCl was bubbled through the solution for 35 min while the reaction was stirred in an ice bath. Diethyl ether (500 mL) was then added to the reaction to precipitate the product and the resultant slurry stirred 45 min at 0° C. before being filtered. The solids were rinsed with Et2O (50 mL), taken up in water (1 L) and concentrated NH4OH (60 mL) added to the slurry. This mixture was extracted with CHCl3, the organic layer was dried (MgSO4), and the solvent removed in vacuo to give 97.4 g (74%) of 2-(3-bromophenyl)-4,5-dimethyloxazole-3-oxide as a white solid. The compound should be used directly with 24–48 h.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[C:18]([O:26][C:27]1[N:32]=[C:31]([OH:33])[C:30]([C:34]#[N:35])=[CH:29][CH:28]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[C:18]([O:26][C:27]1[N:32]=[C:31]([O:33][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([Br:8])=[CH:10][CH:11]=2)[C:30]([C:34]#[N:35])=[CH:29][CH:28]=1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: N#Cc1ccc(OC(=O)c2ccccc2)nc1O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(OC(=O)c2ccccc2)nc1OC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
Triethylamine (3.46 ml) and 1.82 g of 4-bromobenzoyl chloride were added to a solution of 2.00 g of 6-benzoyloxy-3-cyano-2-hydroxypyridine in 50 ml of dioxane. The mixture was stirred at room temperature for 1 hour. The salt thus produced was separated by filtration and the filtrate was concentrated. The concentrate was applied to silica gel column chromatography using, as an eluent, chloroform, giving 2.97 g of the title compound in a yield of 84%.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2.Cl.[C:15]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl>CCOCC.CC(CC(C)C)=O>[C:15]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][CH:12]=3)[NH:9][C:8](=[O:13])[CH2:7]4)[CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=C1Cc2cc(CCCl)ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOCC
Solvent: CC(=O)CC(C)C
Product: O=C1Cc2cc(CCN3CCN(c4cccc5ccccc45)CC3)ccc2N1

Procedure:
To a 50 ml round bottomed flask equipped with condenser and nitrogen inlet were added 370 mg (1.69 mmol) 5-(2-chloroethyl)oxindole, 400 mg (1.69 mmol) N-(1-naphthyl)piperazine hydrochloride, 200 mg (1.69 mmol) sodium carbonate, 2 mg sodium iodide, and 50 ml methylisobutylketone. The reaction was refluxed 24 hours, cooled, and evaporated. The residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel with ethyl acetate, and the product fractions collected and evaporated to give a foam. The foam was dissolved in ether, treated with hydrochloric acid gas, and the precipitate collected, washed with ether, and dried to afford a white solid, m.p. 303°-305° C., 603 mg (84%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].C(N(CC)CC)C.[CH2:14]([C:19]12[CH2:26][CH2:25][C:22]([C:27]([O:29]C)=O)([CH2:23][CH2:24]1)[CH2:21][CH2:20]2)[CH2:15][CH2:16][CH2:17][CH3:18]>C1C=CC=CC=1.C1COCC1>[C:27]([C:22]12[CH2:21][CH2:20][C:19]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH2:24][CH2:23]1)[CH2:26][CH2:25]2)(=[O:29])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC12CCC(C(=O)OC)(CC1)CC2
Reactant: CCCCBr
Agent: [Mg]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCCCC12CCC(C(=O)CCCC)(CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Bromobutane (10.45 g, 0.076 mol) in dry benzene (9 ml) was added dropwise to magnesium (1.68 g, 0.069 mol) in dry benzene (3 ml) and dry THF (9.98 g) during 75 min. The reaction mixture was stirred at room temperature for 1 h. Triethylamine (28.84 g, 0.285 mol) was added at 5°-10° C. and methyl 4-n-pentylbicyclo(2,2,2)octane-1-carboxylate (3.00 g, 0.013 mol) in dry benzene (27 ml) was added dropwise during 1 h at 5°-15° C. The ice bath was removed and the reaction mixture was left stirring at room temperature for 4 h, and the progress of the reaction was followed by glc until the ester peak had almost disappeared. The reaction mixture was diluted with water and the organic layer was washed with 4N-hydrochloric acid (3×50 ml). The aqueous layer was washed with ether (3×50 ml) and the ether layers were combined with the organic layer and washed with water (3×50 ml) and dried (MgSO4). The ether was removed and the residue dried in vacuo and used directly to make the required compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5](O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S([O-])([O-])(=O)=O.[Mg+2].[CH2:23]([NH2:26])[CH2:24][NH2:25]>C1C=CC=CC=1>[NH2:25][CH2:24][CH2:23][N:26]1[CH2:2][C:3]2[C:4](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCN
Reactant: OCc1ccccc1C(O)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: NCCN1Cc2ccccc2C1c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 127 g. (0.59 mole) of 2-hydroxymethylbenzhydrol was dissolved in 900 ml. of benzene, 80 g. of anhydrous magnesium sulfate was added and the mixture was cooled in an ice bath. Hydrogen bromide was bubbled into the stirred solution until saturation which took about 30 minutes. During this time the temperature of the solution was kept at 15°-18°. The ice bath was removed and the temperature was allowed to rise to 35° in the course of 1 hour. The mixture was heated for another hour at 40°-45° on a steam bath. During the whole time hydrogen bromide was passed into the solution to keep it saturated. The mixture was filtered and the solution was concentrated in vacuo to give a red oil which was dissolved in 200 ml. of benzene and added to 342 g. (5.7 moles) of ethylenediamine in the course of 15 minutes. During the addition the mixture was stirred and cooled to maintain a temperature of ca. 40° . The mixture was stirred at 25° for 70 minutes. Two layers were obtained and separated. The benzene layer was washed with water and concentrated in vacuo. The residual oil was dissolved in 250 ml. of ether. This solution was extracted twice with 300 ml. of cold 1N hydrochloric acid. The acidic aqueous phase was made alkaline with aqueous sodium hydroxide and extracted with 350 ml. of ether. The ethereal solution was washed with 250 ml. of water, dried and concentrated. The residue was an amber oil which crystallized on scratching. This material melted up to ca. 45°.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]1([CH2:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[O:16])[CH:13]=[CH:12][N:11]=[CH:10]1>CCOCC.O1CCCC1>[OH:16][C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:14][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: O=C1CCc2cc(C(=O)Cn3ccnc3)ccc2N1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CCc2cc(C(O)(Cn3ccnc3)c3ccccc3)ccc2N1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3 ml of 3M phenylmagnesium bromide in ether was added to a suspension of 1.0 g of 6-(imidazol-1-yl acetyl)-3,4-dihydrocarbostyril in 25 ml of tetrahydrofuran at 0° C., the mixture stirred for 30 minutes at 0° C., then at 25° C. for 18 hours. The reaction was quenched with 10 ml of water and extracted with 10% methanol in methylene chloride. The organic extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield a gum which was chromatographed on silica gel, eluting with 5% methanol in methylene chloride, to give 6-[1-hydroxy-1-phenyl-2-(imidazol-1-yl)ethyl]-3,4-dihydrocarbostyril as a foam. 1H NMR (CDCl3) δ2.56 (d, 1H, J=8.1 Hz), 2.58 (d, 1H, J=8.1 Hz), 2.78 (s, 1H), 2.88 (t, 2H, J=8.1 Hz), 4.65 (s, 2H), 6.57 (s, 1H), 6.74 (d, 1H, J=8.82 Hz), 6.77 (s, 1H), 7.14 (m, 2H), 7.25 (s, 1H), 7.30-7.40 (m, 5H), 8.62 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:5](=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([NH:25][C:26](=O)[O:27]C2C=CC=CC=2)[N:18]=1.N12CCCCC1C=NCCC2.Cl>C(#N)C.O>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([O:16][CH3:15])[N:18]=[C:19]([NH:25][C:26]([NH:14][S:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=23)(=[O:13])=[O:12])=[O:27])[N:20]=1
Reactant: Cc1nc2c(S(N)(=O)=O)cccc2s1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: CC#N
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccc3sc(C)nc23)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.23 g of the product from Example 2 and 0.28 g of 4,6-dimethoxypyrimidin-2-ylcarbamic acid, phenyl ester in 5 mL of dry acetonitrile was treated at room temperature with 0.15 mL of 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU), added over a period of about one minute. The reaction solution was stirred at room temperature for 1.5 hour and was then diluted with 2 mL of water and acidified by the addition of 5% aqueous hydrochloric acid. The resulting precipitate was collected by filtration, washed well with water and ether, and dried. The yield of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-methyl-4-benzothiazolesulfonamide was 0.21 g as a white powder, m.p. 187°-194° C. NMR (CDCl3 /DMSO-d6): δ 2.7 (3H, s), 4.05 (6H, s), 5.8 (1H, s), 7.5 (1H, t, J=8 Hz), 8.15 (1H, dd, J=2, 8 Hz), 8.25 (1H, dd, J=2, 8 Hz), 8.7 (1H, br s), 13.3 (1H, br s); IR(KBr): 3330, 1730, 1610, 1350, 1160 cm-1.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1)[C:27]([OH:29])=O.[C:39]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=[O:42])[NH:40][NH2:41].C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1)[C:27]([NH:41][NH:40][C:39]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:29]
Reactant: COc1cc(C(=O)O)ccc1-n1cnc(C)c1
Reactant: NNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NNC(=O)OCc2ccccc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
IPEA (1.05 mL) and 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (1.16 g) were sequentially added to a solution of 3-methoxy-4-(4-methylimidazol-1-yl)benzoic acid (CAS#937026-26-1, 933 mg), benzyl carbazate (737 mg) and HOBT (817 mg) in DMF (15 mL), and the mixture was stirred at room temperature overnight. Ethyl acetate, ice water and a saturated sodium bicarbonate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was sequentially washed with water and brine. The combined aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Ethyl acetate and NH silica gel were added to the resulting residue and then the mixture was concentrated under reduced pressure.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29](O)=[O:30])=[CH:21]1.C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C>CN(C=O)C>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:30])=[CH:21]1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1c[nH]c2ccccc12
Reaction time: 18 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (49.2 mg, 0.196 mmol), indole-3-carboxylic acid (37.9 mg, 0.235 mmol) and 1M DCC in CH2C2 solution (0.235 ml, 0.235 mmol) were mixed in DMF (2 ml) and the pH adjusted to 9.0 with triethylamine (32.7 μl, 0.235 mmol). The reaction was stirred 18 hrs. at 25° C., the DMF removed in vacuo, and the residue chromatographed on a Waters Semi-Prep C-18 30×0.9 cm column (gradient elution of 5 to 95% CH3CN in H2O) to give the title compound as a white solid from MeOH/ether: (m.p. 265°-268°).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Br:10]Br>>[F:1][C:2]1[CH:7]=[C:6]([Br:10])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1F
Reactant: BrBr
Product: COc1ccc(Br)cc1F

Procedure:
The procedure for synthesis is briefly explained below. First, 2-fluoroanisole [1] is reacted with bromine to give 2-fluoro-4-bromoanisole [2], which is subsequently reacted with magnesium to give a compound [3] of Grignard reagent type. This compound is condensed with 2-fluoro-4-bromoanisole [2] in the presence of a palladium chloride catalyst to give 3,3'-difluoro-4,4'-dimethoxybiphenyl [4]. In this way, the biphenyl skeleton is formed. Then, the both terminals of 3,3'-difluoro- 4,4,-dimethoxybiphenyl [4] are demethylated by boron tribromide to give 3,3'-difluoro-4,4'-dimethoxybiphenyl [4]. One of the two hydroxyl groups in the compound [5] is blocked by acylation with acetic acid chloride to give a compound [6]. The remaining hydroxyl group in the compound [6] is alkylated with a halogenated alkyl having a specific chain length (p=6 to 15) to give a compound [7]. Finally, the compound [7] undergoes hydrolysis by an alkali catalyst (sodium hydroxide) to remove the acyl group. Thus there is obtained an unblocked compound [8], which is ready for coupling with a cyclohexane ring through an ester linkage.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:14])=[C:5]([Cl:13])[C:6]=1[C@@H:7]1[CH2:9][C@H:8]1[C:10](=O)[CH3:11].N1C=CC=CC=1.Cl.[CH3:22][O:23][NH2:24]>CO.O>[CH3:22][O:23][N:24]=[C:10]([C@@H:8]1[CH2:9][C@H:7]1[C:6]1[C:5]([Cl:13])=[C:4]([Cl:14])[S:3][C:2]=1[Cl:1])[CH3:11]
Reactant: CC(=O)[C@@H]1C[C@H]1c1c(Cl)sc(Cl)c1Cl
Reactant: CON
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: CON=C(C)[C@@H]1C[C@H]1c1c(Cl)sc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
To a stirred solution of trans 1-[2-(2,4,5-trichloro-thiophen-3-yl)-cyclopropyl]-ethanone (2.7 g; 10 mmol) prepared as described in example P29, in methanol (20 ml) at ambient temperature was added pyridine (1.25 ml; 15 mmol) and methoxyamine hydrochloride (1.3 g; 15 mmol). The reaction mixture was stirred for 4 hours at ambient temperature then poured in water (50 ml) and extracted with dichloromethane (3×30 ml). Combined organic layers were washed with water (30 ml) and dried over anhydrous sodium sulphate. The solvent was removed in vacuo to afford 2.85 g (95% of theory) of trans 1-[2-(2,4,5-trichloro-thiophen-3-yl)-cyclopropyl]-ethanone O-methyl-oxime as an E/Z mixture in form of an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[CH:3]=1.[Li]CCCC.[Br:16][C:17]1[CH:18]=[N:19][C:20](I)=[N:21][CH:22]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[Br:16][C:17]1[CH:18]=[N:19][C:20]([C:3]2[C:2]([F:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=2[F:10])=[N:21][CH:22]=1
Reactant: Brc1cnc(I)nc1
Reactant: COc1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(F)c(-c2ncc(Br)cn2)c(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a three neck round bottle flask, to a mixture of 1,3-difluoro-5-methoxybenzene (8.39 mmol, 0.98 ml) in THF (40 ml) at −78° C. under argon atmosphere, a solution of n-BuLi (9.13 mmol, 3.65 ml) in THF (2.5M) was added. The mixture was stirred at −78° C. for 30 minutes and then it was heated to −50° C. A solution of ZnCl2 (9.13 mmol, 18.3 ml) in THF (0.5M) was added dropwise and the mixture was stirred at this temperature for 20 minutes. A solution of 5-bromo-2-iodopyrimidine (7.02 mmol, 2.0 g) in THF (5 ml) and Pd(PPh3)4 (0.70 mmol, 0.81 g) were added respectively and the crude mixture was heated at 40° C. overnight. The solvent was evaporated and the crude mixture was purified over SiO2 eluting with mixtures of hexane/ethyl acetate affording 0.89 g (39% of yield) of the expected product.
Reaction SMILES: [N:1]1([CH:8]=[N:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[OH:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27]>O1CCCC1>[CH3:24][N:25]([CH3:29])[C:26]([O:16][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[N:9]=[CH:8][N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:27]
Reactant: Oc1cnccc1N=CN1CCCCCC1
Reactant: CN(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1cnccc1N=CN1CCCCCC1

Procedure:
A mixture prepared from 4-[[(hexahydro-azepin-1-yl)methylene]amino]-3-pyridinol (2.9 g), triethylamine (2.86 ml), dimethylcarbamyl chloride (1.83 ml) and tetrahydrofuran (85 ml) was refluxed for 1 hour, cooled, poured directly onto a silica column and eluted successively with ethyl acetate and 5% Et3N/ethyl acetate. The eluate was concentrated and dried under high vacuum to obtain 3.88 g of oil. The oil solidified in a refrigerator over the weekend, and was triturated with cold pentane to yield 3.31 g of solid, m.p. 68°-70° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.Cl.[CH2:12](N=C=N)[CH3:13].C(O)C.CN(C1C=CC=CN=1)C>ClCCl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:12][CH3:13])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(I)nc1
Reactant: CCN=C=N
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(I)nc1
Temperature: 50 °C

Procedure:
To a suspension of 6-iodonicotinic acid (23.38 g, 94.20 mmol) in dichloromethane (100 ml) was added a solution of 13-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.86 g, 103.6 mmol) in dichloromethane (250 ml). To this mixture was added ethanol (12.40 g, 269.27 mmol) followed by dimethylaminopyridine (1.15 g, 9.41 mmol). The mixture was heated at 50° C. for 24.5 hours, concentrated in vacuo, and diluted with water (200 ml) then extracted with ethyl ether (550 ml). The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO4) and concentrated to a yellow solid. Purification by flash chromatography (silica, 10% EtOAc-hexane) afforded the title compound as white needles: mp 48-49° C.; 1H NMR (CDCl3): δ 8.94 (1H, d, J=2.1 Hz), 7.91 (1H, dd, J=2.1, 8.2 Hz), 7.85 (1H, d, J=8.2 Hz), 4.41 (2H, q, J=7.1 Hz), 1.41 (3H, t, J=7.1 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:2]([N:27]2[CH2:28][CH2:29][O:25][C:26]2=[O:30])[CH:7]=1
Reactant: O=C1NCCO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCOC3=O)CC2)c(C)c1
Yield: 56.4 %

Procedure:
Using (2-bromo-4-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.79 g) described in Preparation Example 167 and oxazolidin-2-one (0.381 g) and by the reaction and treatment in the same manner as in Preparation Example 48, the title compound (1.023 g) was obtained.