Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[NH3:20].O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][NH2:20])=[CH:4][CH:3]=1
Reactant: N
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Solvent: CO
Solvent: O
Product: NCCOC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 135 °C
Reaction time: 6 h
Yield: 58.5 %

Procedure:
A mixture of 28.2 g (0.1 mole) of 2-[bis(p-fluorophenyl)methoxy]ethyl chloride and 17 g (1 mole) of ammonia in 187.5 ml of methanol is shaken in an autoclave for a period of 6 hours at 135° C. The reaction mixture is poured into water and extracted with diethyl ether. The extract is acidified with 2N hydrochloric acid. The acid aqueous layer is separated off, made alkaline with 2N sodium hydroxide and extracted with diethyl ether. The extract is dried over potassium carbonate and the ether is distilled off. The residue is distilled, yielding 15.4 g of 2-[bis(p-fluorophenyl)-methoxy]ethylamine, boiling point 130° C/0.2 mm.Hg. The base is dissolved in diethyl ether and an ethereal solution of maleic acid is added. The precipitate is filtered off and crystallised from a mixture of ethanol and diethyl ether. 2-[Bis(p-fluorophenyl)methoxy]ethylamine hydrogen maleate is obtained. Its melting point is 126°-127° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1([OH:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:13][CH2:14][Cl:15]>>[Cl:15][CH2:14][CH2:13][N:6]1[CH2:5][CH2:4][C:3]([C:2]([F:1])([F:10])[F:11])([OH:9])[CH2:8][CH2:7]1
Reactant: OC1(C(F)(F)F)CCNCC1
Reactant: ClCCBr
Product: OC1(C(F)(F)F)CCN(CCCl)CC1

Procedure:
A solution of 4-(trifluoromethyl)piperidin-4-ol and 1-bromo-2-chloroethane are reacted using the procedure for Example OO to afford 1-(2-chloroethyl)-4-(trifluoromethyl)piperidin-4-ol.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([N+:11]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5]>C(O)C>[NH2:11][C:7]1[C:8]([OH:10])=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])c(O)cc1F
Solvent: CCO
Product: N#Cc1cc(N)c(O)cc1F
Yield: 95.3 %

Procedure:
A solution of 2-fluoro-4-hydroxy-5-nitrobenzonitrile (D147; 270 mg, 1.483 mmol) in ethanol (35 mL) was passed through an H-Cube flow hydrogenator at room temperature and atmospheric pressure on full H2 mode, with a flow rate of 1 mL min−1 and using a CatCart30 (approx. 140 mg catalyst). The residual solution was diluted with further ethanol (8 mL) to ensure maximum recovery of material. The collected product solution was evaporated to dryness to give the desired product as a tan solid (215 mg).
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+]>CO>[CH2:13]([C:12](=[CH:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:11]=[O:16])[CH2:14][CH3:15]
Reactant: CCCCC=O
Reactant: O=CC=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C=O)=CC=Cc1ccccc1
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of cinnamaldehyde (400 g) and valeraldehyde (300 g) was added to a solution of 52 g of NaOH in 1950 g methanol over a period of 2 hours. After the addition is completed, stirring was continued for another 2 hours. The reaction mixture was washed with water, the solvent removed and the resulting product distilled. 412 g 2-n-Propyl-5-phenylpenta-2,4-dienal were obtained as a yellowish oil (content 90%; 60% theoretical yield).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[CH2:13]([OH:17])[CH2:14][C:15]#[CH:16].COC(C)(C)C>C(N(CC)CC)C.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:7]1[C:2]([C:16]#[C:15][CH2:14][CH2:13][OH:17])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9]
Reactant: C#CCCO
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: OCCC#Cc1c(F)c(F)c(F)c(F)c1F
Temperature: 80 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
To a solution of 1-bromo-2,3,4,5,6-pentafluorobenzene (50 g) in triethylamine (200 mL), 3-butyn-1-ol (15 g), triphenylphosphine (2.7 g), dichlorobistriphenylphosphinepalladium (3.6 g) and copper (I) iodide (1.9 g) were added, followed by stirring at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, and tert-butyl methyl ether (500 mL) was added thereto, followed by stirring at 0° C. for 30 minutes. The reaction mixture was filtered through Celite®, and the filtrate was concentrated. The resulting residue was purified by flash column chromatography (hexane:ethyl acetate=95:5→65:35) to give the title compound (43 g) having the following physical properties.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5]([CH2:10][OH:11])[N:4]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(F)(F)F.CCOCC>>[OH:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:1][CH2:2][C:3]=2[N:4]=1
Reactant: O=Cc1ccccc1
Reactant: OCc1ccc(O)c(CO)n1
Agent: FB(F)F
Solvent: CCOCC
Product: OCc1ccc2c(n1)COC(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a stirred suspension of 31 g. (0.2 mole) of 2,6-bis-(hydroxymethyl)-3-hydroxypyridine (U.S. Pat. No. 3,700,681) in 101 ml. (1 mole) of benzaldehyde at 20°-25° C. is added dropwise over 45 min. 56.7 g. (0.4 mole) of borontrifluoride etherate. The mixture is allowed to stir at room temperature for 2 hrs., and the excess benzaldehyde removed under reduced pressure. The residue, after standing at room temperature, is added to 75 ml. of a 10M aqueous sodium hydroxide solution, and the product extracted into methylene dichloride. The organic phase is separated, concentrated in vacuo to 100 ml. and the methylene dichloride diluted with n-hexane. The crude product which crystallizes is filtered and dried, 37.4 g. (77% yield), m.p. 85°-89° C. Further purification is effected by recrystallization from acetone-n-hexane, 22.1 g., m.p. 114°-118° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+].[CH2:22](O)[CH3:23]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH3:18])[C:15]([O:17][CH2:22][CH3:23])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1cccc(Oc2ccccc2)c1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)C(C)c1cccc(Oc2ccccc2)c1
Temperature: 0 °C

Procedure:
Two hundred grams of 2-(3-phenoxyphenyl)propionic acid, prepared according to Example 2, were dissolved in 1500 ml. of ethanol, and hydrogen chloride gas was passed into the ethanolic solution until it was saturated. The reaction mixture was then refluxed with stirring overnight after which a large portion of the ethanol was evaporated in vacuo, and the remaining reaction mixture was poured into ice water. The reaction mixture was basified with 10 percent sodium hydroxide, and extracted twice with ethyl ether. The combined ether extracts were washed twice with water and dried over sodium sulfate. The ethyl ether was evaporated, leaving crude ethyl 2-(3-phenoxyphenyl)propionate as an oily residue. The preparation was repeated with an additional 200 g. of 2-(3-phenoxyphenyl)propionic acid. The crude residues were combined and distilled through a 15 cm. Vigreux column to yield 339.9 g. of ethyl 2-(3-phenoxyphenyl)propionate, b.p., 128°-134° C./0.15 mm., nD25 = 1.5458.
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[NH2:31])([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].C(=O)([O-])[O-].[K+].[K+].C1C(=O)N([O:45][C:46]([CH2:48][CH2:49][C:50]2[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][CH:51]=2)=O)C(=O)C1>O.CS(C)=O>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[NH:31][C:46](=[O:45])[CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][CH:51]=1)([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: O=C(CCc1ccc(O)cc1)ON1C(=O)CCC1=O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](N)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](NC(=O)CCc2ccc(O)cc2)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
3'-Amino-3'-deoxyadenosine 5'-triphosphate (6 mg, 11 mmol) and potassium carbonate (7.2 mg, 55 mmol.) were dissolved in 0.8 ml of water. 3-(4-Hydroxyphenyl) propionic acid N-hydroxysuccinimide ester (27 mg, 0.1 mmol) in 0.4 ml of DMSO was added at room temperature, and the mixture was stirred for 24 hours at room temperature. The product was purified by the procedure described for 3'-acetylamino-3'-deoxyadenosine 5'-triphosphate (above); t=14 min (4.3 mg obtained, 41% yield). UV: lmax =259 nm. High resolution MS for C19H24N6O14P3 : calcd. 653.0563, found 653.0596 (MH3-).
Reaction SMILES: [S:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])[NH:3]1.[C:13]1([C:19](S)([CH3:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(C(F)(F)F)=O>C([O-])(O)=O.[Na+]>[C:13]1([C:19]([S:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([OH:12])[N:3]=2)([CH3:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1Cc2ccccc2C(=S)N1
Reactant: CC(C)(S)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(O)cc2ccccc12)c1ccccc1
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To a 50 mL round bottom flask was added 1-thioxo-1,4-dihydro-2H-isoquinolin-3-one (250 mg, 1.41 mmol), and 2-phenylpropan-2-thiol (192 mg, 1.41) followed by a solution of TFA (10 mL, 20% v/v in DCM). The reaction mixture was stirred under Ar for 1 h, neutralized with NaHCO3 (100 mL, sat. aq.), and then extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, and then the solvent was removed by rotary evaporation to yield a crude residue. The crude residue was purified via silica gel chromatography to provide the title compound as an orange solid (188 mg, 0.636 mmol, 45%). 1H NMR (400 MHz, CDCl3): δ ppm 8.11 (d, J=8.79 Hz, 1H), 7.55 (t, J=7.47 Hz, 3H), 7.42-7.50 (m, 1H), 7.14-7.29 (m, 5H), 6.74 (s, 1H), 1.95 (s, 6H). LC/MS m/z 296 [M+H].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[N:24]1([CH:30]2[CH2:36][CH2:35][C:34]3[CH:37]=[C:38]([NH2:41])[CH:39]=[CH:40][C:33]=3[CH2:32][CH2:31]2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])=[N:7][C:2]([NH:41][C:38]2[CH:39]=[CH:40][C:33]3[CH2:32][CH2:31][CH:30]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:36][CH2:35][C:34]=3[CH:37]=2)=[N:3][CH:4]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCC(N2CCOCC2)CC3)ncc1Cl

Procedure:
The title compound was prepared from (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine and 7-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine in an analogous manner as Example 179. Product isolated as a white solid (46 mg, 60%). LCMS (m/e) 565 (M+H); 1H NMR (CDCl3, 400 MHz) δ 8.27 (d, 1H, J=7.6 Hz), 8.00 (s, 1H), 7.59 (s, 1H), 7.38 (s, 1H), 7.35 (d, 1H, J=9.3 Hz), 7.04 (d, 1H, J=8.1 Hz), 6.84 (s, 1H), 6.55 (s, 1H), 6.51 (d, 1H, J=9.3 Hz), 3.92 (s, 3H), 3.90 (m, 5H), 3.69 (m, 4H), 3.16 (m, 4H), 2.81 (2H, m), 2.67 (2H, m), 2.55 (m, 4H), 2.08 (m, 2H), 1.44 (m, 2H).
Reaction SMILES: O.[CH:2]([O-:4])=[O:3].[NH4+].Cl[C:7]1[S:8][C:9](Cl)=[C:10]2[C:14](=C=O)[N:13](OC(C)(C)C)[CH2:12][C:11]=12>CO.[Pd]>[CH3:9][C:10]([CH3:14])([O:3][C:2]([N:13]1[CH2:12][C:11]2=[CH:7][S:8][CH:9]=[C:10]2[CH2:14]1)=[O:4])[CH3:11]
Reactant: CC(C)(C)ON1Cc2c(Cl)sc(Cl)c2C1=C=O
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2cscc2C1
Yield: 134.3 %

Procedure:
17.6 g of 10% palladium-on-charcoal containing 50% of water and then 41.6 g (600 mmol) of ammonium formate are added to a solution of 8.82 g (30 mmol) of 1,3-dichloro-5(1,1-dimethylethoxy)-carbonyl-5,6-dihydro-4H -thieno[3,4-c]pyrrole in 75 ml of methanol. The mixture is heated at reflux for 24 hours and it is then cooled, filtered through a Celite column, rinsed with twice 50 ml of dichloromethane and evaporated to dryness. The residue is taken up in 100 ml of dichloromethane, filtered and evaporated to dryness. There are obtained 4.54 g of an oily product which crystallizes slowly. Yield 68%. Melting point: 36°-38° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-])(=[O:13])=[O:12])[CH3:10].P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)(=[O:12])=[O:13])[CH3:10]
Reactant: Cc1ccc(C)c(C(C)S(=O)(=O)c2cccc[n+]2[O-])c1
Solvent: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C)c(C(C)S(=O)(=O)c2ccccn2)c1

Procedure:
A mixture of 4.7 g (0.017 mole) of 2-[1-(2,5-Dimethylphenyl)-ethylsulfonyl]-pyridine-N-oxide, 60 ml of chloroform, and 7.5 g (0.055 mole) of PCl3 were placed in a 100 ml round bottom flask equipped with a magnetic stirrer and reflux condenser. The mixture was refluxed for one hour, and then the solvent was removed under reduced pressure using a rotovap. To the residue was added 25 ml of ethanol, followed by a second evaporation. The residue crystallized to give a white solid, which was recrystallized from ethanol. Obtained were 3.0 g of product having a melting point of 95-96° C. The IR, NMR and mass spectra were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1.[Na].O>C(O)CC>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:11]([CH3:13])([CH3:12])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:9])[CH2:10][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[CH:16][CH:17]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Agent: [Na]
Solvent: O
Solvent: CCCO
Product: CC(C)(Oc1ccc(Cl)cc1)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Reaction time: 48 h
Yield: 18.4 %

Procedure:
A solution of 30 g (0.093 mol) of 2-(4-chlorophenyl)-2-[2-(p-chlorophenoxy)-prop-2-yl]-oxirane in 40 ml of n-propanol is added dropwise to a solution of 7.6 g (0.107 mol) of sodium 1,2,4-triazole in 60 ml of n-propanol at room temperature. The reaction mixture is subsequently stirred at the reflux temperature for 48 hours and is cooled, water is added and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated in vacuo. The oily residue is purified by column chromatography. 6.7 g (18.4% of theory) of 3-(4-chlorophenoxy)-2-(4-chlorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-2-butanol are obtained. This product is stirred with 20 ml of saturated hydrogen chloride/ether solution at room temperature. The precipitate which has separated out is filtered off with suction, rinsed with a little ether and dried at 40° C. in vacuo. 6.5 g (89% of theory, based on the base employed) of 3-(4-chlorophenoxy)-2-(4-chlorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-2-butanol hydrochloride of melting point 135° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:35]=[C:36]([NH2:41])[CH2:37][CH2:38][O:39][CH3:40]>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:41]=[C:36]([CH2:37][CH2:38][O:39][CH3:40])[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COCCC(N)=NO
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COCCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.70 mmol) in dichloromethane (30 ml) was treated with 1,1′-carbonyidiimidazole (272 mg, 1.70 mmol) and the solution was stirred at room temperature for 1 hour. N′-hydroxy-3-methoxypropanimidamide (J.Amer.Chem.Soc.; 80; 1958; 3769-3771) (201 mg, 1.70 mmol) was then added and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was heated neat at 120° C. under a nitrogen atmosphere for 2 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1) to afford the title compound as a colourless oil (410 mg).
Reaction SMILES: [CH3:1][O:2][NH3+:3].[Cl-].[C:5]([C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:38])[NH:16][CH2:17][C:18]([N:20]([CH2:27][C:28]([N:30]([CH3:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:29])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH:11]=[CH:12][CH:13]=1)(=O)[CH3:6]>O.C(O)C>[CH3:1][O:2]/[N:3]=[C:5](\[C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:38])[NH:16][CH2:17][C:18]([N:20]([CH2:27][C:28]([N:30]([CH3:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:29])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH:11]=[CH:12][CH:13]=1)/[CH3:6]
Reactant: CO[NH3+]
Reactant: CC(=O)c1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccccc2)c2ccccc2)c1
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CO/N=C(/C)c1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccccc2)c2ccccc2)c1
Yield: 33.2 %

Procedure:
0.16 g of 0-methylhydroxylamine hydrochloride in solution in 2 cm3 of water is added to a solution of 0.92 g of 2-{2-[3-(3-acetylphenyl)ureido]-N-phenylacetamido}-N-methyl-N-phenylacetamide in 10 cm3 of ethanol. The mixture is stirred under reflux for 3 hours and then at a temperature close to 25° C for 12 hours and concentrated to a volume of about 3 cm3 under reduced pressure (2.7 kPa) at 40° C. 20 cm3 of distilled water are then added and the insoluble product is separated off by filtration and air-dried. After recrystallization from a methanol/diisopropyl ether mixture (60/40 by volume), 0.31 g of (Z)-2-{2-{3-[3-(1-methoxyiminoethyl)phenyl]ureido}-N-phenylacetamido}-N-methyl-N-phenylacetamide melting at 165° C is obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8]=[N:9][OH:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:11]N1C(=O)CCC1=O>CN(C=O)C>[F:1][C:2]1[C:3]([C:8]([Cl:11])=[N:9][OH:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ncccc1F
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ncccc1F
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-fluoropicolinaldehyde oxime (1.0 g, 7.1 mmol) in DMF (15.8 mL) was added N-chlorosuccinimide (1.05 g, 7.85 mmol). The r×n was heated to 50° C. After 30 min, the r×n was added to ice water and extracted with EtOAc. The collected organic layers were washed with H2CO (2×50 mL), brine (30 mL), dried (MgSO4) and filtered. Concentration provided 3-fluoro-N-hydroxypicolinimidoyl chloride as a yellow solid, which was taken through to the next step.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[CH:9]=2)[CH:4]=[CH:3]1.C([Li])CCC.[C:26](=[O:28])=[O:27]>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=3)[CH:9]=2)[C:4]([C:26]([OH:28])=[O:27])=[CH:3]1
Reactant: Cn1ccc2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(C(=O)O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-methyl-6-(4-trifluoromethyl-phenyl)-1H-indole (0.483 g, 1.75 mmol) in dry THF (10 mL) at −78° C. was added n-butyllithium (0.84 mL, 2.1 mmol). The reaction mixture was stirred under nitrogen at −78° C. for 30 minutes then at −50 to −40° C. for 30 minutes. It reaction temperature was cooled to −78° C. and crushed dry ice (3.5 g, 80 mmol) was added. The reaction mixture was stirred overnight at room temperature. It was then concentrated and partitioned in 2N hydrochloric acid and ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography using 10-50% ethyl aceate in hexane as an eluant. The title compound was obtained as a yellow solid (0.108 g, 19%), mp: 237-239° C. (dec). Mass spectrum (−APCI, [M−H]−) m/z 318. 1HNMR (400 MHz, DMSO-d6): δ 12.8-13.2 (br s, 1H), 8.0 (d, 2H, J=8.1 Hz), 7.95 (s, 1H), 7.75-7.85 (m, 3H), 7.5 (dd, 1H, J=8.3 and 1.5 Hz), 7.25 (s, 1H), and 4.10 ppm (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:22]>CN(C=O)C>[CH3:22][N:14]([CH:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CI
Reactant: CS(=O)(=O)NC1CCCc2ccc([N+](=O)[O-])cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C1CCCc2ccc([N+](=O)[O-])cc21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A solution of 1.2 g (4.4 mmol) of N-(7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl)methanesulfonamide in 16 ml of DMF was added dropwise to a suspension of 0.15 g (5.1 nmol) 80 percent sodium hydride in 10 ml of DMF. After stirring at room temperature for 1 hr., 0.62 g (4.4 mmol) of iodomethane were added and the mixture was allowed to stand at room temperature overnight. The reaction mixture was completely concentrated in vacuo and the residue was then taken up in EA and water. After washing the organic phase with dil. hydrochloric acid and sodium bicarbonate solution and concentrating, the residue was purified by chromatography on silica gel using cyclohexane/EA 3:1 and 0.3 g of N-methyl-N-(7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl)methanesulfonamide was obtained; m.p. 138-140° C.
Reaction SMILES: P(O[CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)(OCC)(OCC)=O.[C:21]1([CH2:27][CH:28]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:20][O:19][C:13]1[CH:12]=[C:11](/[CH:10]=[CH:28]/[CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=1
Reactant: CCOP(=O)(OCC)OCc1cc(OC)cc(OC)c1
Reactant: O=CCc1ccccc1
Product: COc1cc(/C=C/Cc2ccccc2)cc(OC)c1
Yield: 78 %

Procedure:
Use diethyl 3,5-dimethoxybenzyl phosphate and phenylacetaldehyde as materials, and follow the method described in Example 5 to obtain a pale yellow solid as the target product (78%). 1H NMR (400 MHz, DMSO-d6): 3.22 (d, J=7.6 Hz, 2H), 3.79 (s, 6H), 6.25 (s, 1H), 6.34 (d, J=16.0 Hz, 1H), 6.66 (m, 1H), 6.72 (s, 2H), 7.16 (m, 3H), 7.27 (m, 2H).