Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32]Cl)=[CH:28][CH:27]=2)=[CH:20][C:19]=1[Cl:34].BrCC1C=CC(Cl)=C(Cl)C=1.OCC1C=CC(O)=CC=1.ClCC1(C(F)(F)F)C=CC(OCC2C=CC=CC=2)=CC1>>[Cl:34][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:18]=1[Cl:17])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[CH:28][CH:27]=1
Reactant: ClCc1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Agent: Clc1ccc(CBr)cc1Cl
Agent: FC(F)(F)C1(CCl)C=CC(OCc2ccccc2)=CC1
Agent: OCc1ccc(O)cc1
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 1,2-Dichloro-4-(4-chloromethyl-phenoxymethyl)-benzene prepared from 1-bromomethyl-3,4-dichloro-benzene and 4-hydroxymethyl-phenol in the manner analagous to Examples 14A and 14B. MS m/z 503 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:17])=[CH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:5])[CH3:2].C(N(CC)CC)C.F[B-](F)(F)F.C(C(=N[O:39][C:40](N(C)C)=[N+:41](C)C)C(OCC)=O)#N.[CH2:47]([NH2:51])[CH2:48][CH2:49][CH3:50]>CN(C)C=O>[CH2:47]([NH:51][C:10]([C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[CH:7]=[C:6]([CH3:17])[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:12])[CH2:48][CH2:49][CH3:50].[CH2:10]([C:9]1[C:13]([C:40](=[O:39])[NH2:41])=[CH:14][CH:15]=[CH:16][C:8]=1[CH:7]=[C:6]([CH3:17])[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:47][CH2:48][CH3:49]
Reactant: CCCCN
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Reactant: CCOC(=O)C(C)=Cc1ccccc1C(=O)O
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNC(=O)c1ccccc1C=C(C)C(=O)OCC
Product: CCCCc1c(C=C(C)C(=O)OCC)cccc1C(N)=O
Yield: 156.2 %

Procedure:
Ethyl 3-(2-butylcarbamoylphenyl)-2-methylacrylate is prepared as described in Example 30, starting with 1.17 g (5.0 mmol) of 2-(2-ethoxycarbonylpropen-1-yl)benzoic acid in 10 cm3 of dimethylformamide, a solution of 0.69 cm3 (5.0 mmol) of triethylamine, 1.64 g (5.0 mmol) of O-[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (“TOTU”) in 6 cm3 of dimethylformamide and a second solution consisting of 366 mg (5.0 mmol) of n-butylamine and 0.69 cm3 (5.0 mmol) of triethylamine in 10 cm3 of dimethylformamide. 1.13 g of ethyl 3-(2-butyl-carbamoylphenyl)-2-methylacrylate are thus obtained in the form of a yellowish oil, which can be reacted in the following step without further purification.
Reaction SMILES: OC1C=CC(C(O)=O)=CC=1.C(O)C1C=CC=CC=1.O[C:20]1[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=O)=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:27]([O:26][CH2:24][C:23]1[CH:34]=[CH:35][CH:20]=[CH:21][CH:22]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)c1ccc(O)cc1
Solvent: OCc1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(COCc2ccccc2)cc1

Procedure:
In the same way as in Example 13, 69.1 g (0.5 mole) of p-hydroxybenzoic acid and 216.2 g (2 moles) of benzyl alcohol were reacted at 120° C. for 4 hours in 138 g of toluene in the presence of 1.44 g of p-toluenesulfonic acid as a catalyst. The yield of benzyl p-hydroxybenzoate was 26%. Dimerization and dehydration of benzyl alcohol occurred simultaneously, and dibenzyl ether was formed in a ratio of as high as 45%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].N1C=CC=CC=1>C(Cl)(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CNOC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4-difluorobenzoyl chloride (5.25 g) in chloroform (30 mL) at 0° C. was added N,O-dimethylhydroxylamine hydrochloride (3.2 g) followed by pyridine (5.8 mL) dropwise. The mixture was stirred at r.t. for 2 hr, diluted with EtOAc, washed with HCl 1N, with H2O, saturated NaCHO3 sol., brine, dried (MgSO4) and the solvents evaporated to give the title product.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH:19]1([NH:22][CH:15]2[CH2:16][CH2:17][N:12]([C:10]3[O:9][N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:11]=3)[CH2:13][CH2:14]2)[CH2:21][CH2:20]1
Reactant: O=C1CCN(c2nc(-c3ccccc3)no2)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(-c2noc(N3CCC(NC4CC4)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-one (400 mg), cyclopropylamine (120 μL), sodium triacetoxyborohydride (420 mg), and glacial acetic acid (0.20 mL) in dichloromethane (7 mL) is stirred for two days at room temperature. Dichloromethane is added and the mixture is washed with aqueous K2CO3 solution. The organic phase is dried over Na2SO4 and concentrated in vacuo to afford the title compound. TLC: rf=0.30 (silica gel, CH2Cl2/MeOH 95:5); Mass spectrum (ESI+): m/z=285 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]3[N:18]=[C:19]([O:29][C@H:30]4[C@H:34]5[O:35][CH2:36][C@@H:37]([OH:38])[C@H:33]5[O:32][CH2:31]4)[N:20](COCC[Si](C)(C)C)[C:15]3=[CH:14][C:13]=2Cl)=[CH:8][CH:7]=1.[C:46]([Zn]C#N)#[N:47]>CC(N(C)C)=O.CN(C=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[C:6]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:7]=[CH:8][C:9]([C:12]2[N:17]=[C:16]3[N:18]=[C:19]([O:29][C@@H:30]4[CH2:31][O:32][C@@H:33]5[C@H:37]([OH:38])[CH2:36][O:35][C@H:34]45)[NH:20][C:15]3=[CH:14][C:13]=2[C:46]#[N:47])=[CH:10][CH:11]=1
Reactant: N#C[Zn]C#N
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: N#Cc1cc2[nH]c(O[C@@H]3CO[C@H]4[C@@H]3OC[C@H]4O)nc2nc1-c1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of PdOAc2 (15.48 mg, 0.069 mmol) and 1,1′-bis(di-tert-butylphoshino)ferrocene (32.7 mg, 0.069 mmol) in DMAc (0.25 ml) was treated with sulfuric acid (6.76 mg, 0.069 mmol) and stirred at 80° C. for 30 min. Then a solution of (3R,3aR,6R,6aR)-6-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (Intermediate 8, 40 mg, 0.069 mmol) and dicyanozinc (9.71 mg, 0.083 mmol) in DMAc (0.25 ml) was added to the reaction and the reaction was heated to 120 degrees for 16 h. The residue was diluted with 0.7 ml DMF, filtered and purified by mass directed reverse phase column chromatography eluting with acetonitrile/water+0.1% TFA to give the title compound. LC-MS: calculated for C25H20N4O4, 440.15, observed m/e: 441.15 (M+H)+ (RT 0.58/2.00 min).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7](Cl)=[N:6][N:5]2[CH:11]=1.O1C[CH2:15][CH2:14][CH2:13]1.C([Mg]Br)CC.Cl>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:13][CH2:14][CH3:15])=[N:6][N:5]2[CH:11]=1
Reactant: C1CCOC1
Reactant: Clc1cn2nc(Cl)ccc2n1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: CCC[Mg]Br
Agent: Cl
Solvent: O
Product: CCCc1ccc2nc(Cl)cn2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,6-Dichloroimidazo[1,2-b]pyridazine (10.0 g, 53.2 mmol) and [1,3-bis(diphenylphosphino)propane]nickel(II) dichloride (0.43 g, 0.80 mmol) were added to tetrahydrofuran (80.0 ml) under a nitrogen stream, and a solution of n-propylmagnesium bromide in tetrahydrofuran (2 M, 31.9 ml, 63.8 mmol) was added dropwise thereto under ice-cooling over 60 minutes. The reaction mixture was stirred for 10 minutes under ice-cooling, warmed to room temperature, and stirred for 2 hours at room temperature. To the reaction mixture was added cold water (700 ml), and acidified with concentrated hydrochloric acid. Then the deposited solid was collected by filtration, and insoluble solid was washed with dilute hydrochloric acid, then with water. At the same time, the filtrate was extracted with ethyl acetate, the extracts were combined, and washed with dilute hydrochloric acid, saturated brine, saturated sodium hydrogen carbonate solution, and saturated brine, in that order. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue and the solid collected by filtration were purified by silica gel column chromatography (ethyl acetate:hexane=3:7) to give the title compound as white crystals. The yield was 9.21 g (88.5%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15](=O)[C:16]([CH3:18])=[O:17].C1(C)C(S([CH:29]([N+:37]#[C-:38])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)(=O)=O)=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CCOCC.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]([C:16](=[O:17])[CH3:18])=[C:29]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[N:37]=[CH:38]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccccc1C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(=O)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1c(-c2ccc(F)cc2)ncn1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1.75 h
Yield: 27.2 %

Procedure:
To a solution of t-butyl-4-amino-piperidinecarboxylate (0.95 g, 4.75 mmol) in 40 mL of Et2O was added pyruvaldehyde (40% w/w solution in water, 0.94 mL, 1.11 g, 6.17 mmol) at room temperature. After 1.75 h, the solution was poured into a separatory funnel, diluted with 30 mL of Et2O and 10 mL of EtOAc, and washed with 2×10 mL of water. The organics were concentrated in vacuo and the residue was diluted in 10 mL of DMF and α-(toluenesulfonyl)-4-fluoro-benzylisonitrile (1.37 g, 4.75 mmol) and K2CO3 (0.72 g, 5.23 mmol) were added. After 16 h, the solution was diluted with 100 mL of water and extracted with 2×40 mL of EtOAc. The combined organics were washed with 3×40 mL of 10% HCl. The aqueous layers were combined and neutralized with excess solid NaHCO3, then basified with 20 mL of 10% KOH. The aqueous layer was transferred to a separatory funnel and extracted 3×30 mL of EtOAc. The combined organics concentrated in vacuo to yield the imidazole product (0.5 g, 27%): 1H NMR (CDCl3) δ 7.74, 7.44 (2H, m), 7.13 (2H, t, J=8.6 Hz), 4.97 (1H, tt, J=3.7, 12.0 Hz), 4.29 (2H, m), 2.88 (2H, m), 2.15 (2H, m), 2.11 (3H, s), 1.78 (2H, dq, 4.2, 12.2 Hz), 1.48 (9H, s).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5][C:6]2[CH:7]=[C:8]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=2)[C:9]([N:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[O:26][CH3:27])[CH3:12])=[O:10])[CH2:2]1.[OH:35]OS([O-])=O.[K+].[O-]S([O-])(=S)=O.[Na+].[Na+].CCOC(C)=O.[OH2:54]>CO>[NH:1]1[CH2:4][CH:3]([S:5]([C:6]2[CH:7]=[C:8]([CH:28]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:30]=2)[C:9]([N:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[O:26][CH3:27])[CH3:12])=[O:10])(=[O:35])=[O:54])[CH2:2]1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SC2CNC2)cc(C(F)(F)F)c1
Reactant: O=S([O-])OO
Reactant: O
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)C2CNC2)c1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To an ice-cold solution of 3-(azetidin-3-ylthio)-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-5-(trifluoromethyl)benzamide (0.257 g, 523 μmol, example 275) in MeOH (6 mL) and water was added Oxone® (804 mg, 1.31 mmol) and stirring was continued at room temperature for 3.5 hours. The reaction mixture was poured on 10% aqueous Na2S2O3 solution and EtOAc and the layers were separated. The aqueous layer was saturated with sodium chloride, extracted eight times with EtOAc. The organic layers were washed once with brine, dried over MgSO4, filtered and evaporated. The product (43 mg) was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.05% triethylamine) (20:80 to 98:2). Colorless solid (0.135 g; 49%). MS (ESI): m/z=524.13 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O>C(COC)OC>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(-c2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
Similarly to a method reported in Tetrahedron Lett., 1991, 923, to a stirred solution of (S)-2-t-butoxycarbonylamino-3-(biphenyl-4-yl)-propionic acid (3 g, 8.8 mmol) in dimethoxyethane (DME; 8 mL) at -15° is added N-methylmorpholine (0.975 mL, 8.8 mmol), followed by isobutyl chloroformate (1.2 mL, 9.25 mmol). After 5 minutes, the precipitate is removed by filtration and washed with DME (5 mL). The filtrate is cooled to 0° and treated at once with a freshly prepared clear solution of sodium borohydride (500 mg) in water (5 mL). After the strong evolution of gas has ceased, water (100 mL) is added and the product is extracted in ethyl acetate. The organic layer is separated, dried over magnesium sulfate, decolorized with activated charcoal, filtered and concentrated in vacuo to yield (S)-2-(t-butoxycarbonylamino)-3-(biphenyl-4-yl)-propan-1-ol as a white solid, m.p.: 116°, [α]D =-22.90 (c 0.74, MeOH).
Reaction SMILES: O.O.O.O.O.[OH-].C[N+](C)(C)C.CN(C=O)C.[C:17]([OH:20])(=[O:19])[CH3:18].[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]Br)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25])[CH3:22]>CCOCC>[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][O:20][C:17](=[O:19])[CH3:18])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCCCCCCCBr)cc2)cc1
Reactant: CC(=O)O
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCCCCCCCOC(C)=O)cc2)cc1
Reaction time: 1 h
Yield: 68.9 %

Procedure:
60 m moles (10.9 g) of tetramethylammonium hydroxide pentahydrate was added into a DMF solution of 60 m moles (3.6 g) of acetic acid, stirred for one hour, then 50 m moles (27.3 g) of the above 4'-(16-bromohexadecyloxy)biphenyl-4-carboxylic acid ethyl ester was added, and stirred for 12 hours. The reaction solution was ether extracted and concentrated, then purified by column chromatography to obtain 18.1 g of 4'-(16-acetyloxyhexadecyloxy)biphenyl-4-carboxylic acid ethyl ester. (yield: 69%)
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([CH:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:11](Cl)=[O:12])[CH2:9][CH2:8]1.[F:21][C:22]1[CH:38]=[CH:37][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=2)[CH:30]([OH:33])[C:31]#[N:32])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH:7]1([CH:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:11]([O:33][CH:30]([C:31]#[N:32])[C:29]2[CH:34]=[CH:35][CH:36]=[C:27]([O:26][C:25]3[CH:37]=[CH:38][C:22]([F:21])=[CH:23][CH:24]=3)[CH:28]=2)=[O:12])[CH2:9][CH2:8]1
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)C1CC1
Reactant: N#CC(O)c1cccc(Oc2ccc(F)cc2)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: N#CC(OC(=O)C(c1ccc(Cl)cc1)C1CC1)c1cccc(Oc2ccc(F)cc2)c1

Procedure:
With stirring, 1 g of pyridine in 3 ml of toluene and 2.3 g of α-cyclopropyl-4-chlorophenylacetyl chloride in 3 ml of toluene are added successively at 0° to 10° C. to a solution of 2.43 g of 3-(4-fluorophenoxy)-α-cyanobenzyl alcohol in 20 ml of toluene. After stirring for 10 hours at room temperature, the reaction mixture is washed with water, 2 N hydrochloric acid and 3% sodium bicarbonate solution. The organic layer is dried over sodium sulfate and the toluene is distilled off, affording the compound of the formula ##STR4## with a refractive index of nD20 =1.5880.
Reaction SMILES: C(OC1C=CC2C(=CC=CC=2)C=1C=NO)C1OC1.[CH2:19]([O:21][C:22]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]=1[CH:40]=[N:41][OH:42])=[O:23])[CH3:20].ClN1C(=O)CCC1=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:19]([O:21][C:22]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]=1[C:40]#[N+:41][O-:42])=[O:23])[CH3:20]
Reactant: CCOC(=O)CCCCCOc1ccc2ccccc2c1C=NO
Agent: O=C1CCC(=O)N1Cl
Agent: ON=Cc1c(OCC2CO2)ccc2ccccc12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCOc1ccc2ccccc2c1C#[N+][O-]
Yield: 93.3 %

Procedure:
As shown in Chemical Formula 4, 88.2 mg (0.268 mmol) of 2-[5-(ethoxycarbonyl)pentyloxy]-1-naphthoaldehyde oxime (7) was dissolved in 30 mL of chloroform and thereto, 38.2 mg (0.325 mmol) of N-chlorosuccinimide (NCS) and 48.3 mL (0.348 mmol) of triethylamine were added in an ice bath, followed by stirring the resultant reaction mixture for 10 minutes to effect the reaction. Then, the reaction solution was washed with 10 mL of pure water, and the organic phase was dried over MgSO4, followed by concentrating the solvent under reduced pressure to obtain 81.9 mg of 2-[5-(ethoxycarbonyl)pentyloxy]-1-naphthonitrile oxide C as a satisfactorily applicable crude product.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10](=[O:19])[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][C:13]1=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OC([NH:27][C@H:28]([C:36](O)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O)(C)(C)C>>[ClH:1].[CH2:2]([O:9][C:10](=[O:19])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:36](=[O:37])[C@H:28]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH2:27])[CH2:14][C:13]1=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(CN1CCNCC1=O)OCc1ccccc1
Agent: Cl
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCN(CC(=O)OCc2ccccc2)C(=O)C1
Yield: 49.4 %

Procedure:
2-Oxopiperazine-1-acetic acid benzyl ester hydrochloride (2 g) and N-t-butoxycarbonyl-L-phenylalanine (5.6 g) were subjected to substantially the same procedure as in Working Example 21 to afford 1.5 g of the title compound as amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:22]3[CH2:24][CH2:23]3)[C:10](=[O:21])[N:11]([S:13]([C:16]3[NH:20][N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:36]=1[CH2:37]Br>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:22]3[CH2:24][CH2:23]3)[C:10](=[O:21])[N:11]([S:13]([C:16]3[N:20]([CH2:37][C:36]4[C:35]([Cl:34])=[CH:42][CH:41]=[CH:40][C:39]=4[Cl:43])[N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: O=c1n(S(=O)(=O)c2ncn[nH]2)nc(-c2ccc(Cl)cc2)n1C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=c1n(S(=O)(=O)c2ncnn2Cc2c(Cl)cccc2Cl)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
37 mg (0.10 mmol) of the compound from Example 93A were dissolved in 3 ml of dichloromethane, and 21 μl (0.13 mmol) of N,N-diisopropylethylamine were added. 30 mg (0.13 mmol) of 2,6-dichlorobenzyl bromide dissolved in 1 ml of dichloromethane were then added, and the mixture was stirred at RT for 20 h. For work-up, the mixture was concentrated under reduced pressure and the crude product was purified chromatographically [Method 19]. This gave 39 mg (74% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2.[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OC(C)C)(C)C.CCCCCC>O1CCOCC1>[C:13]1([NH:19][C:20]([NH:1][C:2]2[C:11]3[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc2c1CC(O)CC2
Reactant: O=C=Nc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: CCCCCC
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)Nc1cccc2c1CC(O)CC2
Reaction time: 16 h
Yield: 51 %

Procedure:
To a solution of 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (20.0 mg, 0.123 mmol) in 1,4-dioxane (1.0 mL) was added phenyl isocyanate. (14.6 mg, 0.123 mmol) at room temperature. The mixture was stirred for 16 hours, and then added diisopropyl ether and hexane. The precipitate was filtered and dried to give N-phenyl-N′-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea (17.8 mg, 51% yield).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][CH:14]([P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[F:15].[I:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32]I>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[F:13][C:14]([P:16](=[O:23])([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])([F:15])[CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][I:24]
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: ICCOCCOCCI
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOP(=O)(OCC)C(F)(F)CCOCCOCCI
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of diisopropylamine (1.6 eq) in THF (1.28 M) was slowly added n-butyllithium (1.5 M in cyclohexane, 1.5 eq) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 40 minutes. The mixture was then cooled down to −78° C., and diethyl difluoromethylphosphonate (1 eq) in HMPA (2.1 M) was slowly added to the solution. Then the mixture was stirred at −78° C. for 40 minutes and to the resulting solution was added a cooled solution of 1,2-bis(2-iodoethoxy)ethane (12.8 M in THF, 4 eq) rapidly. After 1.5 hours, the reaction was quenched by pouring into saturated NH4Cl solution. The aqueous phases were extracted with ethyl acetate three times. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 10-100% EtOAc/Hex to give the product as a yellow oil.