Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH:9][C:10]2[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=2)[C:13](OCCCC)=[O:14])[CH:2]=1.[CH:23]1([O:28][C:29]2[CH:30]=[C:31](I)[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[CH2:27][CH2:26][CH2:25][CH2:24]1.[CH3:38][C:39]([CH3:42])([O-:41])[CH3:40].[Na+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1>[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([N:9]([CH2:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[C:10]3[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=3)[C:13]([O:41][C:39]([CH3:42])([CH3:40])[CH3:38])=[O:14])[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCCCOC(=O)c1cccc(NCCc2cccnc2)c1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(I)cc1OC1CCCC1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(N(CCc2cccnc2)c2cccc(C(=O)OC(C)(C)C)c2)cc1OC1CCCC1
Reaction time: 16 h
Yield: 28.1 %

Procedure:
To a mixture of 103 mg of 1-butyl N-(2-(3-pyridyl)ethyl)-3-aminobenzoate (0.35 mmol) and 200 mg of 3-cyclopentyloxy-4-methoxyiodobenzene (0.63 mmol) in 5 mL of toluene was added 100 mg of sodium t-butoxide (1.0 mmol), 15 mg of tri-t-butylphosphonium tetrafluoroborate (0.05 mmol) and 25 mg of tris(dibenzylidineacetone)dipalladium(0) (0.028 mmol). The mixture was stirred for 16 h and filtered through celite. The celite was washed with 3×5 mL of toluene and the filtrate was concentrated in vacuo. The residue was purified by column chromatography using 30%-40% EtOAc in hexanes as eluant to give 48 mg of t-butyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(2-(3-pyridyl)ethyl)-3-aminobenzoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:14]([CH3:25])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.NC1C=CC(CN2CCN(C(OC(C)(C)C)=O)[C@@H](C)C2)=CC=1.[OH-].[K+]>C(N(CC)CC)C>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@@H:14]([CH3:25])[CH2:13]2)=[CH:3][C:2]=1[F:1]
Reactant: C[C@H]1CN(Cc2ccc([N+](=O)[O-])c(F)c2)CCN1C(=O)OC(C)(C)C
Agent: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N)c(F)c2)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-[(3-fluoro-4-nitrophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D62) using a method similar to that described for D2 in Description 2 although the reaction was carried out on an H-Cube™ continuous flow hydrogenator and triethylamine was used in place of solid KOH. δH (CDCl3, 400 MHz) 6.99 (1H, dd), 6.86 (1H, dd), 6.71 (1H, dd), 4.17 (1H, br.s), 3.79 (1H, d), 3.67 (2H, br.s), 3.40 (1H, d), 3.27 (1H, d), 3.09 (1H, td), 2.73 (1H, m), 2.56 (1H, m), 2.08 (1H, dd), 1.96 (1H, m), 1.45 (9H, s), 1.22 (3H, d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([O:37][CH2:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[O:36])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)O[C@H](CCN)C[C@H](CC(=O)OCc2ccccc2)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OCc2ccccc2)OC(C)(C)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and benzyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:2].[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+].O>C1COCC1.C(OCC)(=O)C>[OH:2][CH:1]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (2R)-2-formylpyrrolidine-1-carboxylate (500 mg, 2.51 mmol) in dry THF (7 mL) at −78° C. was added 1 M phenylmagnesium bromide solution in THF (7.5 mL, 7.5 mmol, 3 eq.). After stirring the reaction mixture for 2 h, saturated aqueous ammonium chloride (1.5 mL) was added. The mixture was warmed to room temperature, and water (50 mL) and ethyl acetate (25 mL) were added. The phases were separated, and the aqueous layer was extracted with ethyl acetate (25 mL). The combined organic phases were washed with 10% citric acid, brine, saturated aqueous sodium bicarbonate, and dried over MgSO4. The solvent was evaporated and the residue was purified by silica gel chromatography (pentane/ethyl acetate, 7:3) to give tert-butyl (2R)-2-[hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate a colorless oil. Subsequent BOC deprotection was carried out by dissolving the intermediate in ethyl acetate (3 mL) and leading a stream of HCl (g) through the solution for 20 min. The solvent was evaporated to give the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[F:13][C:14]([Si](C)(C)C)([F:16])[F:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[C:14]([F:16])([F:15])[F:13])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C=O)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COCOc1ccc(C(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
4-Methoxymethoxybenzaldehyde (658 mg, 3.96 mmol) was dissolved in tetrahydrofuran (4.0 mL). To this, (trifluoromethyl)trimethylsilane (702 μL, 475 mmol) and tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 396 μL, 0.396 mmol) were added under a nitrogen atmosphere at 0° C. and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 4.00 mL, 4.00 mmol) was added and the mixture was further stirred for 10 minutes. After water was added to the reaction mixture, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give 1-methoxymethoxy-4-(2,2,2-trifluoro-1-hydroxyethyl)benzene (Compound CQ) (895 mg, yield: 96%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:19])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[C:8]=2[C:9]=1[CH3:10].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>C(O)(C)C>[CH3:18][O:17][C:11]1[C:8]2[C:9]([CH3:10])=[C:4]([CH2:3][CH2:2][N:31]3[CH2:30][CH2:29][N:28]([C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:34])([F:35])[F:20])[CH:23]=4)[CH2:33][CH2:32]3)[C:5](=[O:19])[O:6][C:7]=2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=1
Reactant: COc1cc(OC)c2c(C)c(CCCl)c(=O)oc2c1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Solvent: CC(C)O
Product: COc1cc(OC)c2c(C)c(CCN3CCN(c4cccc(C(F)(F)F)c4)CC3)c(=O)oc2c1
Yield: 47 %

Procedure:
Process B; starting materials: 3-(2-chloroethyl)-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 39) and 1-(3-trifluoromethylphenyl)piperazine; yield 47%; m.p. 138°-139° C. (from isopropanol).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=2)[CH:14]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.F[C:26](F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@@H:9]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=2)[CH:14]=1)[C:10]([O:12][CH3:26])=[O:11]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc2cc([C@H](NC(=O)OC(C)(C)C)C(=O)O)ccc2c1
Solvent: ClCCl
Product: COC(=O)[C@@H](N)c1ccc2cc(OC)ccc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-2-(6-methoxy-2-naphthyl)acetic acid was then converted into the methyl ester using General Procedure G below. The methyl ester was then dissolved in CH2Cl2 and this solution cooled to 0° C. Trifluoroacetic acid (50 molar eq.) was added and the reaction was allowed to warm to room temperature and stirring was continued for 2 hrs. The reaction mixture was then concentrated and the residue extracted into CH2Cl2 and washed with sodium bicarbonate solution. The organic layer was dried over Na2SO4, filtered and concentrated to yield methyl (S)-2-amino-2-(6-methoxy-2-naphthyl)acetate.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:14]([N:16]1[CH2:44][CH2:43][CH2:42][C@H:17]1[C:18]([NH:20][C@H:21]([C:32]([O:34]CC1C=CC=CC=1)=[O:33])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:31])[NH:27][N+]([O-])=O)=[O:19])=[O:15])[C@@H:11]([CH3:13])[OH:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]>[C].[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:14]([N:16]1[CH2:44][CH2:43][CH2:42][C@H:17]1[C:18]([NH:20][C@H:21]([C:32]([OH:34])=[O:33])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:27])[NH2:31])=[O:19])=[O:15])[C@@H:11]([CH3:13])[OH:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[CH3:21][C:32]([OH:34])=[O:33]
Reactant: C[C@@H](O)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: [Pd]
Product: CC(=O)O
Product: C[C@@H](O)[C@H](NC(=O)[C@@H](N)CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)O

Procedure:
150 mg of Z-Asn-Thr-Pro-Arg(NO2)-OBzl was reduced in the presence of palladium-carbon in the same manner as in Example 7-(4). The resulting product was purified by high-performance liquid chromatography at 12 ml/min. (flow rate), to 10 % (B) 20 min. linear gradient (A) (mobile phase), subjected to Dowex 1×2 (acetate type) treatment and freeze-dried to obtain the desired compound.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([SH:10])=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=1[O:22][CH3:23]>>[Cl:11][C:12]1[C:17]2[C:7](=[O:8])[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[S:10][C:16]=2[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=1[O:22][CH3:23]
Reactant: O=C(O)c1ccccc1S
Reactant: COc1cc([N+](=O)[O-])c(Cl)cc1Cl
Product: COc1cc([N+](=O)[O-])c2sc3ccccc3c(=O)c2c1Cl

Procedure:
Reaction of a mixture of 4.5 g (0.0343 mol) of 2-(diethylaminoethyl)hydrazine, 7.5 g (0.0233 mol) of 1-chloro-2-methoxy-4-nitro-9H-thioxanthen-9-one in 200 ml of DMF as described in Example 53 gave 7.6 g of product. 1-Chloro-2-methoxy-4-nitro-9H-thioxanthen-9-one is prepared from 2-thiobenzoic acid and 2,4-dichloro-5-nitroanisole [C. Bloomfield, A. K. Manglik, R. B. Mootie, K. Schofield, and G. D. Tokin, J. Chem. Soc. Perkin Trans. II, 75 (1983)] in the manner of Example 58.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[CH2:31][CH:32](Br)[CH2:33][CH2:34][C@@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(#N)C>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[CH2:31][C@H:32]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH2:33][CH2:34][C@@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[CH2:31][C@@H:32]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH2:33][CH2:34][C@@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CCC(Br)CN2C[C@H]1Cc1c[nH]c2ccccc12
Reactant: C1COCCN1
Solvent: CC#N
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@@H](N3CCOCC3)CN2C[C@H]1Cc1c[nH]c2ccccc12
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](N3CCOCC3)CN2C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 80 °C

Procedure:
A mixture of 3,5-bis(trifluoromethyl)phenyl-[(3R,9aR)-7-bromo-3-(1H-indol-3-ylmethyl)-octahydropyrido[1,2-a]pyrazin-2-yl]-methanone (2.94 g) and morpholine (0.92 mL) in acetonitrile (100 mL) was heated at 80° C. for 40 hours. After cooling to room temperature the mixture was concentrated in vacuo and the residue purified by flash-chromatography (SiO2, CH2Cl2/MeOH/NH4OH 980:18.75:1.25) to afford 3,5-bis(trifluoromethyl)phenyl-[(3R,7R,9aR)-3-(1H-indol-3-ylmethyl)-7-morpholin-4-yl-octahydropyrido[1,2-a]pyrazin-2-yl]-methanone (1.6 g, Rf 0.33 (CH2Cl2/MeOH/NH4OH 92:7.5:0.5)) (compound 13) and 3,5-bis(trifluoromethyl)phenyl-[(3R,7S,9aR)-3-(1H-indol-3-ylmethyl)-7-morpholin-4-yl-octahydropyrido[1,2-a]pyrazin-2-yl]-methanone (1.28 g, Rf 0.27 (CH2Cl2/MeOH/NH4OH 92:7.5:0.5)) (compound 14).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)#[N:29]>ClCCl.N1C=CC=CC=1>[C:28]([C:30]1[CH:31]=[CH:32][C:33]([S:36]([N:18]2[CH2:17][CH2:16][N:15]([C:13]([CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH2:8][CH2:9]3)=[O:14])[CH2:20][CH2:19]2)(=[O:38])=[O:37])=[CH:34][CH:35]=1)#[N:29]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(C1CCN(c2ccncc2)CC1)N1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(S(=O)(=O)N2CCN(C(=O)C3CCN(c4ccncc4)CC3)CC2)cc1
Temperature: 0 °C

Procedure:
1-(1-(4-pyridyl)piperdin-4-ylcarbonyl)piperazine (0.411 g) was dissolved in dry dichloromethane (20 mL) and stirred under argon at 0° C. To the resulting solution was added triethylamine (0.56 mL) followed by the dropwise addition of a solution of 4-cyanobenzenesulphonyl chloride (0.33 g, 1.6 mmol) in dry pyridine (20 mL). The reaction was then stirred at 0° C. for 10 minutes and then allowed to warm to room temperature and stirred for a further 1 hour. The reaction was quenched by the removal of the dichloromethane and pyridine solvents by evaporation, taken up in water (60 mL) and then extracted with ethyl acetate (3×50 mL). The organic extracts were then washed with water, brine, dried (MgSO4) and evaporated to dryness. The product was then recrystallised to give 1-(4-cyanophenylsulphonyl)-4-(1-(4-pyridyl)piperidin-4-ylcarbonyl)piperazine as a white, hygroscopic solid m.p. 168-169° C.;
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[C:14]([OH:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[C:12]#[N:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:26](=[O:29])([O-])[O-].[Na+].[Na+].ClC1C=C[S:35][C:34]=1C(OC)=O>C(C(C)=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[C:14]([O:25][C:26]([S:35][CH3:34])=[O:29])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:23])([F:24])[F:22])[C:12]#[N:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1Cl
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ccc(C(C#N)=C(O)c2ccccc2C(F)(F)F)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: CSC(=O)OC(=C(C#N)c1ccc(C(C)(C)C)cc1)c1ccccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
A mixture comprising 5.0 g of α-(4-tert-butylphenyl)-β-hydroxy-β-(2-trifluoromethylphenyl)acrylonitrile, 1.5 g of sodium carbonate and 30 ml of methyl ethyl ketone, was heated to 70° C., and a mixture comprising 2.1 g of methyl chlorothiolformate and 10 ml of methyl ethyl ketone, was dropwise added over a period of 10 minutes. After completion of the dropwise addition, the reaction was carried out for 30 minutes at a temperature of from 70 to 75° C. The reaction mixture was cooled, and then an inorganic salt was filtered off. The cake was washed with 20 ml of methyl ethyl ketone. Methyl ethyl ketone in the filtrate was distilled off, and to the residue, 50 ml of an isoparaffin type hydrocarbon (tradename: ISOPAR G, manufactured by EXXON CHEMICAL) was added, followed by heating for dissolution, and the solution was left to cool to room temperature. Precipitated crystals were collected by filtration, and the cake was washed with 10 ml of ISOPAR G (tradename) and then dried at 65° C. for 12 hours to obtain 4.9 g of the desired product (isomer ratio 2:98). The HPLC conditions for the analysis of this product were as follows. Further, the NMR spectrum data of this product were the same as in Preparation Example 4.
Reaction SMILES: [H-].[Na+].[P:3]([O-:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].C12(C)C(C)(C)C(CC1)C[CH2+]2[CH2:20][CH2:21][CH2:22][C:23](=[O:25])[CH3:24].[O:27]1CC[CH2:29][CH2:28]1>>[CH2:28]1[CH2:29][O:25][C:23]([CH3:24])([CH2:22][CH2:21][CH2:20][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[O:27]1
Reactant: CCOP([O-])OCC
Reactant: C1CCOC1
Reactant: CC(=O)CCC[CH2+]1CC2CCC1(C)C2(C)C
Agent: [H-]
Agent: [Na+]
Product: CCOP(=O)(CCCC1(C)OCCO1)OCC
Reaction time: 1.5 h

Procedure:
To a solution of 5.5 g. of pure sodium hydride in 200 ml. of dry tetrahydrofuran under nitrogen, there is added one equivalent of dry diethyl phosphite. The mixture is cooled in an ice-bath and stirred at 0° for 1.5 hours. One equivalent of the ethylene ketal of 1-bormopentan-4-one in 60 ml. of dry tetrahydrofuran is added and the mixture stirred for 15 minutes at 0° and allowed to stand 16 hours at room temperature. The mixture is then heated under reflux for three hours, cooled and filtered. The filtrate is concentrated under reduced pressure and the concentrate taken up in ether. This mixture is shaken with saturated aqueous sodium chloride and then separated. The organic layer is separated and concentrated under reduced pressure to give diethyl 4,4-ethylenedioxypentylphosphonate (V) (R is ethyl) which is purified by distillation in vacuo (b.p. 115° at 0.05 mm.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=3[O:29][CH3:30])=[CH:17][CH:16]=2)[CH:8]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(N(C(C)C)CC)(C)C.[C:51](Cl)(=[O:53])[CH3:52]>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([C:51](=[O:53])[CH3:52])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=3[O:29][CH3:30])=[CH:19][CH:20]=2)[CH:8]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CNc1cccc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(C(C)=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a vial containing [3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenylamino]-acetic acid ethyl ester (47 mg, 0.11 mmol) dissolved in dimethylformide (1 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF, 0.13 mL, 0.13 mmol), diisopropylethyl amine (0.238 mL, 1.3 mmol) and acetyl chloride. The reaction was stirred at room temperature overnight. Reaction was filtered and purified by HPLC with increasing concentration of acetonitrile in water with 0.1% trifluoroacetic acid to yield {acetyl-[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenyl]-amino}-acetic acid ethyl ester as a clear film (10 mg, 21%). LC-MS (ES) calculated for C26H25F2NO5, 469.17; found m/z 470 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:18][CH2:19][N:20]([CH3:22])[CH3:21]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidin-4-ol, sodium hydride, and DMF was stirred at ambient temperature for 5 minutes, here was added 2-chloro-N,N-dimethylethylamine, and the mixture was further stirred at ambient temperature for 30 minutes to yield 2-[(1-tert-butoxycarbonylpiperidin-4-yl)oxy]-N,N-dimethylethylamine, which was stirred together with 4M HCl-dioxane solution at ambient temperature for 7 hours to yield N,N-dimethyl-2-(piperidin-4-yloxy)ethylamine dihydrochloride.
Reaction SMILES: O=[C:2]([CH3:20])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1.[NH2:21][CH2:22][CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)[OH:24].C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:19][O:18][C:16]([CH:11]([C:12]([O:14][CH3:15])=[O:13])[C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH:2]([NH:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[OH:24])[CH3:20])=[CH:10][CH:9]=1)=[O:17]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)C(C(=O)OC)c1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(C(=O)OC)c1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1
Yield: 61.2 %

Procedure:
Following a procedure similar to that described in Example 6, but using 0.42 g of dimethyl 4-(2-oxopropoxy)phenylmalonate (prepared as described in Preparation 38), 0.26 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 50 ml of dry benzene, 50 ml of absolute methanol and 0.9 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 0.4 g of the title compound was obtained, having an Rf=0.28 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:19]([Cl:20])=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[Cl:21])=[CH:4][CH:3]=1.[Cl:22]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:14]([Cl:21])=[CH:15][C:16]([NH2:17])=[C:18]([Cl:22])[C:19]=2[Cl:20])=[CH:4][CH:3]=1
Reactant: Nc1cc(Cl)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccccc1
Product: Nc1cc(Cl)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1Cl
Yield: 56 %

Procedure:
Into a magnetically stirred solution of 4-(4-chloro-1-naphthoxy)-3,5-dichloroaniline (6.00 grams, 17.72 mmol) prepared in Part B in benzene (50 milliliters) was added solid N-chlorosuccinimide (2.84 grams, 21.20 mmol). The mixture was heated to reflux for 1 hour. cooled and filtered. The solvent was evaporated under reduced pressure and the crude product when subjected to flash column chromatography (3:1 hexane:ethyl acetate) afforded pure 4-(4-chloronaphthoxy)-2.3.5-trichloroaniline (3.70 grams. 9.92 mmol, 56%). Elemental analysis of the product indicated the following: