Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:11][C:10]=1[N:22]=[C:23]=[O:24].[OH:25][CH:26]([C:31]([CH3:33])=[CH2:32])[C:27]([O:29]C)=O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[F:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:11][C:10]=1[N:22]1[C:27](=[O:29])[C:26](=[C:31]([CH3:33])[CH3:32])[O:25][C:23]1=[O:24]
Reactant: O=C=Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: C=C(C)C(O)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
Triethylamine (40 ml) was gradually dropwise added to a toluene solution (10 liters) containing 2-fluoro-4-chloro-5-cyclopentyloxyphenylisocyanate (4.0 kg, 15.6 mol) and methyl 2-hydroxy-3-methyl-3-butenoate (2.4 kg, purity about 90 %, 18.4 mol), as put in a 20-liter stainless steel vessel, with cooling in an ice-water bath, in such a way that the temperature of the reaction solution did not rise. The whole was stirred for 2 hours at the determined temperature until the starting materials disappeared by TLC. Next, after addition of potassium carbonate (200 g, 1.45 mol), the reaction mixture was heated in a water bath (100° C.) for 4 hours with stirring with removing the methanol formed therefrom through a distillation device equipped to the reactor. After reaction, the reaction mixture was washed with 1 N hydrochloric acid (10 liters) and 1 N sodium hydroxide (10 liters) and further with 1 N hydrochloric acid (10 liters). The toluene layer was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and hexane of about a half of the oily product formed was added to the oily product formed. This was then allowed to stand at room temperature for a while. A whitish yellow solid precipitated out, which was taken out by filtration and well dried to obtain 3N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-5-isopropylidene-1,3-oxazolidine-2, 4-dione (4.19 kg, 11.8 mol). Yield: 75.7 %. Spectral data and other data of the product are those as shown in Example 27.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH:17]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][PH3+].N12CCCN=C1CCCCC2>C(#N)C>[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=[CH:17][CH2:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCc1ccccc1OCc1ccccc1
Reactant: COCOc1ccccc1C[PH3+]
Agent: [Cl-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COCOc1ccccc1C=CCCc1ccccc1OCc1ccccc1
Yield: 64.4 %

Procedure:
Following a procedure similar to that described in the first part of Preparation 3, 2.51 g of 3-(2-benzyloxyphenyl)propanal, 5.6 g of 2-methoxymethoxybenzylphosphonium chloride (prepared as described in Preparation 2) and 1.91 g of 1,8-diazabicyclo[5,4,0]-undec-7-ene were reacted in 50 ml of acetonitrile. The crude product, extracted as described in the first part of Preparation 3, was purified by column chromatography through silica gel, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.52 g (yield 64%) of 1-(2-methoxymethoxyphenyl)-4-(2-benzyloxyphenyl)-1-butene as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][Br:11])[C:5]#[N:6]
Reactant: Cc1ccc(C#N)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(CBr)c(Br)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 56.5 %

Procedure:
A solution of 3-bromo-4-methylbenzonitrile (1 g, 5.10 mmol) in chloroform (20 mL) was heated to 40-50° C. and N-bromosuccinimide (0.953 g, 5.36 mmol) was added in one portion followed by AIBN (8.38 mg, 0.051 mmol). After 1.5 hr. additional AIBN (20 mg) was added and the reaction was allowed to stir at 50° C. overnight. Additional AIBN (20 mg) and N-bromosuccinimide (1.1 g) were added, a reflux condenser was attached and the solution was heated to reflux. After several hours, additional AIBN (20 mg) was added and the reaction was allowed to stir at reflux overnight. The reaction was quenched by the addition of water and sat. aq. sodium bicarbonate. The organic phase was separated, concentrated in vacuo and purified by flash column chromatography (120 g silica, eluting with 0%-20% Ethyl Acetate in hexanes) to afford 3-bromo-4-(bromomethyl)benzonitrile as a pale yellow solid (800 mg, 2.88 mmol). 1H NMR (500 MHz, MeOD) δ ppm 4.70 (s, 2H), 7.71 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 8.04 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:17]2[C:18]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(Br)cc1
Reactant: OB(O)c1cccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2cccc3ccccc23)cc1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
Into a 2-L three-neck flask were put 25 g (0.15 mol) of 4-bromoaniline, 25 g (0.15 mol) of 1-naphthaleneboronic acid, 450 mL of toluene, and 150 mL of ethanol. While the pressure was reduced, this mixture was degassed by being stirred. After the degassing, the atmosphere in a system was replaced with nitrogen. Into the solution was added 220 mL (2.0 mol/L) of a potassium carbonate solution. The obtained mixture was degassed by being stirred while the pressure was reduced, and then, the atmosphere in the system was replaced with nitrogen. To this mixture were added 0.48 g (2.1 mmol) of palladium(II) acetate and 2.4 g (7.9 mmol) of tris(2-methylphenyl)phosphine, and the obtained mixture was stirred under a nitrogen stream at 80° C. for three hours. After the stirring, this mixture was allowed to cool to room temperature, and an aqueous layer of this mixture was extracted three times with toluene. The extracted solution and an organic layer were combined and washed twice with water and washed twice with saturated saline. Into this mixture was added magnesium sulfate, and the mixture was dried for 18 hours. The obtained mixture was subjected to natural filtration to remove magnesium sulfate, and the filtrate was concentrated to obtain an orange liquid. This orange liquid was dissolved in toluene, and this solution was filtrated through Celite, alumina, and Florisil. The obtained filtrate was concentrated to give 33 g of an objective orange liquid in a yield of 99%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[CH:56](=O)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH2:56]([N:53]1[CH2:54][CH2:55][N:50]([C:41]2([C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:33][C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=[C:23]([CH3:22])[CH:32]=4)=[CH:40][CH:39]=3)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]2=[O:49])[CH2:51][CH2:52]1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C3(N4CCN(Cc5ccccc5)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 26.2 %

Procedure:
Using a procedure analogous to Example 15, the product from example 14 (120 mg, 0.150 mmol) was treated with benzaldehyde (31.8 mg, 2.0 eq) to provide the title barbituric acid (35.0 mg, 26%). MS found: (M+H)+=550.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[N:11]([CH3:19])[C:10]=1[CH3:20].[CH3:21][O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[CH3:21][O:22][C:23](=[O:28])[C:24]([O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:19])[C:10]([CH3:20])=[C:9]2[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:26])[CH3:25]
Reactant: COC(=O)C(C)(C)Br
Reactant: COc1ccccc1-c1c(C)n(C)c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccccc1OC)c(C)n2C

Procedure:
A mixture of 5.34 g (0.02 mole) of 3-(2-methoxy-phenyl)-1,2-dimethyl-1H-indole-5-ol, 5.4 g (0.03 mole) of 2-bromo-2-methyl-propanoic acid methylester, and 14 g (0.1 mole) of potassium carbonate was refluxed for 16 hours in 250 ml of methyl-ethylketone. The precipitate was filtered off, the filtrate was evaporated, and the residue obtained was chromatographed on silicagel (solvent: toluene/acetone (30:1)).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]([CH3:34])[C@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1>>[CH3:26][N:27]([CH3:34])[C@H:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:29]1
Reactant: CN(C)[C@H]1CCCNC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCC[C@H](N(C)C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)—N,N-dimethylpiperidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=11.12 Hz, 1H) 1.78 (m, J=16.20 Hz, 2H) 2.12 (d, J=10.86 Hz, 1H) 2.33 (d, J=2.27 Hz, 3H) 2.67-2.94 (m, 6H) 3.13-4.79 (m, 5H) 7.48-7.70 (m, 1H) 7.70-7.80 (m, 1H) 7.98-8.34 (m, 2H) 8.57 (m, J=1.50 Hz, 2H) 9.44-10.31 (m, 1H). ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[O:19][CH:17]1[CH3:18]>[OH-].[Na+]>[CH2:1]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][CH:17]([OH:19])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CO1
Reactant: Oc1ccc(Cl)cc1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(O)COc1ccc(Cl)cc1Cc1ccccc1

Procedure:
2-Benzyl-4-chlorophenol (43.7 parts) is propoxylated with propylene oxide (12.6 parts) using sodium hydroxide (0.2 part) as catalyst at 145° C. in a manner similar to that used in Example 10 to give 1-(2-benzyl-4-chlorophenoxy)propan-2-ol (16.3 parts)
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(=O)(=O)(O)O.[CH3:21]O>>[C:1]12([CH2:11][CH2:12][C:13]([O:15][CH3:21])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)CCC12CC3CC(CC(C3)C1)C2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCC12CC3CC(CC(C3)C1)C2

Procedure:
To a solution of Intermediate 46 (2.9 g, 13.98 mmol) in methanol (22.6 mL) was added dropwise sulphuric acid (0.4 mL, 6.94 mmol) during 15 minutes at 0° C. The resulting reaction mixture was refluxed for 2 hours. The solvent was removed under reduced pressure and the crude was partitioned between ethyl acetate and water. The organic layer was washed with a solution of sodium hydrogen carbonate (4%), water and brine. The solvent was removed under reduced pressure and the title compound was obtained as a red oil (2.9 g, 95%) and was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:12])=[S:11])=[CH:5][CH:4]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=O.CCN(C(C)C)C(C)C>C(O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:12]=[C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:8][CH:7]=3)[S:11][CH:16]=2)=[CH:20][CH:21]=1
Reactant: NC(=S)Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC(F)(F)c1ccc(Nc2nc(-c3ccc(Cl)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
(4-Trifluoromethylphenyl)thiourea (5.00 g; 22.7 mmol) was dissolved in ethanol (45 mL) by gentle heating. Then, α-bromo-p-chloroacetophenone (5.30 g; 22.70 mmol) and DIPEA (3.22 g; 24.9 mmol) was added. The resulting solution was stirred for 16 hours at ambient temperature. The mixture was then concentrated in vacuo, and the residue dissolved in ethyl acetate. The DIPEA hydrobromide, which crystallized out of solution, was removed by filtration. The filtrate was washed with water (2×50 mL) and brine (50 mL), and dried over anhydrous sodium sulphate. The solvent was removed by rotary evaporation to give 7.00 g (93%) of [4-(4-chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amine as an oil. The material was pure enough for use in the next step (a crystalline sample can be obtained by re-crystallization in heptane).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=1[OH:19])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+:21]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=1[O-:19])([CH3:4])([CH3:3])[CH3:2].[K+:21]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C(C)(C)C)c([O-])c(C(C)(C)C)c1

Procedure:
A dispersion of potassium 2,4,6-tri-tert-butylphenolate was prepared using the procedure of Example 2 starting from 21.6 grams of 2,4,6-tri-tert-butylphenol, 9.7 grams of a 46.3% aqueous potassium hydroxide solution and 250 ml of toluene.
Reaction SMILES: OC[C@H](N[C:11](=[O:23])[C@@H:12]([CH3:22])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C1C=CC=CC=1.S(=O)(=O)(O)[OH:25]>O1CCOCC1>[CH3:22][C@@H:12]([CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:11]([OH:23])=[O:25]
Reactant: O=S(=O)(O)O
Reactant: C[C@@H](CCCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H](CCCc1ccccc1)C(=O)O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution consisting of (S)—N—((R)-2-hydroxy-1-phenylethyl)-2-methyl-5-phenylpentanamide (19mb(i), 3.5 g, 11.24 mmol) in 1,4-dioxane (80 mL) was added aqueous sulfuric acid (36 mL, 3 N solution) and the mixture was stirred overnight at 80° C. The reaction mixture was extracted with ethyl acetate three times and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane-acetic acid (30:70:0.4 v/v/v) afforded the title compound (2.4 g, quantitative yield) as a clear oil; Rf 0.48 (solvent system: 30:70:0.4 v/v/v ethyl acetate-heptane-acetic acid; HPLC retention time 26.0 minutes; Chiralpak IA, 5μ, 4.6×25 mm, ultraviolet detector at 208 nm 0.75 ml/min 99:1:0.5 v/v heptanes-2-propanol-acetic acid; MS (ESI−) m/z 191.1 (M−H)−; 1H-NMR (CDCl3) δ 7.33-7.27 (m, 2H), 7.22-7.16 (m, 3H), 2.67-2.60 (m, 2H), 2.56-2.46 (m, 1H), 1.80-1.60 (m, 3H), 1.59-1.36 (m, 1H), 1.25-1.14 (m, 3H); [α]Tλ=α/cl, [α]21.9D=+0.089/(0.01501 g/1.5 mL)(0.5)=+17.79° (c=1, CHCl3).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=[O:28])[CH:25]=5)[NH:20][CH:19]=4)[CH2:12][CH2:11]3)[C:4]=2[CH:3]=[CH:2]1.[BH4-].[Na+]>C(O)C.O>[OH:28][CH2:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:17][CH2:16][N:13]1[CH2:14][CH2:15][N:10]([C:5]2[C:4]3[CH:3]=[CH:2][NH:1][C:9]=3[CH:8]=[CH:7][N:6]=2)[CH2:11][CH2:12]1
Reactant: O=Cc1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1

Procedure:
A solution of 2 mmol of the compound obtained in Step 4 in 50 ml of ethanol is treated with 2.2 mmol of sodium borohydride for 24 hours. The solvent is evaporated off under reduced pressure and the residue obtained is taken up in water and then extracted with dichloromethane. The organic phase is dried and filtered and then concentrated under reduced pressure, enabling the expected product to be obtained.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23])[CH3:4]>CCO>[CH2:3]([O:5][C:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:23])([F:24])[F:25])[CH3:4]
Reactant: CCOc1cc(C(=O)OC)ccc1-c1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Temperature: 60 °C

Procedure:
A 5 N aqueous solution of NaOH (4.1 mL, 20.5 mmol) was added into a solution of methyl 2-ethoxy-2′-(trifluoromethyl)biphenyl-4-carboxylate (4.45 g, 13.7 mmol) in EtOH (45 mL). The reaction mixture was heated at 60° C. for 30 minutes, and then concentrated under reduced pressure. The residue was taken up with water (50 mL) and a 5N aqueous solution of HCl (7 ml), and then extracted with MTBE (2×100 mL). The organic layers were washed with brine (50 mL), dried over MgSO4 and concentrated under reduced pressure to give a colorless oil. After precipitation from pentane, the title compound was obtained as a white powder. HPLC (Method A), Rt 4.3 min (purity: 99.7%). LC/MS (Method B): M− (ESI): 309.0.
Reaction SMILES: [Br-].[Al+3].[Br-].[Br-].[C:5]1([OH:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.O.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24]>>[Cl:17][C:18]1[CH:23]=[C:22]([CH:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5](=[O:15])[CH2:6][CH2:7]2)[CH:21]=[CH:20][C:19]=1[Cl:24]
Reactant: Oc1cccc2ccccc12
Reactant: Clc1ccccc1Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: O
Product: O=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 65 °C
Yield: 79.6 %

Procedure:
In a solution of 100 g (0.374 mole) of anhydrous aluminium bromide in 130 ml of orthodichlorobenzene, 28 g (0.194 mole) of α-naphthol are added. The green solution obtained is heated for 1 hour at 65° C. then hydrolysed with 400 ml of water at 40° C. After decantation, the organic phase is separated which is concentrated under a vacuum. After crystallization of the residue in 140 ml of methanol at 0° C. for 2 hours, 45 g of the expected compound are obtained after filtration and drying.
Reaction SMILES: [Li+].CC([N-][CH:6]([CH3:8])[CH3:7])C.[Br:9][C:10]1[CH:18]=C[C:13]([C:14]([OH:16])=[O:15])=[C:12](C)[CH:11]=1.CI>C1COCC1>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[C:8]([CH2:6][CH3:7])[CH:18]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCc1cc(Br)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of LDA (10.7 mL, 21.39 mmol) in THF (20 mL) was added 4-bromo-2-methylbenzoic acid (2 g, 9.3 mmol) in THF (5 mL). The mixture was stirred at 0° C. for 1 h, cooled to −70° C., and then MeI (2.3 mL, 37.20 mmol) was added dropwise. The mixture was allowed to warm up to 0° C., stirred for 3 h, then quenched with H2O, and the pH was adjusted to 1-2 with 3 N HCl. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by normal phase silica gel column provided 4-bromo-2-ethylbenzoic acid as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:36][O:37][CH3:38])[C:4]([CH3:35])=[C:5]([C:26]([O:28][CH2:29][O:30][C:31](=[O:34])[CH2:32][CH3:33])=[O:27])[CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:7]=1[C:8]([O:10]COC(=O)CC)=[O:9]>C(OC(C)C)(C)C.O>[CH3:1][C:2]1[N:3]([CH2:36][O:37][CH3:38])[C:4]([CH3:35])=[C:5]([C:26]([O:28][CH2:29][O:30][C:31](=[O:34])[CH2:32][CH3:33])=[O:27])[C@H:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCC(=O)OCOC(=O)C1=C(C)N(COC)C(C)=C(C(=O)OCOC(=O)CC)C1c1cccc([N+](=O)[O-])c1
Solvent: CC(C)OC(C)C
Solvent: O
Product: CCC(=O)OCOC(=O)C1=C(C)N(COC)C(C)=C(C(=O)O)[C@H]1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.5 %

Procedure:
In 20 ml of isopropyl ether saturated with water was dissolved 120 mg of bis(propionyloxymethyl) 1,4-dihydro -2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate obtained in Example 12, and 50 mg of Lipase PS was added thereto, followed by stirring at room temperature for 72 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to obtain 77 mg (yield: 78%) of (R)-1,4-dihydro-2,6-dimethyl-1-methoxymethyl -4-(3-nitrophenyl)-5-propionyloxymethoxycarbonyl -3-pyridinecarbox-ylic acid as a pale yellow crystal.
Reaction SMILES: [CH2:1]([O:3][PH:4]([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:5])[CH3:2].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>O1CCCC1>[CH2:1]([O:3][P:4]([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(OCC)[PH](=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)P(=O)(Cc1ccccc1)OCC
Reaction time: 1.5 h

Procedure:
A solution of diethoxymethylphosphinic acid ethyl ester is added within a period of 90 minutes, under argon, to a suspension of 13.2 g of 99% sodium hydride in 500 ml of tetrahydrofuran, the temperature being maintained at 20°. The reaction is exothermic and is accomplished by the evolution of gas. The mixture is then stirred for 90 minutes, and 85.5 g of benzyl bromide are then added within a period of 20 minutes. The mixture is then stirred at room temperature for 24 hours and cooled to 0°, and 100 ml of water are added carefully. The organic solvents are removed under reduced pressure and the residue is partitioned between water and dichloromethane. The organic phase is separated off, washed with water, dried over sodium sulfate and concentrated by evaporation. Distillation of the residue under reduced pressure yields diethoxymethyl(benzyl)phosphinic acid ethyl ester having a boiling point of 103°-110° (3×10-4 bar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][C:4]=1[CH3:12].Br[CH2:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=O>C(Cl)(Cl)Cl>[CH3:12][C:4]1[CH:5]=[C:6]([C:7]2[NH:9][CH:14]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[N:8]=2)[CH:10]=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: O=C(CBr)c1cccs1
Reactant: COc1ccc(C(=N)N)cc1C
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.3 %

Procedure:
A slurry of 22 (21.6 g, 0.132 mol) in CHCl2 (300 ml) was treated dropwise over 15 minutes with 2-(bromoacetyl)-thiophene (10.84, 0.0476 mol, 92% pure) in CHCl3 (55 ml). The reaction mixture was stirred at room temperature for 24 hours, and then filtered to remove 10.2 g of the hydrobromide of 22. The mother liquors were concentrated to a semisolid which was swirled with 75 ml of methylene chloride and refrigerated overnight. The resultant gray solid was washed with CH2Cl2 and dried to give 10.2 grams (79%) of 23; m.p. 110°-114°. The analytical sample was dried in vacuo at 85°, m.p. 115°-117°.