Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:10]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(C#N)cc1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(-c2nc(=O)c3ccccc3s2)cc1
Yield: 30.9 %

Procedure:
A mixture of terephthalonitrile (1.50 g, 12 mmol), methyl thiosalicylate (2.95 g, 18 mmol), triethylamine (2.10 g, 21 mmol) and toluene (20 ml) was heated and refluxed under a nitrogen flow for 48 hours. The crystals precipitated were taken by filtration and recrystallized from tetrahydrofuran to give the title compound (0.98 g, 32%) as crystals.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])(O)=O.[C:12](=O)([O-:14])[O-:13].[K+].[K+].CI>CC(C)=O>[C:12]([CH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:14])=[O:13]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: O=Cc1ccccc1CC(=O)O
Temperature: 56 °C
Reaction time: 72 h
Yield: 99.5 %

Procedure:
2-Carboxybenzaldehyde (4.53 g, 30 mmoles) was dissolved in acetone (100 mls) and anhydrous potassium carbonate (4.14 g, 30 mmoles) was added. After stirring methyl iodide (5.6 mls, 90 mmoles) was added and the reaction was heated (56° C.) for 30 minutes. The reaction became very thick so further acetone was added (50 mls) and stirring continued at room temperature for a further 72 hours. The reaction mixture was filtered through Celite and then evaporated to leave a viscous oil. The oil was then partitioned between water (30 ml) and ethyl acetate (30 ml). The aqueous layer was washed with further ethyl acetate (2×30 mls) and all the ethyl acetate extracts combined and washed with brine (30 mls) and then water (30 mls) dried over anhydrous magnesium sulphate and evaporated to leave a clear light yellow oil (4.9 g, 100% yield).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[C:17]([C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=1)[C:18]#[N:19])=O)(C)(C)C.[OH-:30].[Na+].O>S(=O)(=O)(O)O>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[C:17]([C:20]1[N:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][N:21]=1)[C:18]([NH2:19])=[O:30]
Reactant: CC(C)(C)OC(=O)N1C(=C(C#N)c2nccc(C(F)(F)F)n2)Nc2ccccc21
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C(=C1Nc2ccccc2N1)c1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
2-[1-(tert-Butoxycarbonyl)benzimidazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)-acetonitrile (8.1 g, 20 mmol) was dissolved in concentrated sulfuric acid (30 mL), and the solution added gradually to ice/water (100 mL), allowed to warm to room temperature, and stirred overnight. The mixture was cooled to 0° C., poured over ice, and neutralized with 50% aqueous sodium hydroxide. Water was added, and the crude product was extracted with 4:1 chloroform/isopropanol. The organic phase was dried over magnesium sulfate, the solvent was removed under vacuum, and the solid was purified by reverse phase preparative HPLC to give 2-[1H-benzimidazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (1.18 g, 18% overall yield) as a yellow solid.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:12]([OH:14])=[O:13].[C:15]([O-])([O-])=O.[K+].[K+].CI.Cl>CN(C=O)C>[CH2:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: C=C1CCCC2(CCCC2)C1C(=O)O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=C1CCCC2(CCCC2)C1C(=O)OC
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
At 5° C., a solution of the previously obtained 7-methylenespiro[4.5]decane-6-carboxylic acid (1.1 g, 5.66 mmol, prepared as described in Example 28) in DMF (20 ml) was treated with K2CO3 (0.86 g, 6.8 mmol). The resulting mixture was stirred for 30 min., treated with methyl iodide (0.53 ml, 8.5 mmol), stirred at 20° C. for 2 h, poured into cold 2N aqueous HCl (30 ml), and extracted twice with hexane (50 ml). The combined organic phases were washed with water (50 ml), with a saturated aqueous solution of NaCl (50 ml), dried (MgSO4), and concentrated. FC (30 g SiO2, hexane/MTBE 50:1) of the crude product (1 g) gave methyl 7-methylenespiro[4.5]decane-6-carboxylate (0.84 g, 71%). Boiling point: 90° C. (1.1 mbar).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:8]=[CH:9][C:10]=1[NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([O-:4])=[O:3].C(N(CC)CC)C.Br[CH2:30][CH:31]=[CH2:32]>CN(C)C=O>[CH2:32]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:6][C:5]=2[N+:2]([O-:4])=[O:3])[CH2:13][CH2:14]1)[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: NS(=O)(=O)c1ccc(NC2CCNCC2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCN1CCC(Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-nitro-4-(piperidin-4-ylamino)benzenesulfonamide hydrochloride (0.27 g), triethylamine (0.2 mL) and 3-bromoprop-1-ene (0.1 g) was dissolved in N,N-dimethylformamide (5 mL). The mixture was stirred at room temperature overnight. The solvent was dried under vacuum. The mixture was chromatographed on silica gel with 0-20% methanol in dichloromethane.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][CH:3]=1.[Br:15]Br.ClC(Cl)(Cl)Cl>O>[Br:15][C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([C:2]=1[CH3:1])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(C)cccc1OC
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(OC)ccc(Br)c1C
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of ethyl 6-methyl-2-methoxybenzoate (8.4 g, 43.2 mmol), bromine (6.9 g, 43.2 mmol) and tetrachloromethane (170 ml) is stirred at room temperature for 60 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is separated and concentrated. The crude product is obtained as a yellow oil, 10.3 g (87%) and is used without further purification.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][PH:11](=[O:15])[O:12][CH2:13][CH3:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([P:11]([CH3:10])(=[O:15])[O:12][CH2:13][CH3:14])=[CH:3][CH:4]=1)=[O:7]
Reactant: CCO[PH](C)=O
Reactant: O=Cc1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc(C=O)cc1
Temperature: 110 °C
Reaction time: 10 h

Procedure:
To a solution of 4-bromobenzaldehyde, 38-a, (500 mg, 2.7 mmol) and ethyl methylphosphinate, 38-b, (650 mg, 5.4 mmol) in toluene (10 mL) was added triethylamine (1.1 g, 11 mmol). After being allowed to stir for 10 h at 110° C. under nitrogen atmosphere, the mixture was cooled to ambient temperature, concentrated, diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (2×30 mL), dried over Na2SO4, filtrated and concentrated to give a residue, which was purified by chromatography on silica gel (dichloromethane/methanol=70:1) to afford compound 38-c as a colorless oil. (530 mg, 93%). 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.93-8.05 (m, 4H), 3.90-3.98 (m, 2H), 1.68-1.73 (d, J=14.4 Hz, 3H), 1.16-1.24 (m, 3H). LC-MS 213 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:5]=[CH:6][C:7](Cl)=[O:8].[C@H:14]1([O:25][C@@H:26]2[C@@H:31]([CH2:32][OH:33])[O:30][C@@H:29]([N:34]=[N+]=[N-])[C@H:28]([OH:37])[C@H:27]2[OH:38])[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]([OH:18])[C@H:15]1[OH:16]>CN(C)C=O.N1C=CC=CC=1>[C@H:14]1([O:25][C@@H:26]2[C@@H:31]([CH2:32][OH:33])[O:30][C@@H:29]([NH:34][C:7](=[O:8])[CH:6]=[CH:5][C:4]3[CH:10]=[CH:11][C:12]([OH:13])=[C:2]([OH:1])[CH:3]=3)[C@H:28]([OH:37])[C@H:27]2[OH:38])[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]([OH:18])[C@H:15]1[OH:16]
Reactant: [N-]=[N+]=N[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Reactant: O=C(Cl)C=Cc1ccc(O)c(O)c1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(C=Cc1ccc(O)c(O)c1)N[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Reaction time: 1.5 h

Procedure:
A method for producing compounds of the formula: ##STR8## wherein A is selected from the group consisting of alkali metal cations and alkaline earth metal cations which comprises reacting 3,4-dihydroxycinnamic acid with acetic anhydride in pyridine for 18-30 hours, in organic solvents, giving 3,4-dihydroxycinnamic acid, diacetate, then converting to 3,4-dihydroxycinnamic acid chloride by treating with thionyl chloride in dimethylformamide at -20° to -18° C. for 30-90 minutes; reacting 4-O-α-D-glucopyranosyl-β-D-glucopyranosyl bromide, heptaacetate with sodium azide in dimethylsulfoxide at 55°-65° C. for 10-30 minutes, extracting in organic solvents, giving 4-O-α-D-glucopyranosyl-β-D-glucopyranosylazide, heptaacetate, then catalytically reducing, giving 4-Oα-D-glucopyranosyl-β-D-glucopyranosylamine, heptaacetate (heptaester); reacting a solution of the 3,4-dihydroxycinnamic acid chloride in dimethylformamide at -20° to -15° C. with a solution of the 4-O-α-D-glucopyranosyl-β-D-glucopyranosylamine, heptaacetate in pyridine at -15° to -5° C. for 20-40 minutes, then at -5° to 20° C. for 1-2 hours followed by extracting with organic solvents, giving N-(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl)-3,4-dihydroxycinnamamide, nonaacetate (nonaester), then converting to N-(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl)-3,4-dihydroxycinnamamide by reacting in a mixture of methanol, triethylamine and water, under an inert atmosphere for 20-30 hours followed by heating at reflux for 2-6 hours and extracting in organic solvents, reacting this derivative with triethylamine sulfur trioxide in N,N-dimethylacetamide under an inert atmosphere at 50°-70° C. for 15-20 hours, and then treating with an alkali metal or alkaline earth metal acetate in water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=2)[C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[S:19][C:17]=2[N:18]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Reactant: COc1ccc(CN)cc1Cl
Product: COc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1Cl

Procedure:
Following the procedure of Example 1, the reaction of 3-chloro-4-methoxybenzylamine with 2,4-dichloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-trifluoromethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]=[O:10].C([Li])CCC.[CH:16]1([CH:19]2[CH2:22][C:21](=[O:23])[CH2:20]2)[CH2:18][CH2:17]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH:16]1([CH:19]2[CH2:22][C:21]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][CH:9]=[O:10])([OH:23])[CH2:20]2)[CH2:18][CH2:17]1
Reactant: O=CNc1ccccc1Br
Reactant: O=C1CC(C2CC2)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=CNc1ccccc1C1(O)CC(C2CC2)C1
Temperature: -100 °C
Reaction time: 2.5 h

Procedure:
In a sulfonation flask, 7.8 g (0.039 mol) N-(2-bromophenyl)form amide was dissolved in a mixture of 100 ml dry tetrahydrofuran. The solution was cooled to −100° C. and 60 ml (0.096 mol) of n-butyllithium solution (1.6M in hexane) was added over a period of 1 hour in such at manner that the internal temperature remained constant at −100° C. (±2° C.). After stirring for 2.5 hours at −100° to −110° C., 5.3 g (0.048 mmol) of 3-cyclopropylcyclobutan-1-one (prepared as described in Example 7), dissolved in 30 ml of dry tetrahydrofuran, were added over a period of 30 minutes in such a manner that the internal temperature remained constant at −100° C. (±2° C.). After stirring for 3 hours at −78° C., the temperature was elevated to 0° C. in ca. 30 minutes. Concentrated ammonium chloride solution and ethyl acetate were added and the organic phase was washed several times with water. After drying and evaporation of the solvent in a water jet vacuum, the crude material was obtained. Purification was achieved by flash chromatography over silica gel (eluant: hexane/ethyl acetate 1:1). Yield: 2.55 g (23% of theory) of N-[2-(3-cyclopropyl-1-hydroxycyclobutyl)-phenyl]formamide in the form of a resin.
Reaction SMILES: [H-].[Na+].C(OC(=O)CC[SH:9])C.[CH2:11]([O:18][C:19]1[CH:24]=[C:23](F)[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.OC1C=CC=C(CC2C=CC(N3CC(=O)NS3(=O)=O)=C(O)C=2)C=1C#N>CN(C=O)C.CCOC(C)=O>[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([SH:9])[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCS
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Agent: N#Cc1c(O)cccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(S)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of NaH (60%, 1.21 g, 30.3 mmol) in dry DMF (20 mL) under N2 at 0° C. is added dropwise 3-mercaptopropionic acid ethyl ester (1.9 mL, 15.2 mmol) and 2-benzyloxy-4-fluoro-1-nitrobenzene (intermediate from Example 27) (2.5 g, 10.1 mmol) in dry DMF (10 mL). The reaction is allowed to warm to ambient temperature and stirred for 4 days. The mixture is then diluted with EtOAc (100 mL) and extracted with 1N HCl (50 mL). The organics are washed with brine and dried with Na2SO4. Evaporation yields a yellow oil which is purified by flash chromatography (30-50% EtOAc). The title compound is isolated as a yellow oil: MS (M−H)−=260.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:34]3[CH2:35][CH2:36][N:31]([C:25]4[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=4[CH3:23])[CH2:32][CH2:33]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccc(F)cc4)n(-c4ccccc4)n3)CC2)c(C)c1

Procedure:
96 mg (70%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.272 mmol), 1-(2,4-dimethylphenyl)piperazine (52 mg, 0.272 mmol), DIPEA (0.071 mL, 0.408 mmol) and NaBH(OAc)3 (173 mg, 0.816 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:10](I)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.C([Li])CCC.CCCCCC.C1(C)C=CC(S([C:32]#[N:33])(=O)=O)=CC=1>O1CCCC1>[Cl:1][C:2]1[C:10]([C:32]#[N:33])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Clc1nn2ccccc2c1I
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1c(Cl)nn2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled −78° C. solution of the title compound from Example 1 Step A (0.20 g, 0.718 mmol) in tetrahydrofuran (3.59 ml) was added a solution of n-butyllithium in hexane (1.6 M, 0.494 ml, 0.790 mmol). After 5 minutes, p-toluenesulfonyl cyanide (0.169 g, 0.934 mmol) was added, and the resulting reaction mixture was allowed to warm to room temperature. After 18 hours, the mixture was concentrated under reduced pressure. Purification by column chromatography on silica gel (0-30% ethyl acetate in hexanes) provided the title compound: LCMS m/z 177.91 [M+H]+, 179.86 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 8.47 (d, J=6.9 Hz, 1 H), 7.70 (d, J=9.0 Hz, 1 H), 7.52 (dd, J=8.0, 8.0 Hz, 1 H), 7.26-7.20 (m, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=2)[C@H:10]([CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[Cl:29][C:30]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([NH:21][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:30]=3[Cl:29])[CH:18]=[CH:19][CH:20]=2)[CH:10]([CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)CC[C@@H]1Oc1cccc(N)c1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC1CN(Cc2ccccc2)CCC1Oc1cccc(NC(=O)c2ccc(F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine racemic 3-(1-benzyl-cis-3-methyl-piperidin-4-yloxy)-phenylamine (preparation 41, 0.80 g, 2.7 mmol), 1,4-dioxane (20 mL), and 2-chloro-4-fluoro-benzoyl chloride (0.625 g, 3.24 mmol), stir and heat at reflux. After 2 hr., cool to ambient temperature. Dilute with methanol and load the resulting solution on 210 g SCX columns. Wash each with methanol (2×50 mL). Elute product from each column with 2M ammonia/methanol (2×50 mL). Combine and concentrate the eluents. Purify residue by silica gel flash chromatography eluting with 5% (2M NH3/methanol)/methylene dichloride to obtain the title compound as a racemic mixture (1.07 g, 87.7%). Resolve using a Chiralpak AD™ 4.6×250 mm column eluting at 1.0 mL/min. with 10% absolute ethanol/90% Heptane with 0.2% DMEA to obtain of the title compound (0.524 g, 49.0%). Mass spectrum (electrospray): m/z=453.2 (M+1); 1H NMR (CDCl3): 7.85 (bs, 1H), 7.8 (dd, 1H), 7.45 (s, 1H), 7.3 (m, 7H), 7.1 (m, 1H), 7.0 (m, 1H), 6.75 (dd, 1H), 4.4 (m, 1H), 3.5 (m, 2H), 2.5 (m, 2H), 2.4 (m, 2H), 2.1 (m, 2H), 1.8 (m, 1H), 1.0 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:19])[C:16]([OH:18])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[C:20]([NH:24][C:16](=[O:18])[C:15]([NH:14][C:5]1[CH:6]=[CH:7][C:8]([C:9]2[O:13][CH:12]=[N:11][CH:10]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:19])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: COc1cc(NC(=O)C(=O)O)ccc1-c1cnco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)C(=O)NC(C)(C)C)ccc1-c1cnco1
Yield: 34.7 %

Procedure:
A solution of 26 mg (0.1 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamic acid, 15 mg (0.2 mmol) of tertiary butylamine, 28 mg (0.15 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 15 mg (0.11 mmol) of 1-hydroxy-7-azabenzotriazole in 1 ml of dimethylformamide was stirred at room temperature for 4 hours then diluted with ethyl acetate and washed with 2M hydrochloric acid, saturated sodium bicarbonate and water. The resulting solution was dried over magnesium sulphate and evaporated to dryness. The residue was triturated with diethyl ether/petrol (1:1) and collected by filtration to give 11 mg of N-tert-butyl-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide as a white solid. MS: m/e 318.0 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]([CH2:16]Cl)=[CH2:15].[OH-].[Na+]>>[O:12]=[C:8]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:16][C:14]([Cl:13])=[CH2:15])[C:9]([OH:11])=[O:10]
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: C=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Product: C=C(Cl)CC(C(=O)C(=O)O)c1ccccc1

Procedure:
By the same operation as in Example 45, 1.64 g (10 mmoles) of phenylpyruvic acid was reacted with 0.11 g (10 mmoles) of 2,3-dichloropropene in a 1N aqueous solution of sodium hydroxide (20 ml, 20 mmoles) to give 2-oxo-3-phenyl-5-chloro-5-hexenoic acid as a pale yellowish white solid. It was converted to a methyl ester by using diazomethane, and then the methyl ester was purified by silica gel column chromatography. Methyl 2-oxo-3-phenyl-5-chloro-5-hexenoate as a pure product (1.87 g; yield 74 %) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[C@H:30]1[O:34][C:33](=[O:35])[NH:32][C@@H:31]1[CH3:36].[H-].[Na+].Br[CH2:40][C:41]1[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=1>C1COCC1>[F:48][C:47]([F:49])([F:50])[C:45]1[CH:46]=[C:41]([CH:42]=[C:43]([C:51]([F:54])([F:52])[F:53])[CH:44]=1)[CH2:40][N:32]1[C@H:31]([CH3:36])[C@@H:30]([C:21]2[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:20]=2[C:4]2[CH:5]=[C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=3[CH3:19])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[O:34][C:33]1=[O:35]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3[C@H]3OC(=O)N[C@@H]3C)c2)c(C)c1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3[C@H]3OC(=O)N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reaction time: 0.17 h

Procedure:
The starting methyl 4′-methoxy-2-methyl-2″-[(4R,5R)-4-methyl-2-oxo-1,3-oxazolidin-5-yl]-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (40 mg, 0.080 mmol) was dissolved in anhydrous THF (1 mL) and cooled in an ice bath. Sodium hydride (60% w/w in mineral oil, 3.5 mg, 0.088 mmol) was added into the mixture. The reaction mixture was stirred cold (ice bath) for 10 min followed by addition of 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (22 μL, 36.8 mg, 0.120 mmol). The resulting mixture was stirred cold for 20 min then the cold bath was removed. Aliquot at reaction time 2.5 hours indicated about 50% conversion. Reaction crude was cooled (ice bath) and quenched by NH4Cl (aq., sat.). The resulting bi-phasic mixture was worked up with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to afford an oil. This oil was purified by a preparative reverse-phase HPLC (Kromasil 100-5C18, 100×21.1 mm) eluted with a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture. Related fractions were pooled and evaporated to afford methyl 2″-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. Un-reacted starting material was also recovered. LCMS calc.=725.18; found 726.19 (M+1).