Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.OC1C=CC(NC([C@@H]2CCCN2)=O)=CC=1>>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)c1n[nH]c2ccccc12
Agent: O=C(Nc1ccc(O)cc1)[C@@H]1CCCN1
Product: O=C(Nc1ccc(O)cc1)c1n[nH]c2ccccc12

Procedure:
This compound was prepared from 1H-Indazole-3-carboxylic acid (4-benzyloxy-phenyl)-amide, using the same method used to prepare (S)-pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide. The product was purified by flash chromatography, on silica gel, eluted with 5 to 10% methanol in DCM, to give the product as an off white solid, 2.6 g (60% for 2 steps). MS m/z 254 (MH+). 1H NMR(DMSO-d6) δ 6.74 (d, 2H), 7.26-7.34 (m, 1H), 7.43-7.51 (m, 1H), 7.67-7.73 (m, 3H), 8.24 (d, 1H), 9.25 (s, 1H), 10.10 (s, 1H) and 13.72 (s, 1H). Anal. calcd for C14H11N3O2: C, 66.40; H, 4.38; N, 16.59. Found: C, 66.15; H, 4.20; N, 16.82.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](C(N=[N+]=[N-])=O)=[N:2]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.O.C[N:30](C)[CH:31]=[O:32]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:30][C:31]([N:25]2[CH2:26][CH2:27][N:22]([C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[CH2:23][CH2:24]2)=[O:32])=[N:2]1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: [N-]=[N+]=NC(=O)c1n[nH]c2ccccc12
Reactant: CN(C)C=O
Solvent: O
Product: O=C(Nc1n[nH]c2ccccc12)N1CCN(c2ccc(F)cc2)CC1
Temperature: 100 °C
Yield: 18 %

Procedure:
1H-Indazole-3-carbonylazide (synthesized according to the method described in Tetrahedron, 32, 4, 1976, 493-497, 200 mg) was dissolved in dimethylformamide (4 ml), and the mixture was stirred with heating at 100° C. for 30 min. 1-(4-Fluorophenyl)piperazine (Aldrich Co., 211 mg) was dissolved in dimethylformamide (1 ml) and added thereto, and the mixture was stirred with heating at 100° C. for 1 hr. After allowing to cool, water was added to the reaction mixture and the precipitated solid was collected by filtration and dried. The solid was washed in a suspension state with methanol to give 4-(4-fluorophenyl)-1-piperazinecarboxylic acid (1H-indazol-3-yl)amide (64 mg, yield 18%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[N:17]=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(C(C)C)CC)(C)C.Br[CH2:42][CH2:43][O:44][CH3:45].[N-]=C=O>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:45][O:44][CH2:43][CH2:42][N:11]1[CH2:10][CH2:9][N:8]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[N:17]=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:13][CH2:12]1
Reactant: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N2CCNCC2)n1
Reactant: COCCBr
Agent: [N-]=C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COCCN1CCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(C#N)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 4-(piperazin-1-yl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt (Example 1; 100 mg) and diisopropylethylamine (78 μl) in acetonitrile (3 ml) was added 2-bromoethylmethylether (31 μl). The resulting solution was stirred at room temperature for 16 hrs, followed by heating at 45° C. for 24 hrs. Polymer bound isocyanate (1 mmol/g, 300 mg) was then added and the mixture was shaken at room temperature for 72 hrs before filtering and concentrating in vacuo. Residue was dissolved in dimethylsulphoxide and purified using the prep-HPLC to give 4-[4-(2-methoxyethyl)piperazin-1-yl]-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt as a white solid (8 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(CNc2nc(Cl)nc3scc(C)c23)cc1Cl
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3scc(C)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13](=[O:21])OC1C=CC=CC=1.[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([CH3:29])[CH:28]=1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13]([N:33]1[CH2:34][CH2:35][N:30]([C:25]2[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH3:22])[CH:24]=2)[CH2:31][CH2:32]1)=[O:21]
Reactant: COc1nc2c(cc1NC(=O)Oc1ccccc1)CCC2
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc2c(cc1NC(=O)N1CCN(c3cc(C)cc(C)c3)CC1)CCC2
Yield: 55 %

Procedure:
Phenyl N-(2-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].O.[Li+].[OH-]>O1CCOCC1>[C:26]([N:23]1[CH2:22][CH2:21][CH:20]([N:10]([C:11]([CH:13]2[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C:9]2[CH:8]=[C:7]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:25][CH2:24]1)(=[O:28])[CH3:27]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(C(C)=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1CCC(N(C(=O)C2CCC(C)CC2)c2cc(-c3ccccc3)sc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
3-[(1-Acetyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (50 mg, 0.104 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (1 ml) and then LiOH 1N (310 ul, 0.310 mmol) was added. After 5 hours of stirring at room temperature and 4 hours at reflux, 10 solvents were removed and then partitioned between 5 ml of H2O acidified to pH 4 and 5 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×5 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was purified by preparative chromatography (100/90/16/1 CH2Cl2/CHCl3/MeOH/Et3N) to obtain 27 mg (56%) of 3-[(1-Acetyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (Compound 48).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([NH:29][C@@H:30]2[C:36](=[O:37])[N:35]([CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[C:34]3[CH:46]=[CH:47][CH:48]=[CH:49][C:33]=3[S:32][CH2:31]2)[C:24]([O:26]CC)=[O:25])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(O)(=O)C.Br.C(OCC)C>C(O)(=O)C>[C:24]([C@@H:23]([NH:29][C@@H:30]1[C:36](=[O:37])[N:35]([CH2:38][C:39]([OH:41])=[O:40])[C:34]2[CH:46]=[CH:47][CH:48]=[CH:49][C:33]=2[S:32][CH2:31]1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:26])=[O:25]
Reactant: CCOC(=O)[C@H](CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCCCCC2CCNCC2)C(=O)O)CSc2ccccc21
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
In 1.5 ml of acetic acid is dissolved 0.3 g of tertbutyl 3(R)-[7-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 1 ml of 30% hydrogen-bromide acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 0.5 hour. Ethyl ether (80 ml) is added to the reaction solution, which is then allowed to stand. The supernatant liquid is decanted, and the precipitate is dissolved in 10 ml of 1N aqueous sodium hydroxide solution, followed by allowing the solution to stand at room temperature for 30 minutes. The solution is neutralized with 2 ml of acetic acid, and purified by XAD-2 column chromatography (water:methanol=1:1). The eluent is concentrated under reduced pressure, and the residue is lyophilized to give 0.1 g of 3(R)-[1(S)-carboxy-7-(4-piperidyl)heptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.
Reaction SMILES: [Mg].C(Br)C.[CH3:5][C:6]1[CH2:7][CH:8]2[CH:12]([CH2:13][CH:14]=1)[C:11](=O)[O:10][C:9]2=[O:16].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C1COCC1>[CH3:5][C:6]1[CH2:7][CH:8]2[CH:12]([CH2:11][O:10][C:9]2=[O:16])[CH2:13][CH:14]=1
Reactant: CC1=CCC2C(=O)OC(=O)C2C1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCBr
Solvent: C1CCOC1
Product: CC1=CCC2COC(=O)C2C1
Temperature: 25 °C

Procedure:
A 5-L round bottom reaction flask was charged with magnesium metal (Mg) (140 g) and THF (1 L) under nitrogen. Ethyl bromide (EtBr) (630 g) was fed into the reaction mixture dropwise while the temperature was maintained at 25° C. or below using a dry ice bath. After the feeding was completed, the reaction mixture was aged at room temperature for half an hour. Crude 5-methyl-3a,4,7,7a-tetrahydro-isobenzofuran-1,3-dione (1.7 L, ˜56% of the mass of the resulting mixture obtained in EXAMPLE I) was then added dropwise while the temperature was maintained at 25° C. using a dry ice bath. The reaction mixture was consequently further aged at room temperature for another hour. The reaction mixture was poured into sulfuric acid (H2SO4) (10%) containing ice. Toluene was added. The organic and aqueous layers were shaken in a separatory funnel and separated. The aqueous layer was further washed with toluene. The organic layers were combined and washed with sodium carbonate (Na2CO3) solution until basic. The resulting solution was then distilled to afford 3,3-diethyl-5 or 6-methyl-3a,4,7,7a-tetrahydro-3H-isobenzofuran-1-one (457 g).
Reaction SMILES: [Mg].[CH3:2][Si:3]([CH3:6])(Cl)[Cl:4].II.Cl[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1>O1CCCC1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([Si:3]([CH3:6])([CH3:2])[Cl:4])=[CH:11][CH:12]=1
Reactant: COc1ccc(Cl)cc1
Reactant: C[Si](C)(Cl)Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc([Si](C)(C)Cl)cc1
Reaction time: 5 h
Yield: 61 %

Procedure:
The following were placed in a dry four-neck flask equipped with a stirrer, reflux condenser, addition funnel, and thermometer under a nitrogen blanket: 23.3 g (1.0 mol) powdered magnesium, 129.1 g (1.0 mol) dimethyldichlorosilane, and 200 mL tetrahydrofuran. A small quantity of iodine was added in order to activate the magnesium. Then, while cooling the flask to below 10 degrees Centigrade, a mixture of 142.6 g (1.0 mol) p-chloroanisole and 300 mL tetrahydrofuran was dripped in from the addition funnel with stirring over 5 hours. The reaction mixture was aged by heating under reflux for 2 hours, the precipitate was removed by suction filtration, and the filtrate was distilled to give 122 g (0.61 mol) product. The yield was 61%. The properties of this product are reported below.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]([NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([O:19][CH3:20])=[O:18])(=[O:12])[CH3:11]>>[C:10]([NH:13][C:14]1[C:23]([CH3:24])=[CH:22][C:21]([N+:1]([O-:4])=[O:2])=[C:16]([CH:15]=1)[C:17]([O:19][CH3:20])=[O:18])(=[O:12])[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(C)c(NC(C)=O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(NC(C)=O)c(C)cc1[N+](=O)[O-]
Temperature: 5 °C
Yield: 84.3 %

Procedure:
a mixture of fuming nitric acid (8.4 g) and conc. sulfuric acid (260 g) was cooled to 0-10° C. and the known methyl 3-acetylamino-4-methylbenzoate (26.3 g, 127 mmol) was added portionwise with stirring. After stirring for several hours, the mixture was poured onto ice which subsequently melted. The product was collected by suction filtration, washed with water and dried. The solid was recrystallized from isopropanol to give 27 g of yellow powder.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][N:9]=1.[CH3:16][C:17]1[N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:20]=[CH:19][C:18]=1[CH:28]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[Cl:3][C:4]1[C:5]([N:10]2[CH2:11][CH2:12][N:13]([CH2:28][C:18]3[CH:19]=[N:20][N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:17]=3[CH3:16])[CH2:14][CH2:15]2)=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: Cc1c(C=O)cnn1-c1ccccc1
Reactant: Clc1nccnc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1-c1ccccc1
Yield: 88 %

Procedure:
Dissolve 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (0.500 g, 1.84 mmol) in 1,2-dichloroethane (19 mL). Add 5-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (0.396 g, 2.13 mmol), triethylamine (594 μL, 4.26 mmol), sodium triacetoxyborohydride (0.677 g, 3.20 mmol) and acetic acid (200 μL) and stir at room temperature for 18 hr. Add aq. saturated sodium bicarbonate and extract four times with DCM. Dry combined organic layers (magnesium sulfate), filter, concentrate, and purify (silica gel chromatography, eluting with 0:100 to 100:0 ethyl acetate:hexanes) to give 3′-chloro-4-(5-methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (597 mg, 88%) MS (ES): m/z=369[M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.CI.[C:14]([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[C:3]([O:11][CH3:14])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: COC(=O)c1scc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1scc(Br)c1OC
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of 36 g (0.15 mole) of methyl 4-bromo-3-hydroxy-2-thiophenecarboxylate in 300 mL of dimethyl sulfoxide (DMSO) was added 32 g (0.23 mole) of methyl iodide and then 32 g of powdered K2CO3. After 2 hr, the reaction mixture was poured into water and extracted with ether. The organic phase was washed with water (4×200 mL), dried over MgSO4, filtered and concentrated to give 36 g of a colorless solid. 1H NMR (300 MHz, CDCl3): δ 7.4 (s, 1H); 4.0 (s, 3H); 3.9 (s, 3H). Anal. Calc'd for C7H7BrO3S: C, 33.48; H, 2.81; S, 12.77. Found: C, 33.18; H, 2.70; S, 12.49.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)[C:9](=[O:14])[CH:10]=[C:11]([CH3:13])C)C.[CH2:17]1COC[CH2:18]1>C(NC1CCCCC1)(C)C>[CH:3]1[CH:4]=[CH:5][C:17]2[C:18](=[CH:13][CH:11]=[CH:10][C:9]=2[OH:14])[CH:2]=1
Reactant: [Li]CCCC
Reactant: CCN(CC)C(=O)C=C(C)C
Reactant: C1CCOC1
Agent: CC(C)NC1CCCCC1
Product: Oc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 29 %

Procedure:
To a stirred solution of isopropylcyclohexylamine (7.5 mL, 0.45 mmol) in 60 mL of THF at -78° C. under N2 was added n-BuLi (20.0 mL, 50.0 mmol, 2.5M in hexanes). The mixture was stirred for 20 min, warmed to 0° C., and then stirred for 1 h. The mixture was cooled to -78° C. and solution of N,N-diethyl-3,3-dimethylacrylamide (2.10 g, 13.0 mmol) in 40 mL of THF was added. This mixture was stirred at -78° C. for 1 h. The cold bath was removed and the reaction mixture was allowed to warm to -20° C. over a period of 10 min. A solution of 2,4-dibromo-1-methoxymethoxybenzene (9) in 30 mL of THF was added. The reaction mixture was stirred overnight at room temperature, and then quenched with saturated NH4Cl Et2O was added and the solution was washed with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes/EtOAc; 9:1) to yield napthol 12 (1.15 g, 29%) as a brown oil; 1H NMR (CDCl3, 300 MHz): δ9.31 [s, OH], 7.54 [d, J=8.4 Hz, ArH(6)], 7.49 [s, ArH(4)], 6.82 [s, ArH(2)[, 6.81 [d, J=8.4 Hz, ArH(7)], 5.46 [s, OCH2OCH3 ], 3.55 [s, OCH3 ], and 2.47 [s, ARCH3 (3)]; 13C NMR (CDCl3, 75 MHz): 67 154.3, 153.5, 139.5, 134.5, 129.6, 118.2, 115.5, 114.5, 113.6, 107.3, 95.9, 56.9, and 22.0; LRMS (EI): m/z 298 (M+, 13), 296 (M+, 11), 128 (5), 115 (9), and 45 (100).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH3:41])=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][O:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)=[CH:35][CH:34]=1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCc1ccc(OC)cc1
Agent: [Cl-]
Agent: [Na+]
Product: COc1ccc(CCCOCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of 3-(4-methoxyphenyl)propane chloride are treated as described in Example 5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](Cl)=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:12][C:13]1[C:14]([NH:20][CH2:21][CH3:22])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1.C([O-])(O)=O.[Na+].O>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH:12][C:13]2[C:14]([NH:20][CH2:21][CH3:22])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCNc1nc(Cl)ccc1N
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCNc1nc(Cl)ccc1NC(=O)c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A solution of 5-bromo-2-chloro-3-pyridinecarbonyl chloride (30.0 g, 97.0 mmol) in MeCN (100 mL) was added via cannula to a solution of 3-amino-6-chloro-2-(ethylamino)pyridine (16.6 g, 97.0 mmol) in MeCN (180 mL) containing solid NaHCO3 (14.2 g, 169 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. Water (200 mL) was added and the mixture was stirred for 10 min. The resulting suspension was filtered. The solid was washed with Et2O (50 mL) and concentrated from pyridine solution (3×50 mL) to give the title compound (28.4 g, 75% yield).
Reaction SMILES: [C:1]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1=[O:19])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl[Si](C)(C)C>C(OCC)(=O)C>[OH:37][C@H:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:2]([CH2:3][CH2:4][C:5]#[CH:6])[C:1]([N:8]1[C@@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][O:10][C:9]1=[O:19])=[O:7]
Reactant: C#CCCCC(=O)N1C(=O)OC[C@@H]1c1ccccc1
Reactant: O=Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCC[C@@H](C(=O)N1C(=O)OC[C@@H]1c1ccccc1)[C@H](O)c1ccccc1
Reaction time: 72 h
Yield: 80.9 %

Procedure:
To a stirred solution of 56.8 g (221 mmol) of (45)-3-hex-5-ynoyl-4-phenyl-1,3-oxazolidin-2-one from step A above in 265 mL of anhydrous ethyl acetate at ambient temperature under an atmosphere of nitrogen was added 6.31 g (66.2 mmol) of anhydrous magnesium chloride, 61.5 mL (442 mmol) of triethylamine, 26.9 mL (265 mmol) of benzaldehyde and 42.3 mL (331 mmol) of chlorotrimethylsilane and the resulting mixture was stirred for 72 h. The heterogeneous reaction mixture was filtered through a 300 mL plug of silica gel eluting with an additional 1 L of ethyl acetate. The filtrate was evaporated to dryness in vacuo and the residue suspended in 265 mL of methanol and 10 mL of trifluoroacetic acid. The resulting mixture was stirred at ambient temperature under nitrogen for 5 h during which time the reaction became homogeneous. All volatiles were then removed in vacuo and the residue was purified by silica gel chromatography eluting with a 5-15% ethyl acetate in hexanes gradient to afford the title compound as a white solid (65.0 g, 81.2%). 1H NMR (500 MHz, CDCl3): δ 7.30-7.28 (m, 8H), 7.09-7.07 (m, 2H), 5.42 (dd, J=8.7, 3.7 Hz, 1H), 4.76-4.72 (m, 1H), 4.72-4.67 (m, 1H), 4.65 (t, J=8.7 Hz, 1H), 4.18 (dd, J=8.7, 3.7 Hz, 1H), 3.05 (d, J=7.8 Hz, 1H), 2.24 (td, J=7.1, 2.5 Hz, 2H), 2.00-1.93 (m, 2H), 1.67-1.61 (m, 1H). LC-MS: m/z (ES) 346.1 (MH-H2O)+, 386.0 (MNa)+.
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11].C[O:22][C:23]([C:25]1([CH2:39][O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:29][C:28](=[O:30])[N:27]([C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:26]1)=O.CC(O)=O>C1COCC1>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:9]=[C:10]([NH:11][C:23]([C:25]2([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:29][C:28](=[O:30])[N:27]([C:31]3[C:32]([CH3:38])=[CH:33][CH:34]=[CH:35][C:36]=3[CH3:37])[CH2:26]2)=[O:22])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)C1(COCc2ccccc2)CC(=O)N(c2c(C)cccc2C)C1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1CC(COCc2ccccc2)(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1=O
Temperature: 25 °C
Yield: 10 %

Procedure:
n-BuLi (2.8 M solution in hexanes, 183 μL, 0.513 mmol) was added to a cooled (−50° C.) solution of 3,5-bis-trifluoromethylaniline (84.5 μL, 0.545 mmol) in THF (3 mL). The resulting dark brown colored solution was slowly warmed to room temperature and stirred for an hour. A solution of 3-benzyloxymethyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step a, 100 mg, 0.27 mmol) in THF (2 mL) was added and the solution was stirred for 2 h at 70° C. The reaction mixture was then cooled to room temperature, AcOH (100 μL) was added and the solution was purified by automated flash chromatography (SiO2, 10→50% EtOAc/hexanes) followed by preparative HPLC (15→85% gradient of MeCN—H2O with 0.1% TFA). The pure fractions were lyophilized to afford 3-benzyloxymethyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid (3,5-bis-trifluoromethylphenyl)-amide (15 mg, 10% yield). LC-MS: Rt (retention time): 3.38 min, MS: (ES) m/z 565.2 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ 10.2 (s, 1H), 8.28 (s, 2H), 7.8 (s, 1H), 7.2-7.28 (m, 5H), 7.05-7.15 (m, 3H), 4.5-4.58 (m, 2H), 4.03 (d, 1H, J=8 Hz), 3.86-3.92 (m, 2H), 3.6 (d, 1H, J=8 Hz), 3.08 (d, 1H, J=16 Hz), 2.64 (d, 1H, J=16 Hz), 2.05 (s, 3H), 2.06 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:18][C:19]1([CH3:36])[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[C:25]2[CH:24]=[C:23]([CH:31]=[CH:32][C:33](Cl)=[O:34])[CH:22]=[CH:21][C:20]1=2>>[CH3:18][C:19]1([CH3:36])[CH2:28][CH2:27][C:26]([CH3:29])([CH3:30])[C:25]2[CH:24]=[C:23]([CH:31]=[CH:32][C:33]([O:1][C:2]3[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[O:7])=[CH:4][CH:3]=3)=[O:34])[CH:22]=[CH:21][C:20]1=2
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Cl)ccc21
Product: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)ccc21

Procedure:
In a similar manner to that of Example 1 (d), by reaction of 2.3 g (10 mmol) of benzyl 4-hydroxy-benzoate with 2.8 g (10 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acryloyl chloride, 1.7 g (37%) of the expected benzyl ester, with a melting point 97-9° C., are obtained.