Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].C(N(CC)C(C)C)(C)C.[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[C:17]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=Cc1ncc[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 30 °C
Reaction time: 21 h
Yield: 46.3 %

Procedure:
To a suspension of imidazole-2-carboxaldehyde (1.00 g, 10.4 mmol) in DMF (16 mL) was added N,N-diisopropylethylamine (4.0 mL, 23.0 mmol) followed by a solution of trityl chloride (3.19 g, 11.4 mmol) in DMF (10 mL), and the mixture was stirred at 30° C. for 21 h. The mixture was concentrated in vacuo then dissolved in EtOAc (60 mL). The solution was washed with saturated NaHCO3(aq) (2×30 mL) and brine (15 mL) then dried (MgSO4) and concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (20% EtOAc/hexanes) gave a yellow solid (1.63 g, 46%). 1H NMR (CDCl3) δ 7.03 (s, 1H), 7.12 (m, 6H), 7.32 (m, 10H), 9.23 (s, 1H).
Reaction SMILES: [C:1]([NH:5][C:6]1[S:7][CH2:8][C:9]2([N:25]=1)[C:22]1[CH:21]=[C:20](Br)[CH:19]=[CH:18][C:17]=1[O:16][C:15]1[C:10]2=[CH:11][C:12]([Cl:24])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([NH:5][C:6]1[S:7][CH2:8][C:9]2([N:25]=1)[C:10]1[CH:11]=[C:12]([Cl:24])[CH:13]=[CH:14][C:15]=1[O:16][C:17]1[C:22]2=[CH:21][C:20]([C:30]2[CH:31]=[N:26][CH:27]=[N:28][CH:29]=2)=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC1=NC2(CS1)c1cc(Cl)ccc1Oc1ccc(Br)cc12
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)NC1=NC2(CS1)c1cc(Cl)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 100 °C

Procedure:
A 10-20 mL microwave vial was charged with racemic-N-tert-butyl-2′-bromo-7′-chloro-spiro[1,3-thiazole-4,9′-xanthen]-2-amine (363 mg, 829 μmol), pyrimidin-5-ylboronic acid (257 mg, 2073 μmol), tetrakis(triphenylphosphine)palladium(0) (95.8 mg, 82.9 μmol), THF (8292 μl, 829 μmol), and potassium carbonate (3455 μl of a 1.2 M aqueous solution, 4146 μmol). The vial was covered with a blanket of Ar (g), capped, and heated in a Biotage Initiator microwave reactor for 1 h at 100° C. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on an 80-g Redi-Sep column, eluting with 0-50% EtOAc/Hexane to give rac-N-tert-butyl-2′-chloro-7′-(5-pyrimidinyl)spiro[1,3-thiazole-4,9′-xanthen]-2-amine as an orange-yellow solid. MS m/z=437.2 [M+H]+. Calc'd for C23H22ClN4OSS: 437.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[Cl:42])[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=5[Cl:42])[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Fc1cccc(-c2cncc(Br)c2)c1Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5cccc(F)c5Cl)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(2-chloro-3-fluoro-phenyl)-pyridine.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[CH2:24][CH2:23][NH:22][CH2:21][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[C:5]([C:26]([F:29])([F:28])[F:27])[CH:4]=1.C(N(C(C)C)CC)(C)C.[C:39](Cl)(=[O:41])[CH3:40]>CN(C=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[CH2:24][CH2:23][N:22]([C:39](=[O:41])[CH3:40])[CH2:21][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[C:5]([C:26]([F:29])([F:27])[F:28])[CH:4]=1
Reactant: CC(=O)Cl
Reactant: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2ccc(F)cc2C(F)(F)F)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(C(=O)N3CCC(c4ccc(F)cc4C(F)(F)F)CC3)n[nH]c2C1
Reaction time: 16 h
Yield: 30.4 %

Procedure:
To a solution of (4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride (63 mg, 0.15 mmol) and diisopropylethylamine (70 L, 0.40 mmol) in DMF (3.0 mL) was added acetyl chloride (11 μL, 0.15 mmol). The mixture was stirred for 16 hour. The solvent was removed under reduced pressure and the residue was diluted with H2O (10 mL) and extracted with EtOAc (2×10 mL). The combined organic extracts were washed with saturated brine (1×20 mL), dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 100% (10% CH3OH in CH2Cl2 with 0.01% NH4OH) in CH2Cl2) and further purified by reverse phase chromatography (Isco CombiFlash Rf unit, 12 g Redisep c18 gold column, 0% to 100% acetonitrile in water) to give 1-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanone as a white solid (20 mg, 94%): mp 176-180° C.; 1H NMR (500 MHz, DMSO-d6) δ 12.86 (s, 1H), 7.71-7.68 (m, 1H), 7.56-7.49 (m, 2H), 4.94-4.55 (m, 3H), 3.66-3.62 (m, 2H), 3.10 (br s, 2H), 2.85-2.48 (m, 4H), 2.10-2.08 (m, 3H), 1.73 (m, 4H); ESI MS m/z 439 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH:5]([PH:17]([OH:19])=[O:18])[CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2].[H-].[Na+].[CH2:22](I)[CH:23]([CH3:25])[CH3:24].C(O)(=O)C>CS(C)=O>[C:1]([NH:4][CH:5]([PH:17]([OH:19])=[O:18])[C:6]([CH2:22][CH:23]([CH3:25])[CH3:24])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(NC(C)=O)[PH](=O)O
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(CC(C)C)(C(=O)OCC)C(NC(C)=O)[PH](=O)O
Temperature: 10 °C
Yield: 44 %

Procedure:
12.0 g of diethyl 2-[(acetamido)(hydroxyphosphinyl)methyl]malonate were dissolved in 100 ml of dry dimethyl sulphoxide and the solution was cooled to 10° C. while stirring under a nitrogen atmosphere. 3.2 g of 60% sodium hydride in mineral oil were added, the mixture was stirred at room temperature for 2 hours and then 8 g of isobutyl iodide were added. The mixture was stirred at room temperature in the dark for 20 hours and 20 ml of glacial acetic acid were added. The volatiles were removed by evaporation in a high vacuum and the resulting semi-solid residue was dissolved in 100 ml of water containing 15 ml of 50% hypophosphorous acid. The solution was extracted eight times with ethyl acetate and the combined extracts were dried over sodium sulfate and evaporated. The residue was dissolved in dichloromethane and the solution was washed in sequence with water and saturated sodium chloride solution. The dichloromethane solution was dried over sodium sulfate and evaporated, and the residue was crystallized from diethyl ether/n-hexane to give 6.28 g of diethyl 2-[(acetamido)-(hydroxyphosphinyl)methyl]-2-isobutylmalonate in the form of a white solid; MS: 352 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=O.[CH3:14][C:15]1([CH3:29])[C:19]([CH3:21])([CH3:20])[O:18][B:17]([C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[O:16]1>>[CH3:20][C:19]1([CH3:21])[C:15]([CH3:14])([CH3:29])[O:16][B:17]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:11]([C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:2]=3[CH3:1])=[O:13])=[CH:24][CH:23]=2)[O:18]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Cc1c(C(=O)O)oc2ccccc12
Product: Cc1c(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)oc2ccccc12
Yield: 55 %

Procedure:
Amide coupling of 3-methyl-benzofuran-2-carboxylic acid with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine was done according to Example 20, Step 4, to give 3-methyl-benzofuran-2-carboxylic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide in 55% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (s, 12 H) 2.6 (s, 3 H) 7.4 (m, 1 H) 7.5 (m, 1 H) 7.7 (m, 3 H) 7.8 (d, J=7.3 Hz, 1 H) 7.9 (d, J=8.6 Hz, 2 H) 10.5 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]2[CH:24]=[CH:23][C:15]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:14][CH:13]=2)=[N:6][CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]3[CH:24]=[CH:23][C:15]([CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:14][CH:13]=3)=[N:6][CH:7]=2)=[CH:28][CH:27]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: Brc1ccc(C#CCCc2ccc(CN3CCOCC3)cc2)nc1
Product: Clc1ccc(-c2ccc(C#CCCc3ccc(CN4CCOCC4)cc3)nc2)cc1

Procedure:
Prepared analogously to Example 2.20c from 90 mg (0.23 mmol) 4-{4-[4-(5-bromo-pyridin-2-yl)-but-3-ynyl]-benzyl}-morpholine and 73 mg (0.47 mmol) 4-chlorophenylboric acid.
Reaction SMILES: [OH-].[Na+].O1CCCC1.C([O:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18]C=C(O)[CH:21]=2)[N:16]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1)=[O:12])C.[C:30]([O:33][C:34](=[O:36])[CH3:35])(=O)[CH3:31]>ClCCl>[C:34]([O:33][C:30]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:31]=1)[N:16]=[C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[C:13]2[C:11]([OH:12])=[O:10])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc(-c2ccccc2)nc2ccc(O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)Oc1ccc2nc(-c3ccccc3)cc(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An aqueous sodium hydroxide solution (0.3184 g/30.0 mL) was added to a tetrahydrofuran (30.0 mL) solution of 6-hydroxy-2-phenyl-4-quinolinecarboxylic acid ethyl ester (1.1120 g, 3.79 mmol) obtained above, and the mixture was stirred at room temperature for 3 hours. To the reaction solution, dichloromethane (30.0 mL) and acetic anhydride (2.0 mL) were added. The mixture was washed with water and saturated saline and dried over anhydrous sodium sulfate, and then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1.0903 mg, 3.55 mmol) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1.S(OC)(O[CH3:29])(=O)=O>>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:29])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: COS(=O)(=O)OC
Product: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione and dimethyl sulphate there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 90°-93° C.;
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:9][C:8]2[N:10]=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:13][C:7]=2[NH:6][C:5]1=[O:38].[C:39](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:11]3[C:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[CH:13][C:7]4[N:6]([CH3:39])[C:5](=[O:38])[CH:4]([CH2:3][CH2:2][OH:1])[O:9][C:8]=4[N:10]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1)([CH3:35])([CH3:34])[CH3:36]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)C(CCO)O4)cc2)CCC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(CCO)Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 1-(4-(3-(2-hydroxyethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (40 mg, 0.078 mmol) in DMF(1 ml) was added potassium carbonate (32 mg) and methyl iodide (13.2 mg, 0.093 mml) were added. The reaction mixture was stirred at room temperature for 4 h.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>C(O)C>[NH2:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[N:4][C:3]=1[NH:17][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1
Reactant: COc1ccc(CN)cc1
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(CNc2ncnc(Cl)c2N)cc1

Procedure:
Part A. A solution of 5-amino-4,6-dichloropyrimidine (24.6 g, 150 mmol), 4-methoxybenzylamine (20.0 mL, 150 mmol) and diisopropylethylamine (30.0 mL, 172 mmol) in ethanol (200 mL) was heated to ref lux for 4 days. After cooling, the solution was evaporated and the residue partitioned between water and ethyl acetate. The organic layer was washed with more water and brine, and the three aqueous phases were back-extracted in sequence with ethyl acetate. The extracts were combined, dried over sodium sulfate, filtered and evaporated. The resulting solid was triturated with ether, collected by filtration and dried under vacuum to afford pure product, 5-amino-4-chloro-6-(4-methoxybenzylamino)pyrimidine. m.p. 187-188° C. TLC RF 0.11 (30:70 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): Δ 8.12 (1H, s), 7.33 (2H! d, J=9.0 Hz), 6.89 (2H, d, J=9.0 Hz), 5. 01 (1H, br), 4. 61 (2H, d, J=5. 1 Hz), 3. 81 (3H, s), 3.35 (2H, br). MS (NH3-CI): m/e 268 (4), 267 (31), 266 (15), 265 (100).
Reaction SMILES: [Na].[CH2:2](Br)[CH3:3].[CH:5]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>N>[CH2:2]([C:5]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:3]
Reactant: CCBr
Reactant: N#CC1CCCCCCC1
Agent: N
Agent: [Na]
Product: CCC1(C#N)CCCCCCC1

Procedure:
Sodium (3.7 g, 0.16 mole) was added to liquid ammonia (300 ml.) at 35° C. A catalytic amount of ferric nitrate was then added. After the solution had become grey in colour, ethyl bromide (17.4 g, 0.16 mole) and cyclooctyl cyanide (20.0 g, 0.14 mole) were added very slowly. The liquid ammonia was then allowed to evaporate over a period of 20 hours. Benzene and then water were added to the residue. The benzene layer was dried (MgSO4) and distilled to give 1-ethylcyclooctyl cyanide, bp. 130°-132°/17 mm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:32]1([C:38]2[O:39][C:40]([CH3:56])=[C:41]([CH2:43][CH2:44]OS(C3C=CC(C)=CC=3)(=O)=O)[N:42]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:44][CH2:43][C:41]2[N:42]=[C:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:39][C:40]=2[CH3:56])=[C:9]([CH2:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1OCCc1nc(-c2ccccc2)oc1C
Temperature: 55 °C
Yield: 60 %

Procedure:
A solution of 3-(4-hydroxy-3-propylphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (266 mg, 1.0 mmol) in DMF (10 mL) was treated with cesium carbonate (407 mg, 1.25 mmol) and toluene-4-sulfonic acid 2-(2-phenyl-5-methyloxazol-4-yl)-ethyl ester and then heated at 55° C. for 18 h. After cooling to ambient temperature, the mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and then the organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (100 mL SiO2, hexanes to 30% EtOAc/hexanes) to provide the desired product (315 mg, 60%) as a clear, colorless oil: MS (EI) 528.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N=Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (3.3 g, 20.0 mmol), benzaldehyde (2.4 g, 22.0 mmol) and p-toluenesulfonic acid (76 mg, 0.4 mmol) in toluene (60.0 mL) was heated to reflux for 12 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-(benzylidene-amino)-benzoic acid ethyl ester (5.1 g, quant.) as a light yellow solid: LC/MS m/e calcd for C16H15NO2 (M+H)+: 254.3, observed: 254.1.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17](O)=O)=[N:15][CH:16]=1)[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[N:15][CH:16]=1)[CH3:10]
Reactant: Nc1ccccc1N
Reactant: CCc1ccc(C(=O)O)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(-c2nc3ccccc3[nH]2)nc1

Procedure:
11.3 g. of o-phenylenediamine, 15.1 g. of 5-ethylpicolinic acid and 80 g. of polyphosphoric acid were heated at 180°-190° C. under a nitrogen gas current for 3 hours with stirring. The reaction mixture was diluted with 1,000 ml. of water and then neutralized with sodium carbonate. The resulting crystals were filtered off, dried and recrystallized from ethyl acetate to give 17.1 g. of colorless needles of the product (78% of theory). M.P. 172.5°-173° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([N:13]([C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[N:25]=1)[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:10]([CH3:12])[CH3:11].[C:41](=O)([O:44]C)[O:42][CH3:43]>>[CH3:43][O:42][C:41](=[O:44])[CH2:30][C:28]1[CH:27]=[C:26]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=2)[N:25]=[C:24]([N:13]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[CH:29]=1
Reactant: COC(=O)OC
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(N(CC(C)C)c2ccc(C(F)(F)F)cc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(N(CC(C)C)c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A solution of LDA (1.8 M in THF/heptane/ethyl benzene, 340 mL, 0.6 mmol) was added slowly to a stirred solution of isobutyl-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-trifluoromethyl-phenyl)-amine (135 g, 0.3 mmol) under N2 at −78° C. After 30 minutes dimethyl carbonate (55 mg, 0.6 mmol) was added. After stirring at −78° C. for 30 minutes, the solution was allowed to warm up slowly and stirred at 0° C. for 30 minutes. The reaction was quenched with saturated aqueous NH4Cl (1 mL). The mixture was partitioned between CH2Cl2 and H2O. The aqueous layer was extracted with CH2Cl2 (2×). The combined extracts were washed with brine, then dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (40-80% CH2Cl2 in heptane) to give the product as light yellow oil (75 mg, 49%). 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=7.91 Hz, 2H), 7.70 (d, J=8.29 Hz, 2H), 7.65 (d, J=8.29 Hz, 2H), 7.40 (d, J=8.29 Hz, 2H), 7.14 (s, 1H), 6.50 (s, 1H), 3.96 (d, J=7.16 Hz, 2H), 3.69 (s, 3H), 3.51 (s, 2H), 2.05-2.22 (m, 1H), 0.98 (d, J=6.78 Hz, 6H). MS m/e 511.2 (M+H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[CH:14]=[CH:15][C:16]([OH:18])=O)(=[O:10])[CH3:9].CCN=C=NCCCN(C)C.Cl.Cl.[NH2:36][C@H:37]([C:48]([O:50][CH3:51])=[O:49])[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1>C(Cl)Cl>[C:8]([O:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[CH:14]=[CH:15][C:16]([NH:36][C@H:37]([C:48]([O:50][CH3:51])=[O:49])[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1)=[O:18])(=[O:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(=O)Oc1ccccc1C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1OC(C)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.4 %

Procedure:
Triethylamine (4.8 mL), 2-acetoxycinnamic acid (7.1 g) and WSC.HCl (6.6 g) were added to a methylene chloride (180 mL) suspension of methyl L-tryptophanate hydrochloride (7.3 g) at 0° C. The mixture was stirred for 20 hours at room temperature. The reaction mixture was washed with water, and thereafter the organic layer was dried over anhydrous sodium sulfate. The residual oily product obtained by distilling off the solvent under a reduced pressure was purified by silica gel column chromatography (BW-127ZH, chloroform:methanol=100:1), to give the captioned compound (8.9 g, 76%) as crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[CH2:32][C:33]([O:35][CH3:36])=[O:34].CN(C)C=O.[H-].[Na+]>O>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[C:25]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:26]=1
Reactant: COC(=O)Cc1cc(OC)ccc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cc(OC)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.2 %

Procedure:
To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.54 g), methyl 2-(2-hydroxy-5-methoxyphenyl)acetate (0.80 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.18 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give crystals (1.22 g, 63%) of methyl 2-[5-methoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 160-161° C.