Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[NH:33][C:32](=[O:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[NH:33][C:32](=[O:34])[O:31][N:30]=4)=[CH:27][CH:28]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc(-c2noc(=O)[nH]2)cc1
Product: CC(C(=O)Nc1ccc(-c2noc(=O)[nH]2)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
120 mg (purity 93%, 0.37 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 2.2B) and 1.2 eq. of 3-(4-aminophenyl)-1,2,4-oxadiazol-5(4H)-one (Example 1.5A) were reacted according to General Method 1. Yield: 23 mg (13% of theory)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Br:11]Br.O>C(O)(=O)C>[Br:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[OH:1])[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(O)c(Br)c1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
50 g (0.37 mol) of commercially available p-hydroxybenzoic acid was dissolved in 370 ml glacial acetic acid by heating with stirring. Heating was continued after the acid dissolved and 59 g (0.37 mol) bromine dissolved in 60 ml glacial acetic acid was rapidly added to the boiling solution to avoid bumping. The solution was refluxed for six hours with continuous stirring. Following reflux, the reaction solution was permitted to stand and cooled to room temperature. The cooled solution was poured into two liters of cold water. A white precipitate was formed. The white crystals were filtered by suction and were recrystalized with glacial acetic acid to yield 55.2 g of purified 3-bromo-4-hydroxybenzoic acid. The calculated yield was 70.3%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]2[C:14]([C:15]3[N:16]=[CH:17][S:18][C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[Cl:27])=[CH:13][C:12](Br)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].CC1(C)C(C)(C)OB([C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)O1>C(COC)OC.O>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]2[C:14]([C:15]3[N:16]=[CH:17][S:18][C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[Cl:27])=[CH:13][C:12]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: COc1ccc(CNc2ncc(Br)cc2-c2ncsc2-c2cccc(Cl)c2Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(CNc2ncc(-c3cccnc3)cc2-c2ncsc2-c2cccc(Cl)c2Cl)cc1
Temperature: 120 °C

Procedure:
A solution of N-(4-methoxybenzyl)-5-bromo-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)pyridin-2-amine (50 mg, 0.116 mmol) in dimethoxyethane (0.5 mL) and water (0.5 mL) was degassed with nitrogen while adding NaHCO3 (30 mg, 0.347 mmol), and palladium tetrakis triphenylphosphine (13 mg, 0.012 mmol). 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (28 mg, 174 mmol)was added under nitrogen and the mixture was heated to 120° C. overnight. The reaction mixture was concentrated and taken up in ethyl acetate, filtered through silica with ethyl acetate eluant, and the filtrate concentrated to provide N-(4-methoxybenzyl)-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)-5-(pyridin-3-yl)pyridin-2-amine, which was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:24]=3)[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1ccc(F)cc1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)c3ccc(F)cc3)CC2)c1

Procedure:
Example 64 was prepared from 2-(4-fluorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 440.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:13][C:14]3([C:17]4[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=4)[CH2:16][CH2:15]3)=[O:12])[CH:10]=1)[N:7]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[CH:6]=[CH:5]2.[OH-].[K+:39]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:13][C:14]3([C:17]4[CH:26]=[CH:25][C:20]([C:21]([O-:23])=[O:22])=[CH:19][CH:18]=4)[CH2:16][CH2:15]3)=[O:12])[CH:10]=1)[N:7]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:33]=1)[CH:6]=[CH:5]2.[K+:39]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(F)cc4ccn(Cc5ccc(C(F)(F)F)cc5)c34)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])c1ccc(C2(NC(=O)c3cc(F)cc4ccn(Cc5ccc(C(F)(F)F)cc5)c34)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 4-{1-[({5-fluoro-1-[4-(trifluoromethyl)benzyl]-1H-indol-7-yl}carbonyl)amino]cyclopropyl}benzoate (67 mg, 0.13 mmol) was dissolved in 1 ml THF/MeOH (1:1) and 0.5 ml 2N KOH. Then reaction mixture was stirred at RT for 18 h. The mixture was cooled and the solvents were evaporated under reduced pressure. 2N HCl was added (until pH=3) and the aqueous phase was extracted 3× with DCM. The combined organic layers were washed with water and brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in 1 ml methanol and 1 eq of KOH (0.065 ml of 2N KOH) was added, the methanol was then evaporated under reduced pressure. The resulting solid was solubilised in water and the solution was lyophilized. 1H NMR (500 MHz, DMSO-d6): δ 9.15 (s, 1H), 7.70 (d, 2H), 7.55 (m, 4H), 7.15 (m, 1H), 7.05 (d, 2H), 6.90 (d, 2H), 6.65 (d, 1H), 5.65 (s, 2H), 1.70 (s, 2H), 1.05 (s, 2H), 0.80 (s, 2H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([C@:22]([OH:35])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH2:17]1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+]=[N-].O>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([C@:22]([OH:35])([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH2:17]1)=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CN=[N+]=[N-])Cc2ccccc2)C1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CN)Cc2ccccc2)C1
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
Crude (3R)-N-((S)-3-azido-1-phenylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide (210.7 mg, 91% purity, 0.4 mmol) from the previous step was dissolved in MeOH (10 mL) and was added to 0.2 g of Pd/C previously wetted with a drop of H2O. After 3 vacuum/purge cycles using 12 torr vacuum and 14 psi H2, the reaction was stirred under an atmosphere of H2 at 14 psi for 30 minutes. The crude mixture was filtered through a plug of Celite and the solvent was removed. The resulting oil was dissolved in a minimal volume of 1:1 acetonitrile:H2O then separated by prep HPLC on a C-18 column using a gradient of 0.05% TFA in H2O and acetonitrile. Appropriate fractions were combined, made slightly basic with 1 N NaOH, and the solvent was removed at 50° C. and 150 torr. The residue was taken up in CH2Cl2 (50 mL) and 1 N NaOH (10 mL). The organic layer was dried (Na2SO4), decanted and stripped to afford (3R)-N-((S)-1-amino-3-phenylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide (61.5 mg, 34% overall yield from (R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbonyl chloride) as a clear colorless film. MS ESI +ve m/z 454 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:11])[N:3]=1.Cl>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:8]=[C:9]([I:10])[C:2]([NH2:1])=[N:3][C:4]=1[CH3:11]
Reactant: Cc1nc(N)c(I)cc1C#N
Agent: Cl
Solvent: C1CCOC1
Product: Cc1nc(N)c(I)cc1CN
Yield: 66.9 %

Procedure:
6-Amino-5-iodo-2-methylnicotinonitrile (3.70 g, 14.2 mmol) were initially charged in THF (45 ml), and 42.8 ml (42.8 mmol) of a 1 molar borane-THF complex solution in THF were added dropwise. The mixture was heated at reflux temperature for 3 hours and cooled, and 5 ml of a 2N HCl solution were cautiously added dropwise. The reaction mixture was heated under reflux for another hour and then allowed to cool for 15 hours while standing. The solvent was removed under reduced pressure and the residue was taken up in saturated sodium bicarbonate solution, which was subsequently extracted repeatedly with ethyl acetate. After drying over magnesium sulphate, the solvent was removed under reduced pressure, giving 2.50 g (60.0% of theory) of 5-(aminomethyl)-3-iodo-6-methylpyridine-2-amine, which was directly reacted further. HPLC-MS: log P=0.73; mass (m/z): 264.0
Reaction SMILES: N.[Li].C([N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([CH2:16][CH2:17][C:18]2([CH3:23])[O:22][CH2:21][CH2:20][O:19]2)[C:11]1=[O:24])C1C=CC=CC=1>CO.C1COCC1>[CH3:15][C@H:14]1[NH:10][C:11](=[O:24])[C@@H:12]([CH2:16][CH2:17][C:18]2([CH3:23])[O:22][CH2:21][CH2:20][O:19]2)[CH2:13]1
Reactant: C[C@@H]1C[C@H](CCC2(C)OCCO2)C(=O)N1Cc1ccccc1
Agent: N
Agent: [Li]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H](CCC2(C)OCCO2)C(=O)N1
Reaction time: 0.33 h

Procedure:
Into a 3-necked 500 mL flask at -78° C. was condensed 200 mL of ammonia. Lithium (64 mg, 9.25 mmol) was washed with MeOH, then THF and then added to the ammonia. After 20 minutes, 11-6 (560 mg, 1.85 mmol), dissolved in 25 mL of THF, was added. After 30 minutes, the reaction was quenched with NH4Cl; 200 mL of THF was added, the cooling bath was removed and the solution purged with argon for 30 minutes to remove the ammonia. The solution was dried (MgSO4) and concentrated. Flash chromatography (silica, EtOAc→5% MeOH/EtOAc) gave 11-7 as an oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.Cl.[CH:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:24])[CH3:23]>>[CH:22]([N:25]1[CH2:30][CH2:29][N:28]([C:16]([C:15]2[CH:18]=[CH:19][C:12]([CH2:10][N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)=[CH:13][CH:14]=2)=[O:17])[CH2:27][CH2:26]1)([CH3:24])[CH3:23]
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: CC(C)N1CCNCC1
Agent: Cl
Product: CC(C)N1CCN(Cc2ccc(C(=O)N3CCN(C(C)C)CC3)cc2)CC1

Procedure:
Prepared from the product of Example 15 and the product of Example 10.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:23][C:8](=[O:10])[CH3:9])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(NC(C)=O)c1

Procedure:
120 ml of triethylamine and 56.7 ml of acetic anhydride were added dropwise to a stirred solution of 70.5 g of m-anisidine in 500 ml of a methylene chloride under ice cooling. After completion of the dropwise addition, the reaction mixture was washed and dried, and insolubles were filtered off. The filtrate was concentrated, and the residue was recrystallized from hexane-ethyl acetate to afford 80.9 g of N-(3-methoxyphenyl)acetamide as pale yellow needles. Melting point: 81° to 82° C.
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:35][C:36]#[N:37].C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([O:33][CH2:35][C:36]#[N:37])[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCBr
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: N#CCOc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Yield: 92.2 %

Procedure:
In a similar manner as described in step 1 of Example 3, the title compound was prepared from 6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthol (0.250 g, 0.564 mmol), prepared in step 2 of Example 8, bromoacetonitrile (0.081 g, 0.68 mmol) and cesium carbonate (0.920 g, 2.82 mmol). Purification on a Biotage FlashElute™ system with a KP-Sil Flash 40+M column (90 g Silica Gel, 60 Å) using 50% methylene chloride in hexane as the eluent gave [(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]acetonitrile as a white solid (0.251 g, 92%), mp 154–155° C. Elemental Analysis for C30H21F3N2O.0.10 CH2Cl2 Calc'd: C, 73.65; H, 4.35; N, 5.71. Found: C, 73.58; H, 4.46; N, 5.64.
Reaction SMILES: N1(C2C=CC(C([N:13]3[C:17]4[CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[S:20][C:16]=4[C:15]([NH:25][C:26](=[O:39])[C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[CH:29][CH:28]=4)=[N:14]3)=O)=CC=2)CCOCC1>CO.CCN(CC)CC>[N:33]1([C:30]2[CH:31]=[CH:32][C:27]([C:26]([NH:25][C:15]3[C:16]4[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:17]=4[NH:13][N:14]=3)=[O:39])=[CH:28][CH:29]=2)[CH2:34][CH2:35][O:36][CH2:37][CH2:38]1
Reactant: COC(=O)c1cc2c(s1)c(NC(=O)c1ccc(N3CCOCC3)cc1)nn2C(=O)c1ccc(N2CCOCC2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2[nH]nc(NC(=O)c3ccc(N4CCOCC4)cc3)c2s1

Procedure:
A mixture of methyl 1-(4-morpholin-4-ylbenzoyl)-3-[(4-morpholin-4-ylbenzoyl)amino]-1H-thieno[3,2-c]pyrazole-5-carboxylate (4.3 g, 7.5 mmol) in MeOH (200 ml) and Et3N (20 ml) was refluxed for 8 h. After cooling the precipitate was separated by filtration and triturated with hot methyl alcohol. After filtration and drying at 40° C. under vacuum 2.4 g of title compound were obtained. LC-MS, chromatographic method A, Rt 4.52, [M+H]+ 387.
Reaction SMILES: [Na].C[Si](N[Si](C)(C)C)(C)C.C1COCC1.[C:16]([CH:19]=[CH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:31][C:32]3[CH:37]=[CH:36][C:35](Cl)=[CH:34][C:33]=3F)=[N:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:40][CH3:41])([OH:18])=[O:17].OC1C=C2C(=CC=1)[NH:48][C:47]([CH3:52])=[CH:46]2>CS(C)=O>[C:16]([CH:19]=[CH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:31][C:32]3[CH:37]=[C:36]4[C:35](=[CH:34][CH:33]=3)[NH:48][C:47]([CH3:52])=[CH:46]4)=[N:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:40][CH3:41])([OH:18])=[O:17]
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1C=CC(=O)O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
1M Sodium HMDS in THF (0.84 ml, 8.4 mmol) was added to a suspension of 7-(2-carboxyvinyl)-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (105 mg, 0.28 mmol) and 5-hydroxy-2methylindole (82 mg, 0.56 mmol), (prepared as described for the starting material in Example 48), in DMSO (1.5 ml). After stirring for 2 hours at ambient temperature, the mixture was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH3 with 2M hydrochloric acid. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5 followed by 90/10 and 70/30) to give 7-(2-carboxyvinyl)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (75 mg, 71%).
Reaction SMILES: [CH2:1]([C:3]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][OH:9])[CH3:2].[C:29](Cl)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][O:9][C:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(O)CO)c(CC)c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCc1ccc(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC)c1
Reaction time: 72 h
Yield: 95.3 %

Procedure:
A mixture of 11.68 g of 3-(2-ethyl-4-tetradecylphenoxy)-1,2-propanediol, 14.95 g of trityl chloride and ml pyridine was stirred for 72 hours, then diluted with chloroform, washed with two 100 ml portions of aqueous sodium bicarbonate, then water and dried. The solvents were evaporated under reduced pressure and the residue evaporated with toluene. This residue was then diluted with hexane and the solid which formed collected giving 18 g of the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])=[CH:6][CH:5]=1)[CH3:2].O1CCCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:30]([N:37]1[CH2:42][CH2:41][C:40](=[O:43])[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([N:8]([CH3:12])[C:9](=[O:11])[CH2:10][C:40]2([OH:43])[CH2:41][CH2:42][N:37]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:38][CH2:39]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCOc1ccc(N(C)C(C)=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(N(C)C(=O)CC2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 56.3 %

Procedure:
A solution of 4′-ethoxy-N-methylacetanilide (0.97 g) in an anhydrous tetrahydrofuran (30 mL) was cooled to −78° C. under an argon atmosphere, and lithium hexamethyldisilazide (1M tetrahydrofuran solution; 6 mL) was added to the solution at below −65° C., followed by stirring at −78° C. for 15 minutes. Subsequently, 1-benzylpiperidin-4-one (1.1 g) was added to the reaction mixture at below −65° C., and the mixed solution was stirred at −78° C. for 10 minutes. After increasing the temperature to room temperature, water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The titled compound (1.08 g) was obtained by recrystallization of the obtained residue from hexane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7]Cl.[Na].[OH:10][CH2:11][C:12]1([CH3:20])[O:16][C:15]([CH3:19])([C:17]#[N:18])[CH2:14][CH2:13]1>CN(C)C=O>[CH3:19][C:15]1([C:17]#[N:18])[CH2:14][CH2:13][C:12]([CH3:20])([CH2:11][O:10][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[O:16]1
Reactant: ClCc1ccccn1
Reactant: CC1(C#N)CCC(C)(CO)O1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC1(C#N)CCC(C)(COCc2ccccn2)O1

Procedure:
Freshly liberated 2-picolinyl chloride was secured by extracting a mixture of 1.48 g potassium carbonate and 1.64 g 2-picolinyl chloride in 10 ml water with methylene chloride. The extract was dried (MgSO4) and concentrated (rotary evaporator). To the residue was added 10 ml dry dimethylformamide and the remaining methylene chloride was removed by further evaporation. The resulting solution was then added to a mixture of 10 mmol of the sodium salt of tetrahydro-5-(hydroxymethyl)-2,5-dimethyl-2-furancarbonitrile as a mixture of cis-trans isomers in 10 ml dry dimethylformamide prepared as described in Embodiment 10 above. The reaction progress and workup also followed the procedure for Embodiment 10 with the exception that crude product was secured from both pentane and ether extraction of the ice-quenched mixture. The crude product, which consisted of both cis- and trans-isomers, was purified and isomerically separated by preparative hplc using a silica gel column and ethyl acetate:pentane (60:40) as eluent. The cis (Z)-isomer amounted to 0.69 g bp not determined.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]([OH:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(#N)C>[CH2:16]([N:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH2:7][C:8]([OH:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(C)(O)CNC1CCCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(O)CN(Cc1ccccc1)C1CCCC1
Temperature: 80 °C
Yield: 76.4 %

Procedure:
To ethyl 3-(cyclopentylamino)-2-hydroxy-2-methylpropanoate (3.9 g, 18 mmol) in 50 ml of acetonitrile at room temperature, was added benzyl bromide (3.2 ml, 27.2 mmol) dropwise, followed by K2CO3 (7.5 g, 54.3 mmol). The reaction mixture was heated at 80° C. for 18 h. It was then diluted to EtOAc, washed by brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=100:1 to 10:1) to give 4.2 g product (77%). [M+H] calc'd for C18H27NO3, 306; found 306.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([F:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:11][C:5]1[C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]([C:14]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=2[F:12])=[CH:3][CH:4]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: O=C(O)c1nc(Br)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(F)c(C(=O)O)n2)c1
Yield: 89 %

Procedure:
Method 1 was followed using 6-bromo-3-fluoropicolinic acid (1.0 equiv.) and 2-fluoro-5-methoxyphenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.15 equiv.) to give 3-fluoro-6-(2-fluoro-5-methoxyphenyl)picolinic acid in 89% yield. LC/MS=266.1 (M+H), Rt=0.79 min.