Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]#[N:14])[N:4]=1.P(Br)(Br)[Br:16].C([O-])(O)=O.[Na+]>C1COCC1>[Br:16][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]#[N:14])[N:4]=1
Reactant: BrP(Br)Br
Reactant: N#Cc1cc2ccccc2c(CO)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cc2ccccc2c(CBr)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 1-(hydroxymethyl)isoquinoline-3-carbonitrile (0.150 g, 0.814 mmol) in THF (0.8 mL) and treated with PBr3 (0.814 mL, 0.814 mmol). The reaction mixture was stirred at RT for 2 hours, then poured over ice and neutralized with saturated aqueous NaHCO3. The mixture was warmed to RT and extracted with EtOAc (20 mL). The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a yellow solid. The crude product was dried under high vacuum and used without further purification (0.15 g, 75%). ESI-MS m/z [M+H]+ 247.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22].[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][NH:28][C:29]2=[O:34]>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][NH:28][C:29]3=[O:34])=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22]
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(C)c1OC
Reactant: Nc1cccc2c(=O)[nH]ccc12
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cccc2c(=O)[nH]ccc12)C(F)(F)F)c1ccc(F)c(C)c1OC

Procedure:
In the same way as in Example 130, 200 mg (0.62 mmol) of (2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 100 mg (0.62 mmol) of 5-aminoisoquinolin-1(2H)-one and 0.39 ml (1.25 mmol) of titanium tert-butoxide are reacted to give 5-{[(2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}isoquinolin-1 (2H)-one. 460 mg of crude imine are cyclized in the same way as in Example 130 at −30° C. with 7.9 ml (7.9 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50-100%) yields 223 mg of desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][C@@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24].[OH-].[Na+].[NH2:29]O.Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][C@@H:13]([C:15]2[O:22][NH:29][C:17](=[O:18])[CH:16]=2)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(F)cc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(F)cc1F
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
Cis-methyl 2-(2,4-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (870 mg, 2.36 mmol) was dissolved in MeOH (9 mL) and cooled to −45° C. under nitrogen. Sodium hydroxide (0.693 mL, 2.36 mmol) was added during 10 min and the yellow solution continued to stir at −45° C. for 20 min. Hydroxylamine (50% by weight in water, 0.144 mL, 2.36 mmol) was added during 8 min. The resulting solution was stirred at −45° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (12.13 mL, 72.78 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a white solid. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(2,4-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (397 mg, 49%) was isolated. MS m/z 339 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:6]([CH2:12]Cl)=[N:7]2.O.[N:23]1[C:31](=[S:32])[C:30]2[NH:29][CH:28]=[N:27][C:26]=2[NH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:6]([CH2:12][S:32][C:31]1[N:23]=[CH:24][N:25]=[C:26]3[C:30]=1[N:29]=[CH:28][NH:27]3)=[N:7]2
Reactant: Cc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Reactant: S=c1nc[nH]c2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1c(CSc2ncnc3[nH]cnc23)nc2cccc(Cl)c2c1=O
Yield: 52.6 %

Procedure:
Prepared according to Procedure C using Intermediate 2j (200 mg, 0.626 mmol), 6-kinases -mercaptopurine monohydrate (93 mg, 0.546 mmol), K2CO3 (95 mg, 0.689 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 125 mg of an off-white solid (46%), mp 213.9° C. 1H NMR (DMSO-d6) δ: 13.53 (br s, 1H); 8.49 (s, 1H); 8.44 (s, 1H); 7.78 (t, J=7.9 Hz, 1H); 7.63 (d, J=8.2 Hz, 1H); 7.59 (d, J=7.7 Hz, 1H); 7.49 (d, J=6.9 Hz, 1H); 7.24-7.41 (m, 3H); 4.32-4.45 (m, 2H); 2.14 (s, 3H). 13C NMR (DMSO-d6) ppm: 158.9, 157.2, 154.2, 151.5, 149.7, 149.6, 143.5, 136.1, 135.9, 135.1, 133.2, 131.3, 130.3, 130.0, 129.9, 129.1, 127.6, 127.1, 117.8, 32.4, 17.5. MS (ES): m/z 438.0 (M+). Anal. calcd. for C21H15ClN6OS: C, 58.00; H, 3.48; Cl, 8.15; N, 19.32; S, 7.37. Found: C, 58.05; H, 3.38; Cl, 8.89; N, 18.38; S, 7.00.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[C:12]([O:16][C:17]([NH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([CH3:31])([CH3:30])[CH:24]=[C:23]2[CH3:32])=[O:18])([CH3:15])([CH3:14])[CH3:13]>N1C=CC=CC=1.ClCCl>[C:1]([N:26]1[C:27]2[C:22](=[CH:21][C:20]([NH:19][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])=[CH:29][CH:28]=2)[C:23]([CH3:32])=[CH:24][C:25]1([CH3:31])[CH3:30])(=[O:3])[CH3:2]
Reactant: CC1=CC(C)(C)Nc2ccc(NC(=O)OC(C)(C)C)cc21
Reactant: CC(=O)Cl
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(NC(=O)OC(C)(C)C)cc2C(C)=CC1(C)C
Reaction time: 18 h

Procedure:
Acetyl chloride (11.1 ml) and acetic anhydride (11.1 ml) were added dropwise to a solution of 6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline (8.5 g) in pyridine (22 ml) and dichloromethane (212 ml). After stirring for 18 h, the reaction mixture was washed with 2 M HCl and water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=8/2 (v/v) as eluent.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C1COCC1.C(Cl)Cl.O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:15][CH:12]3[CH2:14][CH2:13]3)[C:5]2=[N:4][CH:3]=1
Reactant: NC1CC1
Reactant: Brc1cncc2ncc(Br)n12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Brc1cnc2c(NC3CC3)nccn12
Temperature: 50 °C
Yield: 14.5 %

Procedure:
To a solution of 3,5-dibromo-imidazo[1,2-a]pyrazine (D) (250 mg, 0.9 mmol) in THF (9 ml) was added cyclopropylamine (1.9 ml, 27 mmol) and diisopropylethylamine (DIPEA) (0.782 ml, 4.5 mmol). The mixture was heated at 50° C. in sealed tube overnight. The mixture was then cooled to rt, diluted with DCM and water. The organic layer was washed with brine, dried and concentrated. The residue was purified on a silica gel column to give 33 mg (yield 14.5%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22]>>[C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH:8][C:21](=[O:22])[C:20]1[C:19]([F:18])=[CH:27][CH:26]=[CH:25][C:24]=1[F:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1c(F)cccc1F

Procedure:
L-tyrosine tert-butyl ester (10.0 g) was acylated with 2,6-difluorobenzoyl chloride in a similar manner as described Example 1-(5) to give N-(2,6-difluorobenzoyl)-L-tyrosine tert-butyl ester (15.9 g). mp. 145-148° C.; IR (Nujol) 1728, 1638 cm−1; MS (APCI) m/z 395 (M+NH4), 378 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]=[CH:3]1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([Si](C)(C)C)([F:18])[F:17]>CN(C)C=O>[F:15][C:16]([F:18])([F:17])[CH:7]([C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)[OH:8]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cn1cncc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cncc1C(O)C(F)(F)F
Yield: 73.1 %

Procedure:
According to Reference Example 8-2, by use of 1-methyl-1H-imidazole-5-carbaldehyde (300 mg, 2.72 mmol) dissolved in N,N-dimethylformamide (4.5 mL), potassium carbonate (75 mg, 0.54 mmol) and (trifluoromethyl)trimethylsilane (0.442 mL, 2.99 mmol), the mixture was stirred and reacted at room temperature for 3 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=10/1) was performed to give 2,2,2-trifluoro-1-(1-methyl-1H-imidazol-5-yl)ethanol (Compound DK) (358 mg, yield: 73%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[O:14])[C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[O:11][CH3:12].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][O:11][C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5]=2[C:4]([CH:13]=[O:14])=[CH:3][C:2]=1[C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1
Reactant: COc1c(Br)cc(C=O)c2c1CCC2
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(C=O)c3c(c2OC)CCC3)cc1
Temperature: 87.5 °C
Reaction time: 6 h
Yield: 22.7 %

Procedure:
To a suspension of 6-Bromo-7-methoxy-indan-4-carbaldehyde (0.2 gm, 0.00078 mole), 4-Methoxyphenyl boronic acid (0.122 gm, 0.0008 mole) and Potassium carbonate (0.27 gm, 0.0019 mole) in Toluene (5 ml) and water (5 ml), Tetrakis (triphenylphosphine) palladium(0) (2 mg) was and heated to 85-90° C. and stirred for 6 hrs. Toluene was distilled off and the obtained residue was dissolved in Diethyl ether (50 ml). Further it was washed with water (20 ml) and ether was distilled under vacuum to give a crude mass which was purified by column chromatography using Ethyl acetate:Hexane (1:99) as a mobile phase. The fractions were distilled to give 50 mg of desired product as a solid.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH3:16])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](OCC)=[O:35]>O1CCCC1>[C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)=[O:35])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccccn1
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccccc2)noc1CC(=O)c1ccccn1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A suspension of 28 g. (0.13 mole) of 3-phenyl-N,5-dimethyl- isoxazole-4-carboxamide and 330 milliliters of tetrahydrofuran is cooled to -65° C. and 180 milliliters of 1.6M n-butyllithium in hexane (0.288 mole) is added dropwise, maintaining the temperature between -60° and -70° C. After the addition is complete, the organic suspension is stirred for 11/2 hours at -60° to -70° C., and then 19.6 g. (0.13 mole) of ethyl picolinate in 196 ml. tetrahydrofuran is added drop-wise maintaining the temperature between -60° and -70° C. After addition is complete, the mixture is stirred 11/2 hours at -60° to -70° C. and then warmed to -30° C. and quenched by the addition of saturated ammonium chloride solution. The mixture is further diluted with tetrahydrofuran and the layers are separated. The tetrahydrofuran layer is washed twice with 50% brine, and once with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The solid residue is triturated with ether and filtered to give 3-phenyl-5-(2-pyridylcarbonylmethyl)-N-methyl-isoxazole-4-carboxamide; m.p. 146° to 149° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([NH:15][C:16]2[NH:17][CH2:18][CH:19]([OH:22])[CH2:20][N:21]=2)[CH:14]=1)[C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6].Cl.[NH2:24][C@H:25]([C:32]1[CH:37]=[C:36]([C:38]([OH:44])([CH3:43])[C:39]([F:42])([F:41])[F:40])[CH:35]=[C:34]([Cl:45])[CH:33]=1)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[Cl:45][C:34]1[CH:33]=[C:32]([C@@H:25]([NH:24][C:9](=[O:11])[CH2:8][NH:7][C:5](=[O:6])[C:4]2[CH:12]=[C:13]([NH:15][C:16]3[NH:17][CH2:18][CH:19]([OH:22])[CH2:20][N:21]=3)[CH:14]=[C:2]([OH:1])[CH:3]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:37]=[C:36]([C:38]([OH:44])([CH3:43])[C:39]([F:42])([F:41])[F:40])[CH:35]=1
Reactant: CCOC(=O)C[C@H](N)c1cc(Cl)cc(C(C)(O)C(F)(F)F)c1
Reactant: O=C(O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Cl)cc(C(C)(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetic acid (Example B) (328.3 mg, 1.065 mmol), (3S)-ethyl 3-amino-3-(3-chloro-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)propanoate hydrochloride salt (from step 1 above) (364.2 mg, 0.968 mmol) and 1-hydroxybenzotriazole hydrate (31.5 mg, 0.206 mmol) was dissolved in a mixture of DMF/DCM (1:1) and stirred at room temperature under nitrogen atmosphere for 10 min to give a cream suspension. N,N′-diisopropylcarbodiimde (210 μL, 1.356 mmol) was added to the above suspension and the reaction mixture was stirred at room temperature overnight (19 h) under nitrogen atmosphere. The solvent was evaporated in vacuo to give a yellow-cream gummy residue. LC-MS analysis of the crude residue shows the desired product: (3S)-ethyl 3-(3-chloro-5-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate's mass: m/z 630 (35ClM+H) and m/z 632 (37ClM+H); Calcd for C27H31ClF3N5O7: 630.01. The crude residue is used as such for the saponification with lithium hydroxide monohydrate (Step 3)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)cs1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1nc(/C=C/c2ccc(N)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
A mixture of N-{4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (250 mg), palladium on carbon (25 mg) and methanol (2.5 ml) was stirred under hydrogen atmosphere for 2 hours at ambient temperature. The catalyst was filtered off and the filtrate was concentrated in vacuo. The crystalline residue was collected and washed with isopropyl ether to give N-{4-[(E)-2-(4-aminophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (160 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:2]1[O:4][CH2:3]1.C(O)=[O:11].[OH-].[Na+]>O>[C:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][OH:11])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=CO
Reactant: CC(C)(C)OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OCC(O)CO
Yield: 54 %

Procedure:
Compound 17 was prepared by the method described by Montanari and Tundo (Montanari, F. and Tundo, P., J. Org. Chem. 1982, 47, 1298). tert-Butyl glycidyl ether (Aldrich), (141 ml, 1.0 mol.) was added dropwise to 99% formic acid (83 ml, 2.2 mol). The reaction mixture was stirred and the temperature was maintained below 30° C. The mixture was stirred at room temperature for 12 hours. A solution of sodium hydroxide (100 g, 2.5 mol.) in 125 ml of water was added slowly, keeping the temperature below 40° C. The organic fraction was separated and the aqueous phase was extracted several times with dichloromethane. The combined organic fractions were dried (MgSO4) and evaporated and the oily residue was distilled under vacuum to give 17 (75 g, 54%) as a colorless oil: (bpt. 55°-60° C., 0.015 torr): IR 3400 (OH) cm-1 ; 1H-NMR (CDCl3) d (ppm) 3.25-4.0 (m, 7H), 1.2 (s, 9H); 13C-NMR (CDCl3) d (ppm) 73.5, 70.5, 64.4, 63.6, and 27.16. Mass spectrosocopy, m/e: 148 M+ base peak (Scheme 3). ##STR5##
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[NH:5][N:6]=1.[O:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([C:18](=O)[CH2:19][C:20](OCC)=[O:21])[CH:16]=[CH:17][C:9]1=2>C(O)(=O)C>[O:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([C:18]3[NH:7][C:4]4[N:5]([N:6]=[C:2]([CH3:1])[N:3]=4)[C:20](=[O:21])[CH:19]=3)[CH:16]=[CH:17][C:9]1=2
Reactant: Cc1n[nH]c(N)n1
Reactant: CCOC(=O)CC(=O)c1ccc2c(c1)OCCO2
Solvent: CC(=O)O
Product: Cc1nc2[nH]c(-c3ccc4c(c3)OCCO4)cc(=O)n2n1
Temperature: 120 °C
Reaction time: 16 h
Yield: 11.7 %

Procedure:
A mixture of 5-methyl-2H-1,2,4-triazol-3-amine (147 mg, 1.50 mmol, 1.00 equiv), acetic acid (3 mL), and ethyl 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxopropanoate (375 mg, 1.50 mmol, 1.00 equiv) was stirred for 16 hr at 120° C., then concentrated to dryness. The resulting solid was washed by 5 mL MeOH and collected by filtration. The solid was dissolved in 10 mL of NH4OH (aq.) and filtered. The filtrate was adjusted to pH<5 with HOAc, then concentrated to dryness. The resulting solid was washed by 10 mL water, collected by filtration, and dried to get 50 mg (12%) of 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methyl-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=O)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:22](CC)CC)C.ClC(OCC)=O.N>O1CCCC1>[NH2:22][C:17](=[O:19])[CH2:16][CH2:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:14]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)Nc1cc(CCC(=O)O)ccn1
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(CCC(N)=O)ccn1
Reaction time: 0.17 h
Yield: 106 %

Procedure:
3-{2-[(tert-Butoxycarbonyl)amino]-4-pyridyl}propanoic acid (11.16 g, 41.92 mmol) dissolved in tetrahydrofuran (200 ml) was added with triethylamine (9 ml, 62.89 mmol), cooled with ice, and then added dropwise with ethyl chloroformate (6 ml, 62.89 mmol). The reaction mixture was stirred for 10 minutes, and then added with aqueous ammonia (50 ml) dissolved in tetrahydrofuran (50 ml) at 0° C. The reaction mixture was stirred for 20 minutes under ice cooling, and then the solvent was evaporated under reduced pressure. The resulting residue was washed with water and extracted with chloroform. The resulting organic layer was washed with saturated brine, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 11.794 g (100%) of the title compound as brown crystals without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[CH:19]=[CH:20][CH2:21][OH:22])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.[C:26]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)(=[O:28])[CH3:27].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C)C=O.CCOCC.O>[C:26]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([O:22][CH2:21][CH:20]=[CH:19][CH:18]([O:17][C:16]2[CH:15]=[CH:14][C:13]([O:12][C:7]3[CH:6]=[N:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[N:8]=3)=[CH:25][CH:24]=2)[CH3:23])=[O:35])=[CH:32][CH:31]=1)(=[O:28])[CH3:27]
Reactant: CC(C=CCO)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(=O)Nc1ccc(C(=O)OCC=CC(C)Oc2ccc(Oc3cnc4cc(Cl)ccc4n3)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.6 %

Procedure:
A mixture of 1.5 g (4.2 mmol) of the pentenol obtained in Example 3 above, 0.82 g (4.6 mmol) of 4-(acetylamino)benzoic acid, 0.95 g (4.6 mmol) of dicyclohexylcarbodiimide and 0.05 g of 4-(dimethylamino)pyridine in 20 ml of dimethylformamide was stirred at room temperature for 72 hours. The mixture was diluted with ether and water and filtered. The filtrates were separated, and the organic layer washed with saturated aqueous NaHCO3 and water, dried over MgSO4 and evaporated to dryness. The residue was purified by preparative scale HPLC, eluting with a 65:35 hexane:acetone mixture to give 0.6 g of the desired product as a pale yellow, glassy solid, m.p. 62°-68° C. (Compound 30).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH2:16][CH3:17])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:18](/[CH3:31])=[C:19](/[F:30])\[CH:20]=[CH:21]\[C:22](\[CH3:29])=[CH:23]\[C:24]([O:26]CC)=[O:25])[CH3:2].[OH-].[Na+]>C(O)C.C1COCC1>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH2:16][CH3:17])=[CH:9][C:10]([CH3:14])([CH3:15])[O:11]2)=[CH:6][C:5]=1/[C:18](/[CH3:31])=[C:19](/[F:30])\[CH:20]=[CH:21]\[C:22](\[CH3:29])=[CH:23]\[C:24]([OH:26])=[O:25])[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(cc1OCC)OC(C)(C)C=C2CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)O)C(CC)=CC(C)(C)O2

Procedure:
Following General Procedure G, a solution of ethyl 7-(7-ethoxy-4-ethyl-2,2-dimethyl-2H-chromen-6-yl)-6-fluoro-3-methyl-octa-2E,4E,6E-trienoate (Compound 110, 9.0 mg, 0.02 mmol) in ethanol and THF was hydrolyzed with 1M NaOH. Purification by flash chromatography (silica gel, 75:25 hexane/ethyl acetate) afforded the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](C3C=CC=CC=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:39])([CH3:38])[C:33]([O:35]CC)=[O:34].C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>CS(C)=O.CC(=O)CC>[C:1]1([N:8]2[C:9]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:38])([CH3:39])[C:33]([OH:35])=[O:34])=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)(C)CCCCCCCBr
Reactant: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCC(C)=O
Product: CC(C)(CCCCCCCc1c(-c2ccccc2)nc(-c2ccccc2)n1-c1ccccc1)C(=O)O

Procedure:
A mixture of 2,4,5-triphenylimidazole (4.13 g), ethyl 9-bromo-2,2-dimethylnonanoate (10.95 g), potassium carbonate (10 g) and 2-butanone was stirred at reflux for 48 hours. The mixture was filtered, solvent removed under reduced pressure and the residue was chromatographed on silica gel eluted with chloroform to give a clear oil which was dissolved in dimethyl sulphoxide (30 ml) and treated with potassium hydroxide (3 g). The mixture was stirred at 40° C. for 24 hours when the solvent was removed under reduced pressure. Water (50 ml) was added, the pH of the solution was adjusted to 4 and the aqueous was extracted with chloroform (3×50 ml). The chloroform extracts were dried over magnesium sulphate, filtered and the solvent removed to give a solid which was recrystallised from acetonitrile to give 9-(1,2,4-tri-phenylimidazolyl)-2,2-dimethylnonanoic acid as a white crystalline solid, m.p. 119°-120° C.; Found: C, 79.85; H, 7.64; N, 6.23% (C32H36N2O2); Requires: C, 79.96; H, 5.54; N, 5.82%