Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1.C(OCC)(=O)C>CS(C)=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[Cl:9]
Reactant: COC(=O)c1cc2c(Cl)ccnc2cc1OC
Reactant: Nc1ccc(O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OC
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
After dissolving 4-amino-3-chlorophenol (3.17 g, 22.05 mmol) in dimethylsulfoxide (50 ml), sodium hydride (882 mg, 22.05 mmol) was gradually added at room temperature and the mixture was stirred for 30 minutes. The 4-chloro-7-methoxy-6-methoxycarbonylquinoline (3.70 g, 14.7 mmol) described in WO0050405 was added, and the mixture was heated at 100° C. for 3 hours. After standing to cool to room temperature, the reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, silica gel column chromatography (eluent—ethyl acetate) was performed, the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (3.092 g, 8.62 mmol, 57.4%) as light brown crystals.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:24]([NH2:25])=[CH:23][NH:22][N:21]=2)=[O:19])=[CH:13][CH:12]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O.O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([C:20]2[C:24]([NH:25][C:7]([C:6]3[CH:5]=[CH:4][S:3][C:2]=3[CH3:1])=[O:9])=[CH:23][NH:22][N:21]=2)=[O:19])=[CH:15][CH:16]=1
Reactant: Cc1sccc1C(=O)O
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCCl
Product: Cc1sccc1C(=O)Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Methyl-3-thiophenecarboxylic acid (36 mg, 0.25 mmol) was added to a solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (Example 2B) (50 mg, 0.23 mmol), EDC (53 mg, 0.27 mmol), and HOBt (37 mg, 0.27 mmol) in DMSO (1 ml). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was added dropwise to water (30 ml) and the resultant solid was collected by filtration, washed with water and sucked dry. The title compound was obtained as a beige solid (15 mg, 19%). (LC/MS: Rt 4.08, [M+H]+ 344.67).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Na].[C:8]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:9][C:10]([O-:12])=[O:11].[H-].[Na+].[C:24]1(=[O:30])[CH2:29][CH2:28][CH2:27][CH:26]=[CH:25]1.Cl>C1COCC1>[CH2:15]([O:14][C:8](=[O:13])[CH:9]([CH:26]1[CH2:27][CH2:28][CH2:29][C:24](=[O:30])[CH2:25]1)[C:10]([O:12][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1C=CCCC1
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: O=C1CCCC(C(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 141.7 %

Procedure:
To a solution of LiAlH4 (6 mL, 6 mmol) under N2 at 0° C. was added a solution of (S)-1,1′-binaphthol (3.43 g, 12 mmol) in THF (48 mL) and stirred for 30 min. The reaction was warmed to RT. To this was added a solution of sodium salt benzyl malonate in THF which was prepared by reacting benzyl malonate (14.99 mL, 60 mmol), NaH (60% by wt., 0.216 g, 5.4 mmol), and THF (60 mL) until all bubbling ceased. Next, cyclohexenone (5.82 mL, 60 mmol) and dibenzlmalonate (1.35 mL, 5.4 mmol) were added and the reaction mixture was stirred overnight. 1.0 N HCl was added and extracted with EtOAc (3×). The combined EtOAc layers were washed (brine), dried (MgSO4), filtered, and concentrated. Flash chromatography (silica gel, acetone/hexanes gradient) gave the title compound (16.17 g, 71%). Mass Spectrum (FIA) (m/z) 381.3 [M+1].
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7](Cl)[N:6]=1>O1CCCC1>[Cl:4][C:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7]([CH3:1])[N:6]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 28 %

Procedure:
Methyl magnesium bromide (3M in ethyl ether, 9 ml, 27 mmol) was added dropwise over 10 min to a cooled (0° C.) solution of 2,4,6-trichloro-1,3,5-triazine (5 g, 27 mmol) in tetrahydrofuran (270 ml). The reaction mixture was stirred at ambient temperature for 20 hours and was then quenched with saturated NH4Cl (aq) (100 mL). The aqueous layer was extracted using dichloromethane (3×50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated to remove the most of solvent. Celite was then added to the solution and the resulting suspension was concentrated to dryness under vacuum and purified using silica gel chromatography (120 g SiO2 gel column; solvent dichloromethane/hexane from 0 to 30%) to give 2,4-dichloro-6-methyl-1,3,5-triazine (1.38 g of 90% purity, 7.57 mmol, 28%). MS (ES) m/e 164 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23]O)=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C>[N:37]([CH2:23][CH2:22][C:21]#[C:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:3]3[C:2]([OH:1])=[C:7]([C:8]#[N:9])[C:6](=[O:10])[NH:5][C:4]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1)=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1c(O)c2c(-c3ccc(C#CCCO)cc3)csc2[nH]c1=O
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1c(O)c2c(-c3ccc(C#CCCN=[N+]=[N-])cc3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-3-[4-(4-hydroxy-but-1-ynyl)-phenyl]-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (0.23 g, 0.7 mmol) in 5 mL DMF was added triethylamine (0.28 mL, 2 mmol), followed by MsCl (85 μL, 1 mmol). The mixture was stirred at rt for 2 hr, after which NaN3 (0.36 g, 5.6 mmol) was added, and heated to 90° C. overnight. Solvent was removed in vacuo and purified via reverse phase HPLC to afford the titled compound. MS (ESI) m/e 360 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ 2.76 (t, J=6.61 Hz, 2H), 3.52 (t, J=6.44 Hz, 2H), 6.67 (s, 1H), 7.29 (d, J=8.48 Hz, 2H), 7.44 (d, J=8.48 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].I[C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.C(N(CC)CC)C.CCOC(C)=O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(I)cc1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3; 800 mg; 3.00 mmol), 4-iodoaniline (788 mg; 3.60 mmol) and dichlorobis(triphenylphosphine)palladium(II) (526 mg; 0.75 mmol) in anhydrous THF (20 mL) was treated with cuprous iodide (29 mg; 0.15 mmol), then the mixture was degassed with N2 for 10 minutes, then treated with triethylamine (5.0 ml; 36 mmol). The mixture was stirred for 18 hours at RT, then EtOAc and water were added, the phases separated and the organic phase was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound.
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:8]([OH:10])=[O:9])[CH:5]([CH3:7])[CH3:6].[NH:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=2)=[N:14][N:13]=[N:12]1.[BH4-].[Na+].Cl>O.C(O)C>[CH3:6][CH:5]([CH3:7])[C@H:4]([NH:3][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]2[NH:11][N:12]=[N:13][N:14]=2)=[CH:23][CH:24]=1)[C:8]([OH:10])=[O:9]
Reactant: O=Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)[C@H](NCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)O
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
Aqueous sodium hydroxide solution 2.0 M (approximately 100 ml; 200 mmol) is added to a stirred suspension of L-Valin (11.8 g; 100 mmol) and 2′-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde (25.1 g; 100 mmol) in water (100 ml) at room temperature, until pH 11 is reached. The resulting clear solution is evaporated at 60° C. in vacuo, and remaining water is azeotro-pically removed with 1-butanol. The residue (imine as a solid foam) is dissolved in absolute ethanol (300 ml), and sodium borohydride (3.78 g; 100 mmol) is added in portions to the solution at 0-5° C. The reaction mixture is stirred for 30 min at 0-5° C., and, it the reaction is complete (HPLC), quenched by addition of water (100 ml) and hydrochloric acid 2.0 M (80 ml; 160 mmol). The organic solvent (ethanol) is stripped off from the clear solution (pH 7) at 50° C. in vacuo. The remaining aqueous concentrate is adjusted to pH 2 by slow addition of hydrochloric acid 2.0 M (approximately 70 ml; 140 mmol) at 40° C. During the addition the desired product precipitates. It is collected by filtration, washed with water and dried in vacuo. The crude product is suspended in methanol at 50° C., and the slurry is cooled to room temperature. (S)-3-methyl-2-((2′-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl)-amino)-butyric acid is collected by filtration and then dried in vacuo.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:3]=1.[N:32]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(O)C>[C:19]([NH:18][C:16]1[S:17][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([O:8][C:6]3[CH:5]=[C:4]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[N:3]=[C:2]([N:35]4[CH2:34][CH2:33][N:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37][CH2:36]4)[N:7]=3)[C:14]=2[N:15]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(Cl)n3)cccc2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(N4CCN(C(=O)OC(C)(C)C)CC4)n3)cccc2s1
Temperature: 125 °C

Procedure:
A mixture of N-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide (186 mg, 0.4 mmol, Example 7(d)) and tert-butyl 1-piperazine-carboxylate (149 mg, 0.8 mmol, Aldrich) in ethanol (1 mL) was heated in a microwave synthesizer at 125° C. for 40 min. The reaction mixture was evaporated under reduced pressure and the residue was treated with sat. aqueous solution of NaHCO3 (10 mL), and extracted with EtOAc (2×30 mL). The combined EtOAc extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (20% EtOAc/hexane) to give the title compound as a solid. MS (ESI, pos. ion) m/z: 615 (M+1). M.p.: 211° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH:6][C:17](=[O:19])[CH3:18]
Reactant: COC(=O)[C@H](N)CO
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](CO)NC(C)=O
Temperature: -10 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
D-Serine methyl ester hydrochloride (100 g, 0.6430 mole) was suspended in 500 ml dichloromethane. To this was added triethylamine (136.6 g, 1.35 mole) at 0-5° C., followed by acetyl chloride (53.06 g, 0.6751 mole) drop wise at −10° C. The reaction mixture was stirred at −10° C. for 3 hours, filtered to remove salts and the filtrate was evaporated. The resulting residue was suspended in 400 ml ethyl acetate and stirred for one hour. Salts were filtered and the ethyl acetate layer was concentrated under reduced pressure to get N-acetyl D-serine methyl ester as an oil (93.22 g, Yield: 90%, HPLC: 98.7%),
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]([O:16]C(=O)C)[C@H:10]2[O:11]C(=O)C)[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]2([OH:46])[CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:35][CH:34]=1.[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:15]([OH:16])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]2([OH:46])[CH2:42][CH2:43][CH2:44][CH2:45]2)=[CH:35][CH:34]=1
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#CC4(O)CCCC4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#CC4(O)CCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.73 g 1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-[4-(1-hydroxy-cyclopentyl-ethynyl)-benzyl]-benzene in 4 mL methanol and 2 mL tetrahydrofuran is added 5.1 mL of a 1 M solution of sodium hydroxide in water. The reaction solution is stirred at ambient temperature for 1 h and then neutralized with 1 M hydrochloric acid. The solvent is removed and brine is added to the residue. The resulting mixture is extracted with ethyl acetate and the combined organic extracts are washed with water and brine and dried over sodium sulfate. After removal of the solvent in vacuo the product is yielded.
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=O.[CH:14]1([CH:17]([N:25]([CH2:29][CH2:30][CH3:31])[C:26]([NH2:28])=[S:27])[C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)C>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:28]=[C:26]([N:25]([CH:17]([CH:14]2[CH2:16][CH2:15]2)[C:18]2[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=2)[CH2:29][CH2:30][CH3:31])[S:27][C:2]=1[CH3:13]
Reactant: CCCN(C(N)=S)C(c1ccc(Br)cc1)C1CC1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccc(Br)cc1)C1CC1
Temperature: 65 °C

Procedure:
14 g of 2-bromo-1-(2,4-dichlorophenyl)-1-propanone (Compound 1), 17.1 g of N-(α-cyclopropyl-4-bromobenzyl)-N-propylthiourea (Compound 64) and 7.6 ml of triethylamine are dissolved in 200 ml of ethanol And the solution is heated to 65° C. The reaction is monitored by TLC. At the end of the reaction, the ethanol is removed and the residue is hydrolysed with water and extracted with methylene chloride. The organic phases are washed and dried. The product is purified on a column of silica, using a mixture of cyclohexane and ethyl acetate (20:1 v/v) as eluent.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4]/[CH:5]=[CH:6]/[CH:7]=[CH:8]/[C@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@H:10]1[CH2:16][O:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.[Cl-].[NH4+]>C1COCC1.O.[OH-].[Na+]>[CH:8](/[C@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@H:10]1[CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:7]\[CH:6]=[CH:5]\[C:4]#[CH:3]
Reactant: CC(C)(C)OC(=O)COC[C@@H]1OC(C)(C)O[C@@H]1/C=C/C=C/C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C#C/C=C/C=C/[C@H]1OC(C)(C)O[C@H]1COCC(=O)O
Reaction time: 8 h

Procedure:
A solution of 2-[[(4S,5R)-5-[(1E,3E)-6-(trimethylsilyl)-1,3-hexadien-5-ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid, 1,1-dimethylethyl ester in THF was treated with a solution of tetrabutylammonium fluoride in THF in portions. The reaction mixture was then stirred overnight. The reaction mixture was diluted with water and 1 N NaOH solution (1:1) and stirred overnight. The reaction mixture was poured into a mixture of ethyl acetate and saturated ammonium chloride. The aqueous layer was washed with ethyl acetate (2×). The combined organic layers were washed with water and brine solution, dried, treated with silica gel and concentrated to give 2.8 g of 2-[[(4S,5R)-5-[(1E,3E)-1,3-hexadien-5-ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid, a compound of formula (V), as an oil: 1H NMR (CDCl3) δ 1.37 (s, 3H), 1.46 (s, 3H), 3.06 (s, 1H), 3.49 (m, 2H), 4.06 (m, 2H), 4.37 (m, 1H), 4.65 (t, 1H), 5.54 (d, 1H), 5.66 (dd, 1H), 6.28 (dd, 1H), 6.58 (dd, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:13]([C:14](Cl)=[O:15])=[CH:12][N:11]([CH3:17])[C:10](=[O:18])[NH:9]2)=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[C:29]([CH3:31])[CH:28]=[N:27]2)=[CH:22][C:21]=1[NH2:32].C(#N)CC.N1C=CC=CC=1>O.C1(C)C=CC=CC=1>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[C:29]([CH3:31])[CH:28]=[N:27]2)=[CH:22][C:21]=1[NH:32][C:14]([C:13]1[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[NH:9][C:10](=[O:18])[N:11]([CH3:17])[CH:12]=1)=[O:15]
Reactant: Cc1cnn(-c2ccc(C)c(N)c2)c1
Reactant: CN1C=C(C(=O)Cl)[C@H](c2ccc(F)cc2)NC1=O
Solvent: CCC#N
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cnn(-c2ccc(C)c(NC(=O)C3=CN(C)C(=O)N[C@H]3c3ccc(F)cc3)c2)c1
Yield: 48.7 %

Procedure:
(S)-4-(4-Fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid chloride, (230 mg), prepared as in Example 1, was added to a solution of 163 mg of 2-methyl-5-(4-methyl-pyrazol-1-yl)-phenylamine, 10 mL propionitrile, and 0.1 mL pyridine. The resulting solution was heated at 100° for 30 minutes, then cooled to 50° and diluted with 5 mL water and 10 mL toluene. The mixture was vigorously stirred at 50° and the layers were separated. The warm toluene layer was washed with saturated sodium bicarbonate, and then concentrated under reduced pressure to a brown residue, which was triturated with 2 mL toluene and filtered. The resulting solid was recrystallized from ethanol/water to yield 175 mg of (S)-4-(4-fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid[2-methyl-5-(4-methyl-pyrazol-1-yl)-phenyl]-amide, MS (M+H)=420.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=O)[N:13]=2)=[N:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[C:57]([NH:60][NH2:61])(=[O:59])[CH3:58]>C(#N)C.C1COCC1>[C:57]([NH:60][NH:61][C:16](=[O:18])[CH2:15][CH2:14][C:12]1[N:13]=[C:9]([NH:8][C:5]2[C:4]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[S:10][CH:11]=1)(=[O:59])[CH3:58]
Reactant: O=C(O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reactant: CC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NNC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Yield: 126.7 %

Procedure:
A mixture 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic acid (0.300 g, 0.714 mmol), HOBT-H2O (0.164 g, 1.07 mmol), DIEA (0.261 mL, 1.50 mmol), EDCI (0.205 g, 1.07 mmol), and acetohydrazide (0.106 g, 1.43 mmol) in 10 mL acetonitrile and 2 mL THF was stirred at 50° C. for 3 hours and then overnight at ambient temperature. The mixture was concentrated and diluted with CH2Cl2, washed with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated to provide the title compound (0.431 g, 127% yield) that was carried directly on to the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2].[Br:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][Br:21])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O
Reactant: BrCCOCCOCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOCCBr
Reaction time: 24 h
Yield: 61.6 %

Procedure:
A mixture of 2.8 g (0.01 mole) of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester, 11.0 g (0.034 mole) of 1,11-dibromo-3,6,9-trioxaundecane and 2.8 g (0.02 mole) of anhydrous potassium carbonate in 60 ml of anhydrous acetone and 30 ml of anhydrous dimethylformamide was stirred at reflux for 16 hours. An additional 1.4 g of potassium carbonate was added and reflux was continued for 24 hours. The solvents were removed in vacuo and the residue was chromatographed on 200 g of silica gel. Elution with 10% ethyl acetate-toluene gave 3.2 g (62% yield) of [4-acetyl-3-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[C:21](=[O:22])[C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:12][O:13][C:9]=2[CH2:8][CH2:7]1)[CH3:4].Cl.[F:24][C:25]1[CH:38]=[CH:37][C:28]([C:29]([CH:31]2[CH2:36]CNC[CH2:32]2)=[O:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([CH:31]2[CH2:32][CH2:2][N:3]([CH2:5][CH:6]3[C:21](=[O:22])[C:10]4[C:11]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=5[F:20])=[N:12][O:13][C:9]=4[CH2:8][CH2:7]3)[CH2:4][CH2:36]2)=[O:30])=[CH:37][CH:38]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CN(C)CC1CCc2onc(-c3ccccc3F)c2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)cc1)C1CCN(CC2CCc3onc(-c4ccccc4F)c3C2=O)CC1
Temperature: 25 °C
Yield: 46.5 %

Procedure:
To a solution consisting of 6,7-dihydro-5-dimethylaminomethyl-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one hydrochloride (1.86 g) in distilled water (18.5 ml) was added 4-(4-fluorobenzoyl)piperidine hydrochloride (2.78 g) and potassium carbonate (0.80 g). The reaction mixture was heated at reflux for 3 hours. Upon cooling to room temperature, ethyl acetate was added and the layers were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 40% ethyl acetate/hexane) afforded 1.20 g of 6,7-dihydro-5-(4-(4-fluorobenzoyl)-1-piperidinyl)methyl-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one. The compound was flushed through alumina with dichloromethane to give an oil which solidified on standing. The product was then recrystallized from ether/hexane, m.p. 99°-102° C.