Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[C@H:4]([CH:41]([CH3:43])[CH3:42])[NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[O:25][C:26]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33]CC5C=CC=CC=5)[C:27]=4[CH:28]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:44])[C@H:4]([CH:41]([CH3:42])[CH3:43])[NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]3[O:25][C:26]4[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[C:27]=4[CH:28]=3)=[O:23])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1)(=[O:7])=[O:8]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4c(OCc5ccccc5)cccc4o3)cc2)cc1)C(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4c(O)cccc4o3)cc2)cc1)C(C)C
Reaction time: 5 h
Yield: 80 %

Procedure:
The product of Example 13-Step 1, 4′-[(4-benzyloxy-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonyl-L-valine methyl ester (0.32 mmol), was dissolved in 3 mL of ethyl acetate-MeOH (2:1) and 10% Pd/C (20 mg) was added. The reaction was stirred under a hydrogen atmosphere for 5 h. The reaction mixture was filtered through celite and then concentrated to give 4′-[(4-hydroxy-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonyl-L-valine methyl ester in 80% yield. The product (0.13 mmol) was dissolved in anhydrous DMF (1 mL), and Cs2CO3 (0.26 mmol) was added, followed by 2-bromo-propionic acid ethyl ester (0.13 mmol). After the reaction was complete by TLC the reaction was diluted with ethyl acetate and acidified with 1N hydrochloric acid. The organic layer was washed with brine (2×), dried (magnesium sulfate), filtered and concentrated to afford 79 mg of 4′-{[4-(1-ethoxycarbonyl-ethoxy)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonyl-L-valine methyl ester. The ester was taken up in THF:MeOH (2:1, 2 mL) and treated with NaOH (5N, 5 eq). The reaction was stirred overnight, diluted with ethyl acetate and acidified with 1N HCl. The organic layer was isolated and washed with brine (2×), dried (magnesium sulfate), filtered and concentrated to afford 4′-{[4-(1-carboxy-ethoxy)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonyl-L-valine. LCMS MH+ (m/z) 581. 1H NMR (300 MHz, CD3OD): δ 7.91-7.68 ppm (m, 6H), 7.40-7.09 ppm (m, 3H), 6.70 ppm (d, 1H, J=8 Hz), 4.99 ppm (q, 1H, J=13 Hz), 3.69 ppm (d, 1H, J=5.8 Hz), 2.08-2.00 ppm (m, 1H), 1.69 ppm (d, 3H, J=6.9 Hz), 0.97 ppm (d, 3H, J=7.0 Hz), 0.96 ppm (d, 3H, J=7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH:11]([CH2:19]O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Br)(Br)(Br)[Br:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C(Cl)Cl>[Br:22][CH2:19][CH:11]1[CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10]1
Reactant: BrC(Br)(Br)Br
Reactant: OCC1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(C2CC(CBr)Cc3ccccc32)cc1Cl
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a solution of compound 11 (1.25 g, 4.07 mmol) and CBr4 (2.33 G, 7.04 mmol) in CH2Cl2 (15 ml) was added Ph3P (1.82 g, 6.92 mmol) in CH2Cl2 (15 ml) at 0° C. The reaction was allowed to warm to room temperature overnight, was then poured into water ((40 ml), extracted with CH2Cl2 (75 ml), dried over Na2SO4, and the solvent was evaporated. The residue was purified by chromatography, CombiFlash silica gel column, EtOAC hexanes, EtOAc from 0% to 15%, to give compound 12 as a clear oil (mixture of cis and trans diastereomers, 1.50 g, 99%). 1H NMR. (CDCl3) δ 1.52-1.62 (m) and 1.97-2.15 (m, total 2H), 2.25-2.30 (m, 1H), 2.64-2.77 (m, 1H), 3.02-3.12 (m, 1H), 3.34-3.47 (m, 2H), 4.08 (dd, J=12 Hz, 5.2 Hz) and 4.26 (t, J=3.6 Hz, total 1H), 6.72-7.39 (m, 7H). 13C NMR (CDCl3) δ 31.8, 34.6, 35.6, 36.8, 37.2, 39.2, 39.3, 39.4, 43.3, 46.4, 126.5, 126.8, 126.9, 127.2, 128.3, 128.4, 128.6, 129.0, 129.4, 129.5, 129.7, 130.2, 130.5, 130.7, 130.9, 132.5, 132.8, 136.1, 136.3, 138.3, 147.0, 147.5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[N+:17]([O-:19])=[O:18])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BH4-].[Na+]>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.5 %

Procedure:
To a solution of 2-benzyloxy-5-((E)-2-nitro-vinyl)-pyridine (5.80 g, 22.8 mmol) described in Manufacturing Example 12-1-3 and acetic acid (5.80 mL) in dimethyl sulfoxide (70 mL) was added sodium borohydride (1.44 g, 36.2 mmol) under nitrogen atmosphere at room temperature while cooling appropriately, which was stirred for 10 minutes at room temperature. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4) to obtain the title compound (2.50 g, 43%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2\[NH:14][CH2:15][C:16]3([CH2:23][CH:22]4[NH:24][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[NH:17]\2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[C:57]2[CH:56]=[CH:55][CH:54]=[C:53]([C:58](O)=[O:59])[C:52]=2[CH:51]=[CH:50]1.CN1CCOCC1>CN(C=O)C>[NH:49]1[C:57]2[CH:56]=[CH:55][CH:54]=[C:53]([C:58]([N:24]3[CH:22]4[CH2:21][CH2:20][CH:19]3[CH2:18][C:16]3([CH2:23]4)[CH2:15][NH:14]/[C:13](=[N:12]\[C:10]([C:3]4[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=4)=[O:11])/[NH:17]3)=[O:59])[C:52]=2[CH:51]=[CH:50]1
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CC4CCC(C3)N4)N2)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CC4CCC(C3)N4C(=O)c3cccc4[nH]ccc34)N2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(E)-3,5-diamino-6-chloro-N-(8-azaspiro[bicyclo[3.2.1]octane-3,4′-imidazolidine]-2′-ylidene)pyrazine-2-carboxamide (170 mg, 0.49 mmol) is dissolved in DMF (10 ml) along with HATU (184 mg, 0.49 mmol) and 4-indole-carboxylic acid (78 mg, 0.49 mmol). N-Methyl morpholine (160 ml, 1.45 mmol) is added and the solution stirred at room temperature overnight. The mixture is then concentrated in vacuo. EtOAc (100 ml) is added and the solution washed with water (100 ml). The organic phase is dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (SiO2, DCM/MeOH) gives the title compound as a yellow solid; [M+H]+ 494.15, 496.27 for Cl isotopes.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.[H-].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7](=[O:10])[N:8]([CH2:26][C:27]2[CH:34]=[CH:33][C:30]([CH3:31])=[CH:29][CH:28]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCc1nn(Cc2ccc(C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
The alkylation of 5-n-butyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with 4-methylbenzyl bromide was carried out as described in Example 3, Step A, except that no excess sodium hydride was used. After work-up, flash chromatography of the crude product on silica gel (eluting with 0.6% methanol in CH2Cl2) provided the title compound as a clear oil, homogeneous by TLC (98:2 CH2Cl2 --MeOH), mass spectrum (FAB) m/e 437 (M+1)+.
Reaction SMILES: [BH4-].[Na+].[N+:3]([CH:6]=[CH:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)([O-:5])=[O:4].C(O)(=O)C>C(Cl)(Cl)Cl.C(O)(C)C>[N+:3]([CH2:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])C=Cc1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15.7 g of silica 60 (230-400 mesh) and then 2.95 g of NaBH4 are added to a solution of 32.2 mmol of 2-(2-nitrovinyl)thiophene in 210 ml of chloroform and 70 ml of isopropanol. After stirring the mixture for one hour at ambient temperature, 5 ml of acetic acid are added dropwise and then, after 15 minutes, the resulting suspension is filtered and subsequently rinsed with dichloromethane. Concentration of the filtrate under reduced pressure enables the expected product to be isolated.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]3[N:13]=[CH:14][CH:15]=[C:6]3[N:5]([CH3:16])[C:4]=2[CH:3]=1.ClC1N=CC2C(=O)N3N=C(C)C=C3NC=2C=1>>[CH3:16][N:5]1[C:4]2[CH:3]=[CH:2][N:11]=[CH:10][C:9]=2[C:8](=[O:12])[N:7]2[N:13]=[CH:14][CH:15]=[C:6]12
Reactant: Cn1c2cc(Cl)ncc2c(=O)n2nccc12
Agent: Cc1cc2[nH]c3cc(Cl)ncc3c(=O)n2n1
Product: Cn1c2ccncc2c(=O)n2nccc12
Yield: 83 %

Procedure:
By hydrogenating 6-chloro-4-methylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one of Example 6 by the procedure described in Example 4 for 6-chloro-2-methylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one, 4-methylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one is obtained, yield: 83%; m.p. >300°.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[CH2:16]1COC[CH2:17]1.C([Li])C>O>[CH2:16]([C:2]1([OH:1])[CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:6][CH2:7]1)[CH3:17]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: [Li]CC
Solvent: O
Product: CCC1(O)CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of tert-butyl (4-oxocyclohexyl)carbamate (3.04 g) and THF (100 mL), ethyllithium (0.5 M benzene-cyclohexane solution) (56.8 mL) was added at −78° C. and stirred over 4 hours until it reached −50° C. After addition of water (150 mL), the reaction liquid was heated to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (eluent; chloroform:methanol=30:1) and further purified (eluent; n-hexane:ethyl acetate=2:1 to 1:1) to give tert-butyl (4-ethyl-4-hydroxycyclohexyl)carbamate (Preparation Example 246) (0.202 g), which was a low-polarity product, as a white solid and tert-butyl (4-ethyl-4-hydroxycyclohexyl)carbamate (Preparation Example 248), which was a high-polarity product, as a colorless syrup.
Reaction SMILES: C[Si](C)(C)Cl.Br[CH2:7][C:8]([O:10]C)=[O:9].[CH:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl.[OH-].[K+]>C(OCC)(=O)C.O.[Zn]>[OH:20][CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:7][C:8]([OH:10])=[O:9]
Reactant: COC(=O)CBr
Reactant: CCCCCCCC=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCC(O)CC(=O)O
Temperature: 65 °C
Reaction time: 0.08 h

Procedure:
At room temperature, a three-necked flask fitted with reflux condenser, internal thermometer, dropping funnel and stirrer was charged, under nitrogen protective gas, with 11.1 g of zinc powder (169 mmol) in 70 ml of ethyl acetate. After 3.2 ml of trimethylchlorosilane (25 mmol) had been added, the mixture was heated at 65° C. for 30 min, then left to cool to 60° C., following which, over the course of 6 min, a mixture of 21 g of methyl bromoacetate (137 mmol) and 16 g of octanal (125 mmol) was added dropwise, the temperature being maintained at 65° C. by external cooling. The mixture was then stirred at 55° C. for 5 min, and after cooling to 0° C., was acidified with 75 ml of 2 N hydrochloric acid to a pH of 1 and stirred for 30 min. Excess zinc was removed by filtration and the organic phase separated. The organic phase was then stirred at 0° C. with 80 ml of 1 N hydrochloric acid, and finally washed with 80 ml of saturated sodium hydrogen carbonate solution. Following phase separation, the solvent was removed by distillation under reduced pressure. For the ester hydrolysis, the crude product was treated with a solution of 15.4 g of potassium hydroxide (232 mmol) in 140 ml of water and stirred for 40 min at 50° C., during which a clear solution formed. The solution was extracted with 2×20 ml of toluene, and the aqueous phase was acidified at 0° C. with 100 ml of 2 N hydrochloric acid to a pH of 1 and extracted with 3×20 ml of ethyl acetate. The organic extracts were dried over sodium sulfate and the solvent was removed by distillation under reduced pressure. 3-Hydroxydecanoic acid was obtained in a yield of 21 g (89% of theory). The compound has a melting point of 58° C. following recrystallization from petroleum ether.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]/[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1>C1COCC1>[OH:24][C:23]1[N:8]2[C:9](=[O:15])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2=[N:16][N:17]=1
Reactant: CCCCCn1/c(=N\N)[nH]c(=O)c2[nH]cnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(O)nnc12
Temperature: 100 °C
Yield: 103.7 %

Procedure:
A solution of (2z)-3-pentyl-3,7-dihydro-1h-purine-2,6-dione 2-hydrazone (200 mg, 0.846 mmol), N,N-carbonyldiimidazole (1.65 g, 10.2 mmol) in THF (10 ml) was stirred at 70° C. overnight. The reaction mixture was then heated in microwave reactor at 100° C. for 10 min. The reaction was completed checked by LCMS analysis. The reaction mixture was concentrated, diluted with EtOAc and washed with sat. NaHCO3. The aqueous was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4) and concentrated to yield the desired product (230 mg, 98.4%). LCMS calculated for C11H15N6O2 (M+H) 263.1. Found: 263.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:21][C:20](=[O:22])[CH2:19][CH2:18][N:17]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:15])[CH3:12])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+]>CO.O>[OH:22][CH:20]1[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:16]([C:14](=[O:15])[NH:13][C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[CH3:12])[CH2:21]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(=O)CCN2C(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(O)CCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.6 %

Procedure:
To an ice cooled solution of (R)-tert-butyl 2-(((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-4-oxopiperidine-1-carboxylate (D60) (300 mg, 0.75 mmol) in MeOH (25 ml) under nitrogen, NaBH4 (142 mg, 3.75 mmol) was added portionwise and the resulting mixture was stirred at RT for 18 hrs. The mixture was diluted with water (10 ml) and extracted with EtOAc (3×10 ml). The organic phases were collected, washed with NaCl sat. (20 ml) dried over Na2SO4 and evaporated in vacuo to afford the title compound (D61) (261 mg).
Reaction SMILES: CC(CCO)CCC1C=CC=CC=1.CC[O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:27]CC)=[O:26])=[CH:21][CH:20]=1)=[O:18].C[O-].[Na+]>>[CH:20]1[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[C:22]([C:25]([OH:27])=[O:26])[CH:21]=1
Reactant: CCOC(=O)c1ccc(C(=O)OCC)cc1
Agent: CC(CCO)CCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 100 °C

Procedure:
Phenoxanol in the amount of 35.80 g (0.201 mol) and diethyl p-phthalate in the amount of 13.00 g (0.067 mol) were combined in a 250 ml flask fitted with a heating mantel, take-off condenser, internal thermometer, and argon inlet. Sodium methoxide in the amount of 380 mg (6.70 mmol) was added to the contents of the flask. The mixture was heated to 100° C. for 5 h during which time it became very thick. The mixture was filtered with dichloromethane, concentrated by rotary evaporation, and stripped by Kugelrohr distillation to yield an oil. The oil was purified by column chromatography on silica gel eluting with a 2% solution of ethyl acetate in hexanes to yield a colorless oil that crystallized on standing. Purity of the product was determined by thin layer chromatography and the structure confirmed by 1H and 13C NMR.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([CH3:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C.CCOC(C)=O>O1CCOCC1.O>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:2]2[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([I:15])=[C:11]([CH3:16])[CH:10]=3)=[CH:4][N:3]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(I)c(C)c3)cn2)CC1
Temperature: 115 °C
Reaction time: 9 h
Yield: 45 %

Procedure:
A solution of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide (500 mg, 1.34 mmol), ethyl isonipecotate (250 mg, 1.61 mmol) and diisopropylethyl amine (0.7 mL, 4.02 mmol) in dioxane (15 mL) was heated at 80° C. in a sealed tube for 18.5 h then at 95° C. for 9 h and then at 115° C. for an additional 24 h. The reaction mixture was then cooled, another portion of ethyl isonipecotate (250 mg, 1.61 mmol) was added and the mixture was stirred at 115° C. for 8 h more. The mixture was then cooled and portioned between EtOAc and water. The EtOAc layer was dried over Na2SO4, filtered and concentrated. The residue was chromatographed with a silica gel column and 10-40% EtOAc in hexanes gradient to afford the product. (300 mg, Yield: 45%). HRMS m/z calcd for C21H24N3O3I [M+H]+: 494.0935. Found: 494.0937.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>CN1CCCC1=O>[CH3:11][N:12]([CH2:13][CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CNCCO
Solvent: CN1CCCC1=O
Product: CN(CCO)c1ccc([N+](=O)[O-])cc1
Temperature: 85 °C
Yield: 79 %

Procedure:
A mixture of 4-fluoronitrobenzene (2.8 g, 20 mmol) and 2-(methylamino)ethanol (8.9 g, 120 mmol) in N-methylpyrrolidinone (80 mL) is heated for 19 hours in a 85° C. oil bath. After cooling to room temperature, the reaction mixture is partitioned between ethyl acetate and water. The organic phase is washed five times with water and with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 2-(methyl-4-nitroanilino)ethanol (3.1 g, 79%) as a yellow solid.
Reaction SMILES: C(OC(=O)[N:7]([CH2:23][C:24]1[CH:32]=[CH:31][C:27]2[O:28][CH2:29][O:30][C:26]=2[CH:25]=1)[CH2:8][CH2:9][CH2:10][N:11]([C:13]1[S:17][N:16]=[C:15]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[N:14]=1)[CH3:12])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:28]1[C:27]2[CH:31]=[CH:32][C:24]([CH2:23][NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:13]3[S:17][N:16]=[C:15]([N:18]4[CH:22]=[CH:21][N:20]=[CH:19]4)[N:14]=3)[CH3:12])=[CH:25][C:26]=2[O:30][CH2:29]1
Reactant: CN(CCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C)c1nc(-n2ccnc2)ns1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Yield: 99.5 %

Procedure:
A solution of benzo[1,3]dioxol-5-ylmethyl-{3-[(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-methyl-amino]-propyl}-carbamic acid tert-butyl ester (10.6 g, 22.4 mmol) in TFA/DCM (50%, 70 mL) was stirred at room temperature for 30 min. The solvent was evaporated and a saturated solution of potassium carbonate (50 mL) was added to make it basic (pH 9). The solution was extracted with ethyl acetate (2×200 mL), washed with brine and dried over Na2SO4. Evaporation of the solvent gave 8.30 g (99%) of N′-benzo[1,3]dioxol-5-ylmethyl-N-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-N-methyl-propane-1,3-diamine as a colorless oil. [M+H]+ 373.26; 1H-NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), 7.63 (s, 1H), 7.07 (s, 1H), 6.79 (s, 1H), 6.72 (s, 2H), 5.92 (s, 2H), 3.67 (s, 3H), 3.60 (br s, 1H), 3.10 (br s, 2H), 2.66 (t, 2H), 2.0 (br s, 2H), 1.87 (q, 2H); 13C-NMR (100 MHz, CD3OD) δ 184.3, 156.7, 147.7, 146.6, 136.4, 133.8, 129.9, 121.2, 117.1, 108.6, 108.1, 100.9, 53.7, 45.7, 27.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1.[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:25]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(C=Cc1cccc(F)c1)C(=O)O
Reactant: OCc1cccc(Oc2ccccc2)c1
Product: CC(C)C(C=Cc1cccc(F)c1)C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
The acid chloride of 4-(3-fluorophenyl)-2-isopropyl-3-butenoic acid is reacted with m-phenoxybenzyl alcohol to yield m-phenoxybenzyl 4-(3-fluorophenyl)-2-isopropyl-3-butenoate, MS m/e 404 (M+).
Reaction SMILES: O[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)[CH3:3].S([O-])(O)(=O)=O.[K+].C(C1C=C(O)C(=CC=1)O)(C)(C)C>>[F:11][C:10]([F:12])([F:13])[C:7]1[CH:8]=[CH:9][C:4]([CH:2]=[CH2:3])=[CH:5][CH:6]=1
Reactant: CC(O)c1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)c1ccc(O)c(O)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: C=Cc1ccc(C(F)(F)F)cc1

Procedure:
To the compound (I) (27.0 g/0.142 mol) were added potassium hydrogensulfate (7 g) and 4-tert-butylcatechol (polymerization inhibitor, 0.01 g). The mixture was distilled at 150° to 180° C. using an oil bath to collect the whole distillate. Ether (20 ml) was added to the distillate, an ethereal layer was separated from water, and sodium sulfate was added to the layer for dehydration, followed by filtration. The ether was removed from the filtrate, to which 4-tert-butylcatechol was added again. The filtrate was then distilled at a reduced pressure, giving 4-trifluoromethylstyrene [compound (II)] represented by the formula CF3C6H4CH=CH2, b.p. 78°~80° C. (2660 Pa), colorless transparent liquid, yield 76.5%.