Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH:19]2[CH2:21][CH2:20]2)[C:17]=1N)=[O:12])[CH3:9].C(OC(C1C(N)=NN(C2CC2)C=1)=O)C.[ClH:36]>C(#N)C>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH:19]2[CH2:21][CH2:20]2)[C:17]=1[Cl:36])=[O:12])[CH3:9]
Reactant: Cl
Reactant: CCOC(=O)c1cnn(C2CC2)c1N
Agent: CC(C)(C)ON=O
Agent: CCOC(=O)c1cn(C2CC2)nc1N
Solvent: CC#N
Product: CCOC(=O)c1cnn(C2CC2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of t-butyl nitrite (2.03 mL, 15.38 mmol), cuprous chloride (1.52 g, 15.38 mmol), and anhydrous acetonitrile (30 mL) was added the solution of the mixture of 5-amino-1-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester and 3-amino-1-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (from last step) in anhydrous acetonitrile (20 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h and then at 60° C. for 2 h. The mixture was cooled to room temperature and poured into 6N HCl (20 mL) and extracted with dichloromethane. The aqueous phase was extracted three times with dichloromethane. After the combined organic phases were concentrated in vacuo, the crude residue was purified by flash chromatography eluting with a gradient of 10-20% ethyl acetate/hexanes, then 20% ethyl acetate/hexanes to give 5-chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (eluted first, 296 mg, 13%) and 3-chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (eluted later, 159 mg, 7%). LRMS m/z calcd for C9H11ClN2O2 (M+H) 215.1, found 215.1.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[CH3:15][O:16][N:17]=[CH:18][C:19]1[CH:24]=[C:23]([N:25]=[C:26]=[O:27])[C:22]([F:28])=[CH:21][C:20]=1[Cl:29].O>CN(C)C=O.O1CCCC1.ClCCl>[CH3:15][O:16][N:17]=[CH:18][C:19]1[CH:24]=[C:23]([N:25]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:26]2=[O:27])[C:22]([F:28])=[CH:21][C:20]=1[Cl:29]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CON=Cc1cc(N=C=O)c(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CON=Cc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 168.5 g (0.92 mol) of ethyl 3-amino-4,4,4-trifluorocrotonate in 0.1 l of dimethylformamide was added dropwise with ice-cooling to 30.4 g (1.01 mol) of 80% by weight sodium hydride in 0.5 l of dimethylformamide. After one hour at this temperature, the mixture was cooled to (−30) to (−35)° C., and a solution of 210.3 g (0.92 mol) of 2-chloro-4-fluoro-5-isocyanatobenzaldehyde (O-methyl)oxime in 0.15 l of tetrahydrofuran was added dropwise. The reaction mixture was then stirred for 20 hours at approximately 20° C., and 1.5 l of water were subsequently added with ice-cooling. Undissolved matter in the mixture formed was removed and washed using 300 ml of water. The combined filtrates were acidified using dilute hydrochloric acid. The product of value was then extracted from the solution obtained using dichloromethane. The extract was washed with water, dried over sodium sulfate and finally concentrated. Yield: 289 g; m.p.: 176-177° C. (diisopropyl ether/petroleum ether).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C(C1N(CC2C=CC(C(OCC)=O)=CC=2Cl)C(C=O)=CN=1)CCC.[S:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[CH2:52][CH2:53][C:54]([O:56]C(C)(C)C)=[O:55].C(C1N(CC2C=CC=CC=2Cl)C(/C(/C)=C(\C2C=CN=CC=2)/C(O)=O)=CN=1)CCC.FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)[C:7](/[CH:10]=[C:53](\[CH2:52][C:48]2[S:47][CH:51]=[CH:50][CH:49]=2)/[C:54]([OH:56])=[O:55])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)CCc1cccs1
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1
Agent: CCCCc1ncc(/C(C)=C(/C(=O)O)c2ccncc2)n1Cc1ccccc1Cl
Agent: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OCC)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccc(C(=O)OC)cc1

Procedure:
The title compound was prepared using 2-n-butyl-1-[(4carbomethoxyphenyl)methyl]imidazole-5-aldehyde (prepared by the method described for the preparation of 2-n-butyl-1-[(4-carboethoxy-2-chlorophenyl)methyl]imidazole-5-aldehyde in Example 42) and t-butyl 3-(2-thienyl)-propanoate by the procedure of Example 1 (iv, Method B), except, instead of basic hydrolysis, trifluoroacetic acid hydrolysis of the t-butyl ester was employed; mp 217°-220° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:5]([NH2:6])=[C:4]([CH3:13])[CH:3]=1.C([O-])(=O)C.[K+].[N:19](OCCC(C)C)=O>C1(C)C=CC=CC=1.C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[NH:6][N:19]=[CH:13]2
Reactant: CC(C)CCON=O
Reactant: Cc1cc(Br)cc(C(F)(F)F)c1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(Br)cc2cn[nH]c12
Yield: 51.7 %

Procedure:
To a solution of 4-bromo-2-methyl-6-(trifluoromethyl)aniline (3.3 g, 13 mmol) in toluene (65 mL) and glacial acetic acid (11.2 mL, 195 mmol) was added potassium acetate (10.2 g, 104 mmol) portionwise. After 15 minutes a large amount of precipitate had formed, hindering stirring of the reaction. The reaction was diluted with acetic acid (10 mL). Isoamyl nitrite (1.92 mL, 14.3 mmol) was then added dropwise and the reaction was stirred at room temperature for 3 hours. Additional isoamyl nitrite (0.5 mL, 3.7 mmol) was added and the reaction was left stirring for 15 hours. The reaction was diluted with water (100 mL) and stirred for 1.5 hours. The solution was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (5-50% ethyl acetate/heptanes) gave the title compound (1.78 g, 52%) as a yellow powder. −ESI (M−H+1) 264.9; 1H NMR (400 MHz, CDCl3, δ): 8.13 (s, 1H), 8.09-8.11 (m, 1H), 7.76 (dd, J=1.66, 0.88 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH2:22]([N:25]=[C:26]=[S:27])[CH2:23][CH3:24]>CC(O)C>[CH2:22]([N:25]1[C:12](=[O:14])[C:3]2[C:2](=[CH:11][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH:4]=2)[NH:1][C:26]1=[S:27])[CH2:23][CH3:24]
Reactant: Nc1cc2ccccc2cc1C(=O)O
Reactant: CCCN=C=S
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCn1c(=S)[nH]c2cc3ccccc3cc2c1=O
Temperature: 25 °C
Yield: 72.6 %

Procedure:
To a suspension of 1.88 g of 3-amino-2-naphthalic acid in 25 mL of 2-propanol was added 1.39 mL of triethylamine followed by 1.02 g of n-propyl isothiocyanate with stirring. The mixture was heated at reflux for 2 h, and then allowed to cool to room temperature. The resulting solid was collected by filtration and washed with cold 2-propanol to give 1.97 g of the title compound of Step A as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:13][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of compound 68a (7.5 g, 0.032 mol) in THF (100 mL), 1 M THF solution of NaHMDS (36 mL, 0.036 mol) was added dropwise at 0 C. The resulting solution was allowed to warm to room temperature and stirred for 1 h before cooling back down to 0° C. The cooled reaction mixture was treated dropwise with iodomethane (5.1 g, 0.035 mol). The ice-water bath was removed and stirring was continued for an additional hour at room temperature. The reaction was then quenched by the addition of water (50 mL). The reaction mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 68b as a yellow oil. Mass Spectrum (GCMS, ESI pos.): Calcd. for C10H11BrO2: 242.0 (M). found: 242.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])([O-:3])=[O:2].N1C=CN=C1.[C:31]([Si:35]([CH3:38])([CH3:37])Cl)([CH3:34])([CH3:33])[CH3:32]>O1CCCC1>[C:31]([Si:35]([CH3:38])([CH3:37])[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:17]=[CH:18][C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: O=[N+]([O-])c1cc(OCCCCCCCCO)ccc1-c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCOc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
8-(3-Nitro-4-phenylphenoxy)octan-1-ol (1.23 g, 3.5 mmol) and imidazole (408 mg, 6.0 mmol) were dissolved in tetrahydrofuran (15 mL) and a solution of tert-butyldimethylchlorosilane (750 mg, 5.0 mmol) in tetrahydrofuran (5 mL) was added thereto. After stirring the reaction mixture at room temperature for 18 hours, purified water was added to stop the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of ammonium chloride, and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain tert-butyldimethyl{[8-(3-nitro-4-phenylphenoxy)octyl]oxy}silane (1.38 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:4][C:3]=1[O:18][CH3:19].Cl[CH2:21][C:22]1[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:25][CH:26]=1>>[CH3:19][O:18][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[CH:6]=[CH:7][C:2]=1[O:1][CH2:21][C:22]1[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:25][CH:26]=1
Reactant: COc1cc(CCCC2OC(=O)NC2=O)ccc1O
Reactant: ClCc1csc(/C=C/c2ccccc2)n1
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1csc(/C=C/c2ccccc2)n1

Procedure:
In substantially the same manner as in Working Example 9, 5-[3-(4-hydroxy-3-methoxyphenyl)propyl]-2,4-oxazolidinedione was allowed to react with 4-chloromethyl-2-[(E)-styryl]thiazole to yield 5-[3-[3-methoxy-4-[2-[(E)-styryl]-4-thiazolylmethoxy]-phenyl]propyl]-2,4-oxazolidinedione. The product was recrystallized from chloroform-methanol to give colorless prisms, m.p.202-203° C.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([O:13][C:14](=[O:36])[CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][C:23]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][C:19]=2[N:18]=[C:17]1[CH2:33][CH2:34][CH3:35])([CH3:12])([CH3:11])[CH3:10].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:9]([O:13][C:14](=[O:36])[CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][C:23]([N:25]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])=[CH:24][C:19]=2[N:18]=[C:17]1[CH2:33][CH2:34][CH3:35])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: O=C(Cl)C1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)C3CCCC3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopentanecarbonyl chloride (43 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C29H37N3O3+H: 476, observed: 476.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]1[N:25]([CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23][N:22]2[CH2:32][CH2:33][CH2:34][CH2:35][CH:21]12>>[C:1]1([N:7]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:25]2[CH2:24][CH2:23][N:22]3[CH2:32][CH2:33][CH2:34][CH2:35][CH:21]3[CH2:20]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCN1CCN2CCCCC2C1
Reactant: COc1cc(Nc2ccccc2)cc(OC)c1OC
Product: COc1cc(N(C(=O)CCCN2CCN3CCCCC3C2)c2ccccc2)cc(OC)c1OC

Procedure:
The procedure is as for Example 2 using as substrate phenyl-(3,4,5-trimethoxyphenyl)amine and the compound obtained in Step B of Example 2.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10](/[CH:14]=[CH:15]/[CH:16]([C:21]3[CH:26]=[C:25]([Cl:27])[C:24]([F:28])=[C:23]([Cl:29])[CH:22]=3)[C:17]([F:20])([F:19])[F:18])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].[F:30][C:31]([F:37])([F:36])[CH2:32][C:33](O)=[O:34].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:27][C:25]1[CH:26]=[C:21]([CH:16]([C:17]([F:19])([F:20])[F:18])/[CH:15]=[CH:14]/[C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[N:5]([C:3](=[O:4])[CH2:2][NH:1][C:33](=[O:34])[CH2:32][C:31]([F:37])([F:36])[F:30])[CH:6]=[CH:7]3)[CH:22]=[C:23]([Cl:29])[C:24]=1[F:28]
Reactant: NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Reactant: O=C(O)CC(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC(F)(F)F)NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a stirred solution of (E)-2-amino-1-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl) ethanone (0.04 g, 0.09 mmol) in CH2Cl2 (5.0 ml) was added 3,3,3-trifluoropropanoic acid (17.5 mg, 0.136 mmol), PyBOP (70 mg, 0.135 mmol) and DIPEA (29 mg, 0.225 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with CH2Cl2, and the CH2Cl2 layer was washed with water and saturated brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography (SiO2, 100-200 mesh; 10% ethyl acetate/petroleum ether) to afford the title compound as an off-white solid (30 mg, 60%): mp 121-126° C.; 1H NMR (400 MHz, CDCl3) δ 8.33 (br, 1H), 7.59 (s, 1H), 7.45 (m, 4H), 6.72 (d, J=3.6 Hz, 3H), 6.39 (m, 1H), 4.71 (t, J=7.2 Hz, 2H), 4.15 (m, 1H), 3.51 (m, 1H), 3.28 (m, 1H); ESIMS m/z 553.06 ([M−H]−).
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-])=[O:2].[O:6]1[CH2:10][CH:9]=[CH:8][CH2:7]1>>[CH3:5][C:4]1[C@H:8]2[CH2:7][O:6][CH2:10][C@H:9]2[O:2][N:1]=1
Reactant: C1=CCOC1
Reactant: CC[N+](=O)[O-]
Product: CC1=NO[C@@H]2COC[C@H]12

Procedure:
Intermediate IV-1: Starting from nitroethane and 2,5-dihydro-furan, the product (3aS,6aS)-rel-3-methyl-3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazole was obtained as a pale yellow solid.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].Cl[C:6]1[N:15]2[CH:16]=[N:17][N:18]=[C:14]2[C:13]2[CH:12]=[C:11]([O:19][CH3:20])[C:10]([O:21][CH3:22])=[CH:9][C:8]=2[N:7]=1>>[CH2:1]([O:4][C:6]1[N:18]2[N:17]=[CH:16][N:15]=[C:14]2[C:13]2[CH:12]=[C:11]([O:19][CH3:20])[C:10]([O:21][CH3:22])=[CH:9][C:8]=2[N:7]=1)[CH:2]=[CH2:3]
Reactant: COc1cc2nc(Cl)n3cnnc3c2cc1OC
Reactant: C=CCO
Product: C=CCOc1nc2cc(OC)c(OC)cc2c2ncnn12

Procedure:
To 65 ml. of allyl alcohol cooled to room temperature is added 2.8 g. of sodiuom followed by addition of an additional 120 ml. of allyl alcohol. To the resulting mixture at room temperature is added 15.0 g. of 5-chloro-8,9-dimethoxy-1,2,4-triazolo[4,3-c]quinazoline. The resulting precipitate is filtered off, washed with diethyl ether, dissolved in methylene chloride, washed with water, dried and evaporated in vacuo to dryness. The residue is twice crystallized from ethanol after treatment with charcoal to obtain 5-allyloxy-8,9-dimethoxy-1,2,4-triazolo[1,5-c]quinazoline, m.p. 189°-191° C.
Reaction SMILES: [O:1]([C:8]1[C:9]([OH:18])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:20][C:21](=[O:40])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33](Br)[CH:32]=2)=[CH:26][C:25]=1[CH3:39]>>[CH3:39][C:25]1[CH:26]=[C:27]([O:30][C:31]2[CH:32]=[C:33]([N:10]3[CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:9]3=[O:18])[CH:34]=[C:35]([CH3:37])[CH:36]=2)[CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][C:21]([OH:40])=[O:20]
Reactant: Oc1ncc(C(F)(F)F)cc1Oc1ccccc1
Reactant: COC(=O)CCc1ccc(Oc2cc(C)cc(Br)c2)cc1C
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(-n2cc(C(F)(F)F)cc(Oc3ccccc3)c2=O)c1

Procedure:
The title compound is prepared according to Example 8 by using 3-phenoxy-5-trifluoromethyl-pyridin-2-ol and 3-[4-(3-bromo-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester to afford 37 mg (7%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H24O5NF3 523, found 524 (M+1, 100%).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[C:9]([CH2:14]O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O.O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:1]([C:4]1[C:13]2[C:8](=[C:9]([CH2:14][Cl:18])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nccc2c(CO)cccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)c1nccc2c(CCl)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-iso-Propyl-5-hydroxymethylisoquinoline (6.5 g) was dissolved in 50 ml of chloroform and 6.5 ml of phosphorus oxychloride was added dropwise under ice cooling. The mixture was stirred at room temperature for 1 hour. Water (50 ml) was added to the reaction mixture, and it was made weakly alkaline with potassium carbonate. The chloroform layer was washed in water, and dried. The solvent was distilled off under reduced pressure to afford 7.1 g of 1-isopropyl-5-chloromethylisoquinoline as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH:17](OC)(OC)OC>CO.O>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=1[OH:1]
Reactant: COC(OC)OC
Reactant: O=C(O)c1ccc(O)cc1O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(O)cc1O
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a solution in methanol (50 mL) of 2,4-dihydroxybenzoic acid (1.54 g, 10 mmol) was added sulfuric acid (0.5 mL) and trimethyl orthoformate (1.6 mL, 15 mmol) and the reaction mixture was stirred at reflux for 36 hours. The reaction mixture was cooled to ambient temperature and diluted with water. The methanol was evaporated in vacuo. The residue was diluted with water and extracted with ether (3×). The combined ether extracts were washed with saturated aqueous sodium bicarbonate (2×) and brine, dried, filtered and concentrated in vacuo to give 2,4-dihydroxybenzoic acid methyl ester (1.34 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:5])=[O:4]
Reactant: CCCCCCO
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCOS(=O)(=O)C(F)(F)F
Reaction time: 0.08 h
Yield: 47.5 %

Procedure:
Under a dry nitrogen atmosphere, a solution of 18.1 g (177 mmol) 1-hexanol (dried over 3A sieves) and 14.1 g (178 mmol) pyridine (dried over 3A sieves) in 80 mL carbon tetrachloride (dried over 3A sieves) was added over 1.25 hr to a solution of 50 g (180 mmol) trifluoromethanesulfonic anhydride in 50 mL dry carbon tetrachloride, while cooling in an ice-waterbath. After an additional 5 min, the mixture was filtered, and the solids were washed with cold carbon tetrachloride. The filtrate was evaporated, and the residue was distilled, giving 19.7 g (47.5%) of hexyl trifluoromethanesulfonate: bp 35°-36° C. (0.35-0.40 torr).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[N:19]=1)=[O:17])[CH2:13][CH2:14][CH3:15])=O)(C)(C)C>Cl.CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([C:9]2([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:17])=[N:19][C:20]=1[Cl:25]
Reactant: CCCC1(C(=O)c2ccc(Cl)c(Cl)n2)CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCCC1(C(=O)c2ccc(Cl)c(Cl)n2)CCCN1
Yield: 72 %

Procedure:
A solution of 2-(5,6-dichloro-pyridine-2-carbonyl)-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.280 g, 0.725 mmol) in 1N HCl in MeOH (3 mL) was stirred at ambient temperature under nitrogen for 20 hours. The reaction mixture was concentrated in vacuo and the resulting residue was purified by chromatography (silica, 0 to 30% MeOH in DCM) to yield (5,6-dichloro-pyridin-2-yl)-(2-propyl-pyrrolidin-2-yl)-methanone (0.167 g, 0.522 mmol, 72%) as a yellow solid and as a monohydrochloride salt, MS=287 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][N:7]([CH3:29])[C:8]1[N:28]=[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:17]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][C:20]=3[C:25](O)=[O:26])=[O:18])=[CH:15][N:10]2[N:9]=1>>[CH3:6][N:7]([CH3:29])[C:8]1[N:28]=[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:17]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][C:20]=3[C:25]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:26])=[O:18])=[CH:15][N:10]2[N:9]=1
Reactant: CN(C)c1nc2ccc(NC(=O)c3c(C(=O)O)cnn3C)cn2n1
Reactant: C1CCNC1
Product: CN(C)c1nc2ccc(NC(=O)c3c(C(=O)N4CCCC4)cnn3C)cn2n1

Procedure:
Using pyrrolidine and 5-(2-dimethylamino-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Light brown solid (120 mg, 61%). MS: m/z=383 (M+H+).