Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]O)=[CH:27][CH:26]=1>C(#N)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: COc1ccc(CO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: COc1ccc(CNc2ccc(Cl)cc2C#N)cc1
Temperature: 70 °C
Yield: 98.8 %

Procedure:
A solution of 2-amino-5-chlorobenzonitrile (0.50 g, 3.28 mmol) in 2 mL of acetonitrile was treated with p-toluenesulfonic acid monohydrate. The reaction mixture was heated to 70° C. with stirring. 4-Methoxybenzyl alcohol (0.50, 3.61 mmol) in acetonitrile (1 mL) was added dropwise via syringe keeping the reaction temperature at 70° C. The reaction was stirred at 70° C. for 12 h, allowed to cool to ambient temperature, and concentrated in vacuo. Chromatography afforded 1 (0.884 g, 99%) as light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.36 (d, J=2.4 Hz, 1H), 7.27 (dd, J=9 Hz, 1H), 7.24 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 6.58 (d, J=9 Hz, 1H), 4.95 (br S, 1H), 4.33 (d, J=5.4 Hz, 2H), 3.81 (s, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[O:15][CH2:14][C:11]([CH2:16][CH2:17][CH3:18])([CH2:12][O:13]2)[CH:10]([C:19]([F:22])([F:21])[F:20])[O:9]3)=[CH:4][CH:3]=1.[C:23]([C:27]12CO[C:30](C3C=CC(C#CCOC)=CC=3)(OC1)[O:29][CH2:28]2)(C)(C)C>>[CH3:30][O:29][CH2:28][C:27]#[C:23][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[O:13][CH2:12][C:11]([CH2:16][CH2:17][CH3:18])([CH2:14][O:15]2)[CH:10]([C:19]([F:21])([F:22])[F:20])[O:9]3)=[CH:4][CH:3]=1
Reactant: CCCC12COC(c3ccc(I)cc3)(OC1)OC2C(F)(F)F
Reactant: COCC#Cc1ccc(C23OCC(C(C)(C)C)(CO2)CO3)cc1
Product: CCCC12COC(c3ccc(C#CCOC)cc3)(OC1)OC2C(F)(F)F

Procedure:
1-[4-(3-Methoxyprop-1-ynyl)phenyl]-4-n-propyl-3-trifluoromethyl-2,6,7-trioxabicyclo[2,2,2]octane was prepared from 1-(4-iodophenyl)-4-propyl-3-trifluoromethyl-2,6,7-trioxabicyclo[2,2,2]octane and methyl propargyl ether using the methodology described in Example 3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[O:15][CH:14]=[N:13][CH:12]=1)[C:5]([OH:7])=O.C(OC([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][CH:30]2[CH2:32][CH2:31]2)[CH2:25][CH2:24]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:30]1([N:29]([CH:26]2[CH2:27][CH2:28][NH:23][CH2:24][CH2:25]2)[C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)=[C:2]([F:1])[CH:3]=2)[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Reactant: O=C(O)c1ccc(-c2cnco2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(-c2cnco2)c(F)c1)N(C1CCNCC1)C1CC1

Procedure:
The title compound is prepared from 3-fluoro-4-oxazol-5-yl-benzoic acid and 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester following a procedure analogous to that described for Intermediate 1. The deprotection step is accomplished by using trifluoroacetic acid in dichloromethane. LC (method 2): tR=0.98 min; Mass spectrum (ESI+): m/z=330 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([SH:8])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[O:26][C@H:21]2[C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([S:8][C@@H:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)[C@@H:21]([OH:26])[C:22]([O:24][CH3:25])=[O:23])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1S
Reactant: COC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)[C@H](O)[C@@H](Sc1cc(Cl)ccc1[N+](=O)[O-])c1ccc(OC)cc1

Procedure:
In a 25 ml flask equipped with thermometer and nitrogen admission, there are introduced 26 mg of zinc acetate dihydrate, 948 mg of 5-chloro-2-nitrothiophenol and 5 ml of toluene. To the suspension are added dropwise, within 5 mn, a solution of 1.093 g of methyl (-) (2R,3S) 3-(4-methoxyphenyl)-2,3-epoxy-propionate in 9 ml of toluene at 25° C. The temperature rises to 29° C., whilst stirring is maintained for 45 mn. The mixture is evaporated in vacuo, and a yellow oil is obtained, which is used as it is in the subsequent example.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].C([Li])CCC.[NH2:18][C:19]1[N:30]=[CH:29][C:28]([Br:31])=[CH:27][C:20]=1[C:21](N(OC)C)=[O:22]>C1COCC1>[NH2:18][C:19]1[C:20]([C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][C:9]([F:12])([F:11])[F:10])=[O:22])=[CH:27][C:28]([Br:31])=[CH:29][N:30]=1
Reactant: FC(F)(F)Oc1ccccc1Br
Reactant: CON(C)C(=O)c1cc(Br)cnc1N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ncc(Br)cc1C(=O)c1ccccc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 51.7 %

Procedure:
To a flame-dried 100 ml round bottomed flask was added 1-bromo-2-(trifluoromethoxy)benzene (2.39 g, 9.9 mmol). The flask was fitted with a rubber septum, purged with nitrogen then charged with anhydrous THF (20 ml). The solution was cooled to −78° C. for 10 min, then a 2.5 M solution of n-butyl lithium in hexanes (3.9 ml, 9.8 mmol) was added dropwise over 3 minutes. The resulting solution was stirred at −78° C. for 40 minutes under nitrogen, then a solution of 739 mg (2.84 mmol) of 2-amino-5-bromo-N-methoxy-N-methyl-nicotinamide in 5 ml of THF was added dropwise over 3 minutes. The resulting red solution was allowed to warm to room temperature over 5 hours, then the reaction was quenched by addition of 10 ml of a saturated aqueous solution of ammonium chloride. Ethyl acetate (50 ml) was added, and the layers were separated. The aqueous fraction was extracted three times with ethyl acetate, and the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes gave 530 mg (52%) of (2-amino-5-bromo-pyridin-3-yl)-(2-trifluoromethoxy-phenyl)-methanone as a yellow-orange solid. 1H-NMR (CDCl3) δ=8.29 (d, 1H), 7.60 (m, 2H,), 7.45 (t, 1H), 7.42 (m, 3H), 1.79 (br. s, 2H); MS m/z: 361 [MH]+.
Reaction SMILES: [Br-].[O:2]=[C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:4]1.O1CCCC1.CC(C)([O-])C.[K+].[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([N+:51]([O-:53])=[O:52])=[C:47]([CH:50]=1)[CH:48]=O>O>[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([N+:51]([O-:53])=[O:52])=[C:47]([CH:50]=1)[CH:48]=[C:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:3](=[O:2])[O:4]1
Reactant: O=C1OC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1OC(=Cc2cc(Cl)ccc2[N+](=O)[O-])c2ccccc21
Reaction time: 0.08 h
Yield: 49.7 %

Procedure:
To a mixture of (3-oxo-1,3-dihydro-2-benzofuran-1-yl)(triphenyl) phosphonium bromide (5.1 g) and tetrahydrofuran (50 mL) were added potassium tert-butoxide (1.3 g) and 5-chloro-2-nitro benzoaldehyde (1.0 g) at room temperature under an argon atmosphere, followed by stirring for 5 minutes. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3-(5-chloro-2-nitrobenzylidene)-2-benzofuran-1(3H)-one (808 mg).
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[CH2:8]([CH:10]1[O:12][CH2:11]1)Cl>>[O:12]1[CH2:11][CH:10]1[CH2:8][N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1
Reactant: ClCC1CO1
Reactant: c1cn[nH]c1
Agent: [Na+]
Agent: [OH-]
Product: c1cnn(CC2CO2)c1

Procedure:
Compounds of formula 2. Reaction of sodium hydroxide with appropriate 1H-pyrazole starting material in neat epichlorohydrin at room temperature furnishes the corresponding 1-oxiranylmethyl-1H-pyrazole compound. To this product is added distilled water and an excess of secondary amine. The reaction mixture is then heated at moderate to high temperature (˜80° C.) for several hours. After suitable work-up (typically column chromatography), the corresponding 1-amino-3-(pyrazol-1-yl)-propan-2-ol compound is isolated.
Reaction SMILES: [C:1](Br)#[C:2][CH2:3][CH3:4].[C:6]1([CH:13]=[CH:12][C:10]([OH:11])=[CH:9][CH:8]=1)[OH:7].C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([O:7][C:6]1[CH:13]=[CH:12][C:10]([OH:11])=[CH:9][CH:8]=1)[C:2]#[C:3][CH3:4]
Reactant: Oc1ccc(O)cc1
Reactant: CCC#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC#CCOc1ccc(O)cc1
Yield: 24.7 %

Procedure:
To a solution containing butynyl bromide (1 g, 7.5 mmol), hydroquinone (827 mg, 7.5 mmol), and K2CO3 (1.04 g, 7.5 mmol) was refluxed for 10 h. Solvent was removed in vacuo and the crude product was dissolved in EtOAc and partitioned with water. Organic layer was separated and washed with water and dried over anhydrous Na2SO4. The solvent was removed in vacuo to obtain the crude product (0.3 g, 25%), which was used for the next step without further purification; LCMS 99%, m/z 162.2 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-(4-fluorophenyl)propionic acid (4.75 g, 28.2 mmol) in toluene (130 mL) and methanol (20 mL) was added trimethylsilyldiazomethane (2M solution in hexane, 16.24 mL, 32.5 mmol). The mixture was allowed to stir for 1 hour and gas evolution was observed initially. After 1 hour, the mixture became homogeneous and was quenched via addition of 3.5 mL of acetic acid. The mixture was concentrated in vacuo, and purified via column chromatography on a Biotage 65i column eluting with 0% ethyl acetate in hexanes (1 CV) followed by a gradient to 50% ethyl acetate in hexanes (over 7 CV) to furnish the desired product. 1H NMR (CDCl3, 500 MHz) δ 7.16 (dd, J=8.0 Hz, 5.6 Hz, 2H), 6.97 (t, J=8.5 Hz, 2H), 3.66 (s, 3H), 2.92 (t, J=7.5 Hz, 2H), 2.61 (t, J=7.7 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[O:3]1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([O:30][CH3:31])[CH:21]=1.CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:31][O:30][C:22]1[CH:21]=[C:20]([NH:19][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)[CH:10]=2)[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: CC1(C)OB(c2cccc(C(=O)O)c2)OC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC(=O)c2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1OC
Temperature: 25 °C
Reaction time: 38 h
Yield: 21.9 %

Procedure:
A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (600 mg, 2.4 mmol), methyl 4-amino-2-methoxybenzoate (362 mg, 2 mmol), EDCI (764 mg, 4 mmol) and DMAP (488 mg, 4 mmol) in 10 mL of DMF was stirred at room temperature for 38 hours. The mixture was poured into water and extracted with EtOAc (3×15 mL). The organic layer was washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with (petroleum ether:EtOAc=4:1) to give methyl 2-methoxy-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)benzoate (180 mg, 22%) as solid. 1H NMR (300 MHz, CD3OD): δ 8.31 (s, 1H), 8.05-8.01 (m, 1H), 7.97-7.94 (m, 1H), 7.81 (d, 1H, J=8.7 Hz), 7.71 (d, 1H, J=1.8 Hz), 7.53 (d, 1H, J=7.5 Hz), 7.37 (dd, 1H, J1=8.7 Hz, J2=2.1 Hz), 3.91 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C[Al](C)C.[CH3:10][C:11]1[C:12](=[O:31])[C:13]([C:27](OC)=[O:28])=[N:14][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:16]=1>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:27]([C:13]1[C:12](=[O:31])[C:11]([CH3:10])=[CH:16][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=2)[N:14]=1)=[O:28]
Reactant: CNOC
Reactant: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(C)c1=O
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(C)c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a stirred suspension of N,O-dimethylhydroxylamine hydrochloride (0.468 g, 4.8 mmol) in dichloromethane (5 mL) was added trimethylaluminum (2.4 mL, 4.8 mmol, 2 M solution in toluene) dropwise at 0° C. Following addition, the suspension was stirred at 0° C. for 10 min then at room temperature for 30 min to provide a homogenous solution. The flask was then re-cooled in an ice bath. In a separate flask, methyl 5-methyl-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (0.500 g, 1.6 mmol) was dissolved in dichloromethane (5 mL) and added dropwise and allowed to stir for 2 h. The reaction was quenched with water (5 mL) and 2 N HCl aqueous solution (2 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to provide N-methoxy-N,5-dimethyl-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (0.535 g, 98%) as a yellow solid.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14]>C(O)(=O)C.O>[OH:3][N:1]=[C:12]([C:11](=[O:17])[CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH3:5])[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=N[O-]
Reactant: COCCCCC(=O)CC(=O)OC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCCCC(=O)C(=NO)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.4 %

Procedure:
To an aqueous solution (20 ml) of sodium nitrite (2.20 g) was added dropwise a solution of methyl 7-methoxy-3-oxoheptanoate (5.00 g) obtained in Reference Example 359 in acetic acid (5 ml) under ice-cooling, and the reaction mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (5.91 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([OH:14])=O.[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[NH:24][CH2:23][CH2:22][CH2:21]2>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:15])[CH2:21][CH2:22][CH2:23]1)=[O:14]
Reactant: O=C(O)CSc1nc2ccccc2s1
Reactant: Cc1cccc2c1NCCC2
Product: Cc1cccc2c1N(C(=O)CSc1nc3ccccc3s1)CCC2
Yield: 39 %

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)acetic acid and 8-methyl-1,2,3,4-tetrahydroquinoline to yield 46 as a white solid (39%): MS m/z: 355 (M+H)+. Anal. Calcd. For, C19H18N2OS2: C, 64.38; H, 5.12; N, 7.90; S, 18.09. Found: C, 64.37; H, 5.02; N, 7.74; S, 18.10.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH2:12][CH3:13])=[C:9]([O:14][CH3:15])[C:8]([O:16][CH2:17][CH3:18])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:19].[Na+]>O.[Cu]>[CH2:12]([O:11][C:10]1[C:2]([OH:19])=[C:3]([CH:7]=[C:8]([O:16][CH2:17][CH3:18])[C:9]=1[O:14][CH3:15])[C:4]([OH:6])=[O:5])[CH3:13]
Reactant: [OH-]
Reactant: CCOc1cc(C(=O)O)c(Br)c(OCC)c1OC
Agent: [Cu]
Agent: [Na+]
Solvent: O
Product: CCOc1cc(C(=O)O)c(O)c(OCC)c1OC
Temperature: 120 °C

Procedure:
68 g of 2-bromo-3,5-diethoxy-4-methoxybenzoic acid prepared in Referential Example 4 was suspended in 260 ml of water and 32 g of caustic soda and 0.88 g of copper powder were added thereto. The mixture was heated at 120° C. for 3 hr while stirring, and then cooled. Carbon was added thereto, and the mixture was filtered through Celite. The filtrate was neutralized with 140 ml of 6 N hydrochloric acid and 1 l of chloroform was added thereto. The mixture was subjected to liquid-liquid separation. The organic phase was washed with water, dried and then concentrated to prepare 53 g of the crude product (ocherous solid).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH2:18]>>[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH:18][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CN(C)CCCN
Product: CCCCCCC/C=C/C(=O)NCCCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N,N-dimethylpropane-1,3-diamine as starting materials to give the aimed compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([OH:14])=[O:13].[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6]([C:12]([O:14][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:3][CH:4]=2)=[O:13])=[N:7]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: COc1ccc2[nH]nc(C(=O)O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)c(C(=O)OCc1ccccc1)nn2Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A suspension of 5-methoxy-1H-indazole-3-carboxylic acid (21.5 g; 0.11 mol) and 60% NaH (10.5 g; 0.44 mol) in N,N-dimethylformamide (DMF) (200 ml) was stirred at 70° C. for 1 hour. Benzyl chloride (32.9 g; 0.26 mol) was then added slowly to the suspension and the mixture was stirred at 70° C. for 4 hours. The reaction was stopped by cooling the mixture to room temperature and pouring the mixture into water and ice. The product was extracted with ethyl acetate (3×250 ml). The combined organic phases were concentrated under reduced pressure. The crude residue thus obtained was purified by successive crystallizations from 95° ethanol, to give 18 g of benzyl 1-benzyl-5-methoxy-1H-indazole-3-carboxylate with a melting point of 107-109° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])[NH:8][C:9]=1[CH3:10])[CH2:2][CH2:3][CH3:4].[C:21](O)(=[O:24])[C:22]#[CH:23].N1(C(N2C=CN=C2)=O)C=CN=C1>>[CH2:1]([C:5]1[NH:6][C:7]2[N:8]([C:9]=1[CH3:10])[C:21](=[O:24])[CH:22]=[CH:23][C:11]=2[C:12](=[O:13])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#CC(=O)O
Reactant: CCCCc1nc(CC(=O)c2ccc(F)cc2)[nH]c1C
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCCCc1[nH]c2c(C(=O)c3ccc(F)cc3)ccc(=O)n2c1C

Procedure:
The compounds are prepared as described in example 10 with 200 mg (0.73 mmol) of 2-(4-butyl-5-methyl-1H-imidazo-2-yl)-1-(4-fluorophenyl)ethanone (example XXVI), 77 mg (1.09 mmol) of propiolic acid and 212 mg (1.31 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:11][CH:12]([CH3:16])[C:13]([O-])=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:13](=[O:14])[CH:12]([SH:11])[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCc1ccccc1
Reactant: CC(S)C(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(S)C(=O)OCCCc1ccccc1

Procedure:
Into a 100 ml reaction flask equipped with reflux condenser, hot plate (with stirring apparatus contained within) and spin bar are placed 13.6 grams phenylpropyl alcohol; 4.0 grams of 2-mercaptopropionate acid; and 0.1 grams of para-toluene sulphonic acid. The reaction mass is maintained at reflux for a period of 9 hours with stirring. At the end of the 9 hour period, the reaction mass is cooled and fractionally distilled on a micro distillation apparatus yielding the compound having the structure: ##STR64## (as confirmed by GLC, mass spectral, NMR and IR analyses).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([C:20]4([O:27][CH3:28])[CH2:25][CH2:24][O:23][CH2:22][CH:21]4[OH:26])[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:29].CI.[CH2:32]1OCCOCCOCCOCCOC1>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([C:20]4([O:27][CH3:28])[CH2:25][CH2:24][O:23][CH2:22][CH:21]4[O:26][CH3:32])[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:29]
Reactant: COC1(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCOCC1O
Reactant: C1COCCOCCOCCOCCO1
Solvent: CI
Product: COC1COCCC1(OC)c1cccc(OCc2ccc3c(ccc(=O)n3C)c2)c1
Yield: 78 %

Procedure:
Using the methylation procedure described in the portion of Example 1 which is concerned with the preparation of starting materials, (3RS,4SR)-4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)phenyl]-3-hydroxy-4-methoxytetrahydropyran was reacted with methyl iodide in the presence of 15-crown-5 to give (3RS,4SR)-4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)phenyl]-3,4-dimethoxytetrahydropyran in 78% yield, as a glass.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20]>O1CCCC1>[N+:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][O:21][C:19](=[O:20])[O:10][C:3]2[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=2)=[CH:28][CH:27]=1)([O-:31])=[O:30]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To an ice cooled solution, under argon, of 7.3 g of p-nitrophenol and 7.5 ml of triethylamine in 36 ml of dry tetrahydrofuran, is added, dropwise, a solution of 10.78 g of p-nitrobenzyl chloroformate in 18 ml of dry tetrahydrofuran. The reaction mixture, a suspension, is stirred at room temperature overnight. The formed solid is collected, washed with water and dried to give 5.9 g of the desired product.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].Cl.[CH3:13][N:14]1[C:18]2=[N:19][C:20]([N:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)=[CH:25][C:24]3=[O:39])=[CH:21][CH:22]=[C:17]2[C:16]2[CH2:40][NH:41][CH2:42][CH2:43][C:15]1=2>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:8]([N:41]1[CH2:42][CH2:43][C:15]2[N:14]([CH3:13])[C:18]3[C:17]([C:16]=2[CH2:40]1)=[CH:22][CH:21]=[C:20]([N:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[N:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=2)=[CH:25][C:24]1=[O:39])[N:19]=3)(=[O:10])[CH3:9]
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc31)CNCC2
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc3n2C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
Triethylamine (40 μL, 0.28 mmol), DMAP (3.5 mg, 0.028 mmol) and acetyl chloride (15 μL, 0.21 mmol) were added to a solution of 1-(9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridin-2-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one hydrochloride (80 mg, 0.14 mmol) in CH2Cl2 (8 mL) and the resulting solution was stirred at ambient temperature for 3 h under N2. The resulting solution was concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes, increased to 0:100 over 20 column volumes and held for 14 column volumes) gave the title compound (51 mg, 77%) as a yellow solid and a mixture of rotomers: mp 238-242° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.20 (d, J=2.0 Hz, 1H), 8.50 (dd, J=8.0, 2.0 Hz, 1H), 8.11-8.04 (m, 3H), 7.44-7.37 (m, 1H), 7.03 (d, J=1.5 Hz, 1H), 6.86-6.83 (m, 1H), 4.73-4.68 (m, 2H), 3.90-3.83 (m, 2H), 3.71-3.69 (m, 3H), 3.01-2.86 (m, 2H), 2.16-2.12 (m, 3H); ESI MS m/z 468 [M+H]+; HPLC (Method A)>99% (AUC), tR=17.8 min.