Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:21][C@:20]3([CH3:34])[C@@H:22]([CH3:33])[CH2:23][CH2:24][C@H:25]4[C:26]([CH3:32])([CH3:31])[C@@H:27]([OH:30])[CH2:28][CH2:29][C@@:19]34[O:18][C:11]=2[C:12]2[CH2:13][NH:14][CH2:15][C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)(Cl)Cl>[C:41]([N:14]1[CH2:13][C:12]2[C:11]3[O:18][C@@:19]45[CH2:29][CH2:28][C@H:27]([OH:30])[C:26]([CH3:32])([CH3:31])[C@@H:25]4[CH2:24][CH2:23][C@H:22]([CH3:33])[C@@:20]5([CH3:34])[CH2:21][C:10]=3[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][C:16]=2[CH2:15]1)(=[O:43])[CH3:42]
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c4c(cc(OCc5ccccc5)c2C[C@]13C)CNC4
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1Cc2cc(OCc3ccccc3)c3c(c2C1)O[C@@]12CC[C@H](O)C(C)(C)[C@@H]1CC[C@H](C)[C@@]2(C)C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a solution of Compound (33a) (47 mg, 0.10 mmol) in 5.0 ml of chloroform was added a sodium carbonate aqueous solution (prepared from 14 mg (0.10 mmol) of sodium carbonate and 5.0 ml of water). Under ice-cooling, to the mixture was added 8 μl (0.12 mmol) of acetyl chloride dissolved in 0.3 ml of chloroform in a single portion with vigorous stirring. After the reaction mixture was stirred for 30 min and warmed up to room temperature, it was extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size A; ethyl acetate) to give 47 mg (92%) of Compound (33b).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][N:10]=1)[C:5](Cl)=[O:6].CN(C=O)C.[NH2:20][C:21]1[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=1[OH:31].C(N(CC)CC)C>O>[C:27]([C:25]1[CH:24]=[CH:23][C:22]([OH:31])=[C:21]([NH:20][C:5](=[O:6])[C:4]2[C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][N:10]=[C:2]([Cl:1])[CH:3]=2)[CH:26]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1ccc(O)c(N)c1
Reactant: O=C(Cl)c1cc(Cl)ncc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(O)c(NC(=O)c2cc(Cl)ncc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.66 g of 2-chloro-5-trifluoromethyl isonicotinic acid and 4 ml of thionyl chloride was heated to reflux for 2.5 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to give 2-chloro-5-trifluoromethyl isonicotinic acid chloride. A mixture of the resultant 2-chloro-5-trifluoromethyl isonicotinic acid chloride and 4 ml of DMF was added dropwise to a mixture of 0.48 g of 2-amino-4-tert-butylphenol, 0.59 g of triethylamine and 4 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for one hour, and stirred while heating at 50° C. for one hour. The mixture was cooled to room temperature, and water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.75 g of N-(5-tert-butyl-2-hydroxyphenyl)-2-chloro-5-trifluoromethylisonicotinamide.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:6][CH2:7][NH2:8].C(O[CH:16](OCC)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]=[CH2:28])=[CH:21][CH:20]=1)C.O>C(O)CCC.Cl>[ClH:1].[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH:16]2[C:9]3[C:5](=[CH:4][C:3]([OH:2])=[C:11]([OH:12])[CH:10]=3)[CH2:6][CH2:7][NH:8]2)=[CH:20][CH:21]=1)[CH:27]=[CH2:28]
Reactant: NCCc1ccc(O)c(O)c1
Reactant: C=CCOc1ccc(OCC(OCC)OCC)cc1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: C=CCOc1ccc(OCC2NCCc3cc(O)c(O)cc32)cc1
Yield: 94.8 %

Procedure:
A solution of 3,4-dihydroxyphenethylamine hydrochloride (3.3 g) and (4-allyloxyphenoxy)acetaldehyde diethyl acetal (5.2 g) in a mixture of n-butanol (45 ml), water (12 ml) and concentrated hydrochloric acid (2 drops) was refluxed for 4 hours. After the reaction, the reaction mixture was concentrated to dryness. The residue was crystallized by adding acetone, and the crystals were recrystallized from a mixed solvent of 99% ethanol and ether to give 1-(4-allyloxyphenoxy)methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (6.0 g), mp 114° to 116° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1)=[CH:6][NH:7]2.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)=[CH:6][NH:7]2
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c[nH]c12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(O)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.4 %

Procedure:
A dichloromethane solution (5 ml) of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (249 mg, 0.76 mmol) was cooled to −10° C. in a methanol-ice bath. A 1N boron tribromide (4.08 ml) was added thereto, and the mixture was stirred at room temperature for 6 hours. Ice water and dichloromethane were added to the reaction mixture, and the resultant insoluble matter was collected by filtration. The filtrate was separated and the organic layer was concentrated under reduced pressure. The residue and the substance remaining on the filter were mixed, and the mixture was purified by silica gel column chromatography (dichloromethane:methanol=60:1→25:1). The purified product was concentrated under reduced pressure. Ethyl acetate was added to crystallize the residue. The crystals were collected by filtration, washed with ethyl acetate, and then dried to thereby obtain 220 mg of powdery pale yellow 5-fluoro-3-(4-hydroxyphenyl)-8-propoxy-1H-quinolin-4-one (yield: 92%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]([NH:35][C:36]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:43])=[N:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][NH:11][C:12]([NH:35][C:36]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:43])=[N:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1
Reactant: COc1cc2c(N=C(NCCNC(=O)OC(C)(C)C)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(N=C(NCCN)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
A mixture of N-(2-tert-butoxycarbonylaminoethyl)-N′-(2,6-dimethylphenyl)-N″-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]guanidine (0.31 g), trifluoroacetic acid (1 ml) and methylene chloride (1 ml), was stirred at ambient temperature for 20 minutes. The reaction mixture was evaporated and the residue was dissolved in water (4 ml) and the solution was basified to pH10 by the addition of 10N aqueous potassium hydroxide solution. The mixture was extracted with a 19:1 mixture of methylene chloride and methanol. The organic extract was dried over magnesium sulphate and evaporated. There was thus obtained the title compound (0.16 g); NMR Spectrum: (DMSOd6) 1.2–1.4 (m, 2H), 1.65–1.94 (m, 5H),2.12 (s, 3H), 2.21 (s, 6H), 2.7–2.9 (m, 4H), 3.22 (br s, 3H), 3.4–3.8 (m, 4H), 3.91 (d, 2H), 7.0 (s, 1H), 7.13 (s, 3H), 8.4 (s, 1H); Mass Spectrum: M+H+ 492.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([CH2:20][CH2:21][CH2:22][S:23][CH:24]([C:28](O)=[O:29])[C:25](O)=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[OH:29][C:28]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:25](=[O:26])[C:24]=1[S:23][CH2:22][CH2:21][CH2:20][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)C(SCCCc1ccccc1)C(=O)O
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Product: O=c1oc(-c2ccccc2)cc(O)c1SCCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 1-Phenyl-1-(trimethylsilyloxy)ethylene (0.922 g, 4.83 mmol) and diethyl ester of [(3-phenylpropyl)thio]propanedioic acid (1.00 g, 3.22 mmol). m.p. 114-116° C.; 1H NMR (400 MHz, DMSO-d6) δ1.74 (m, 2 H), 2.71 (m, 4 H), 6.82 (m, 1 H), 7.16 (m, 3 H), 7.25 (m, 2 H), 7.54 (m, 3 H), 7.81 (m, 2 H), 11.95 (bs, 1 H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[CH2:17].Cl>C(O)C.O>[N:21]1[CH:22]=[CH:23][C:18]([CH2:16][CH2:17][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:19][CH:20]=1
Reactant: C=Cc1ccncc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CCc1ccncc1)C(=O)OCC
Yield: 46.4 %

Procedure:
To a solution of diethyl malonate (9.6 g, 0.06mol) in 20 ml of absolute ethanol was added sodium ethoxide (4.1 g) portionwise at room temperature while stirring and the mixture was further stirred for 4 hours followed by dropwise addition of 4-vinylpyridine (2.1 g, 0.02 mol). The mixture was then stirred overnight. Evaporation of ethanol under reduced pressure gave a residue to which was added water followed by neutralization with 3N hydrochloric acid. The mixture was extracted with ethyl acetate. The extracted liquid was treated according to conventional techniques. Evaporation of solvent yielded a residue which was subjected to purification using column chromatography on silica gel to afford diethyl 2-(pyridin-4-yl)ethylmalonate as an oil (2.46 g, 46%).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:14]=3[O:27]COC)[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].Cl>C1COCC1>[C:1]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:21])([CH3:20])[CH3:22])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:14]=3[OH:27])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COCOc1c(-c2cccc3sc(C(C)=O)cc23)cc(C(C)(C)C)cc1C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1cc2c(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3O)cccc2s1
Temperature: 50 °C

Procedure:
A slurry of 365 mg (0.859 mmol) of 2-acetyl-4-(2-methoxymethoxy-3,5-di-tert-butylphenyl)benzo[b]thiophene into a mixture of 5 mL of THF and 5 mL of aqueous 6N HCl was heated to 50° C. overnight. After cooling, the THF was evaporated and the aqueous solution was extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated under reduced pressure. The crude 2-acetyl-4-(2-hydroxy-3,5-di-tert-butylphenyl)benzo[b]thiophene was directly used in the next step. 1H-NMR (CDCl3), δ: 7.92 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.58 (t, J=7.4 Hz, 1H), 7.47 (d, J=2.6 Hz, 1H), 7.42 (d, J=2.3 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 5.03 (s, 1H), 2.57 (s, 3H), 1.48 (s, 9H), 1.34 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C@H:6]1[O:8][CH2:7]1.[CH2:16]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH2:24]([N:23]([CH2:7][C@H:6]([OH:8])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:2]=1[NH2:1])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1c(OC[C@@H]2CO2)cccc1[N+](=O)[O-]
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CO
Product: Nc1c(OC[C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 77.9 %

Procedure:
(S)-3-(2-Amino-3-nitrophenoxy)-1,2-epoxypropane (8.0 g, 38.1 mmol) was dissolved in 250 mL of methanol and treated with dibenzylamine (8.05 mL, 42.0 mmol, d=1.026). The mixture was stirred at reflux for 10 hours and then cooled to 0° C. The resulting orange precipitate was filtered and washed with cold methanol, then dried to yield 12.1 g (78%) of a pale orange solid that was pure by NMR and TLC analysis. The material was used without further purification. NMR.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O.[Cl:16]CCl>C(Cl)(=O)C(Cl)=O.CN(C=O)C>[O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([Cl:16])=[O:15]
Reactant: O=C(O)CCCCCN1C(=O)C=CC1=O
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a stirring solution of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoic acid (3.15 g, 14.9 mM) in 15 mL of dichloromethane, oxalyl chloride (1.61 mL, 17.9 mM) was added followed by one drop of DMF. The reaction was allowed to stir at room temperature for three hours. The reaction was concentrated in vacuo. The residue was dissolved in a one to one solution of heptane and dichloromethane and then concentrated in vacuo. This process was repeated two more times producing a solid #248 (3.43 g, 100%). 1H NMR (400 MHz, DMSO-d6): δ [7.02 (s, 2H), 3.43 (m, 2H), 2.53 (m, 1H), CH2.18 (m, 1H), 1.54 (m, 4H), 1.26 (m, 2H).]
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[NH:3][CH:2]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[N:1]1[CH:5]=[C:4]([CH2:6][N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[CH2:22][C:19]2[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=2)[NH:3][CH:2]=1
Reactant: COc1cccc(NCc2cnc[nH]2)c1
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cccc(N(Cc2ccncc2)Cc2cnc[nH]2)c1
Temperature: 40 °C
Reaction time: 72 h
Yield: 10 %

Procedure:
To a solution of (3H-imidazol-4-ylmethyl)-(3-methoxy-phenyl)-amine (0.05 g, 0.25 mmol, Example 186 step a) in 1,2-dichloroethane (2 ml) were added pyridine-4-carbaldehyde (0.06 ml, 0.64 mmol) and sodium triacetoxyborohydride (0.21 g, 0.98 mmol). The reaction mixture was stirred at 40° C. for 72 h. The reaction mixture was then concentrated in vacuo and the residue was purified using flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: methanol/dichloromethane gradient) to yield a yellow oil (7 mg, 10%); MS (ISP): 295.3 ((M+H)+.).
Reaction SMILES: O.[NH2:2]N.C[N:5]([CH:7]=[N:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1)C>C(O)(=O)C>[N:5]1[N:2]=[C:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[NH:8][CH:7]=1
Reactant: NN
Reactant: CN(C)C=NC(=O)c1cccnc1
Solvent: O
Solvent: CC(=O)O
Product: c1cncc(-c2nnc[nH]2)c1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3.1 g. of hydrazine hydrate in 100 ml. of acetic acid is added 10.0 g. of N-(dimethylaminomethylene)nicotinamide. The reaction mixture is stirred at 90° C. for 1.5 hours, then concentrated in vacuo to about 15 ml. The addition of 50 ml. of ether causes the desired product to precipitate as 7.8 g. of colorless crystals, mp. 169°-172° C.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[NH:13][C:7]2=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1.I[CH3:15].O>CN(C)C=O>[CH3:12][C:11]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:13][C:4]([S:3][CH3:15])=[N:5][C:6]=12
Reactant: Cc1ccnc2[nH]c(S)nc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2c(C)ccnc2[nH]1
Reaction time: 0.17 h

Procedure:
130 mg of sodium hydride was dropwise added at room temperature to a solution of 500 mg of 2-mercapto-7-methyl-3H-imidazo[4,5-b]pyridine in dimethylformamide. The mixture was stirred for 10 min, and 0.21 ml of iodomethane was added thereto, followed by reaction for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off in vacuo. The resultant solid was washed with a small amount of ethyl acetate to prepare 210 mg of 7-methyl-2-methylthio-3H-imidazo[4,5-b]pyridine as a mud yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:51][CH3:52])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:29]=[CH:28][CH:27]=[C:14]([C:15]([N:17]([CH3:26])[CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:16])[CH:13]=2)=[C:6]([C:31]2[CH:36]=[C:35]([C:37](=[O:50])[NH:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=3)[CH:34]=[CH:33][N:32]=2)[CH:5]=1)C.[CH3:53]NCCC>>[CH3:26][N:17]([CH2:18][CH2:19][N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)[C:15](=[O:16])[C:14]1[CH:27]=[CH:28][CH:29]=[C:12]([C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N:3]([CH3:1])[CH2:51][CH2:52][CH3:53])=[CH:5][C:6]=2[C:31]2[CH:36]=[C:35]([C:37](=[O:50])[NH:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:47])[F:48])[CH:41]=3)[CH:34]=[CH:33][N:32]=2)=[O:30])[CH:13]=1
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CCCNC
Product: CCCN(C)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of N1-(4-(diethylamino)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)-N3-methyl-N3-(2-morpholinoethyl)isophthalamide 25, using N-methylpropan-1-amine in place of diethylamine. MS (ES, m/z): 717.3 [M+H]+.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N=C1CC(C)CCN1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH:13]=[C:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][NH:15]1
Reactant: Cc1ccc(N)nc1
Agent: CC1CCNC(=N)C1
Solvent: CC(=O)O
Product: CC1CCC(=N)NC1

Procedure:
The method of preparation of 2-imino-4-methylpiperidine acetate, EXAMPLE 6, was used to convert 2-amino-5-methylpyridine to the title compound which was obtained as a white solid. The analysis of the product was found to be consistent with the proposed structure. m.p. 175-178° C. MH+=113; d1H NMR (D2O): δ3.28-3.21 (m, 1H); 2.79-2.70 (m, 1H); 2.49-2.43 (m, 2H); 1.79-1.67 (m, 2H); 1.73 (s, 3H); 1.30-1.23 (m, 1H); 0.82 (d, J=6.6 Hz, 3H).
Reaction SMILES: [OH-].[Na+].O.[CH2:4]([SH:6])[CH3:5].[CH3:7][C:8]1([CH3:31])[O:12][N:11]=[C:10]([S:13][CH2:14][C:15]2[C:16]([C:27]([F:30])([F:29])[F:28])=[N:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19]=2F)[CH2:9]1>CN(C)C=O>[CH3:7][C:8]1([CH3:31])[O:12][N:11]=[C:10]([S:13][CH2:14][C:15]2[C:16]([C:27]([F:30])([F:29])[F:28])=[N:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19]=2[S:6][CH2:4][CH3:5])[CH2:9]1
Reactant: CCS
Reactant: CC1(C)CC(SCc2c(C(F)(F)F)nn(-c3ccccc3)c2F)=NO1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1c(CSC2=NOC(C)(C)C2)c(C(F)(F)F)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
0.2 g (4.0 mmoles) of sodium hydroxide and 1 ml of water were added to a solution of 0.25 g (4.0 mmoles) of ethanethiol dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 30 minutes. Thereto was added a solution of 0.5 g (1.4 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 5 ml of N,N-dimethylformamide. The resulting mixture was stirred for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.6 g (yield: 100%) of 5,5-dimethyl-3-(5-ethylthio-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:6]([CH3:16])[CH2:5]1)=[N+]=[N-].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23].C(N(CC)CC)C.C(Cl)CCl>C(Cl)Cl>[CH3:16][C@H:6]1[CH2:5][C@@H:4]([NH:1][C:26](=[O:27])[CH2:25][NH:24][C:22](=[O:23])[C:21]2[CH:29]=[CH:30][CH:31]=[C:19]([C:18]([F:17])([F:33])[F:32])[CH:20]=2)[CH2:8][N:7]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: C[C@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1C[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the amine of step D (0.5 g, 2.5 mmol), the carboxylic acid obtained in step A, Example 114 and triethylamine (0.7 mL, 5.0 mmol) in methylene chloride (25 mL) cooled in an ice bath was added EDC (0.53 g, 2.75 mmol). After being stirred at room temperature overnight, the solution was concentrated. The residue was purified on silica gel eluting with a gradient of 0-4% MeOH(CH2Cl2 provided 0.6 g of the title compound. MS calculated (M+H)+ 430, found 430.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:24])[CH:30]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cccc(Cl)c2)cc1
Yield: 43.7 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(3-chlorobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.060 g; 0.173 mmol), 3-chlorophenylboronic acid (0.028 g; 0.181 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.345 mmol), sodium iodide (0.052 g; 0.345 mmol), in dimethoxyethane (3 mL) and water (1 mL), heated in a sealed tube at 130° C. for 18 hours. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.032 g (44%) of the title compound as a white solid.
Reaction SMILES: [C:1]([N:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:8]([C:20]([NH2:22])=[O:21])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.C(O)C.[C].[Pd]>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[C:8]([C:20]([NH2:22])=[O:21])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(/C=C/c2c(C(N)=O)cnn2C(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CCc2c(C(N)=O)cnn2C(C)(C)C)cc1
Yield: 98.1 %

Procedure:
A mixed solution of the compound (80 mg, 0.27 mmol) obtained in step 1, 10% palladium carbon (28.4 mg, 0.27 mmol) in THF (15 mL) and ethanol (15 mL) was stirred under 1 atm hydrogen atmosphere at room temperature for 6 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 1-tert-butyl-5-(4-methoxyphenethyl)-1H-pyrazole-4-carboxamide (80 mg, 0.265 mmol, 99%) as a white powder.