Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[SH:8].[N:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1>>[F:11][C:9]([F:12])([F:10])[C:4]1[CH:5]=[CH:6][C:7]2[S:8][C:19]([C:16]3[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=3)=[N:1][C:2]=2[CH:3]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: O=Cc1ccncc1
Product: FC(F)(F)c1ccc2sc(-c3ccncc3)nc2c1
Yield: 89.2 %

Procedure:
3-Amino-4-mercaptobenzotrifluoride (8.5 g, 0.04 mol) and 4-pyridine carboxaldehyde (4.2 ml, 0.04 mol) were reacted as exemplified in Example 7 step 1, to afford the title compound as a brown solid (10 g, 89%). δH (CDCl3), 7.69 (1H, d of d, J 8.4Hz, J 1.7Hz, ArH), 7.93 (2H, m, ArH), 8.06 (1H, d, J 8.4Hz, ArH), 8.40 (1H, d, J 0.7Hz, ArH), 8.81 (2H, m, ArH). m/z (ES+) 281 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22](I)[CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C.O>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1
Reactant: CCCCCI
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Reaction time: 18 h
Yield: 73.5 %

Procedure:
To a solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.44 mmol) in anhydrous DMF (3 ml) was added sodium carbonate (0.051 g, 0.484 mmol). After 10 minutes stirring at room temperature pentyl iodide (0.063 ml, 0.484 mmol) was added and stirring continued under nitrogen at room temperature for 18 hours. The reaction mixture was diluted with water (25 ml) and extracted with EtOAc (2×25 ml). The combined organic extracts were dried (MgSO4) filtered and evaporated. Purification by SPE (Si, 5 g) eluting with 4:1 EtOAc/cyclohexane afforded the title compound as a white solid (96 mg, 74%); m/z 297.2[MH+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=O)C=1.C[Si]([C:31]#[N:32])(C)C.CN(C)C(Cl)=O>C(OCC)(=O)C.O>[C:31]([C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[CH:6][N:1]=1)#[N:32]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccncc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)/C=C/c1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 45 h
Yield: 73.7 %

Procedure:
tert-Butyl (E)-3-(4-pyridyl)acrylate (0.88 g, 4.3 mmol) was dissolved in ethyl acetate (4 ml), and 3-chloroperbenzoic acid (ca. 77%, 0.95 g, 4.3 mmol) was added thereto. The reaction mixture was stirred at room temperature for 45 hrs and subjected to a silica gel (40 g) column chromatography. The fractions eluted with ethyl acetate-ethanol (4:1) were collected and concentrated. The residue was dissolved in nitroethane (5 ml), and trimethylsilyl cyanide (0.63 g, 6.3 mmol) and N,N-dimethylcarbamoyl chloride (0.68 g, 6.3 mmol) were added thereto. The reaction mixture was stirred at room temperature for 20 hrs and combined with ethyl acetate and water. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to silica gel (30 g) column chromatography. The fractions eluted with hexane-ethyl acetate (5:1, v/v) were collected and concentrated to give the titled compound (0.73 g, 99%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([CH3:8])[C:4]([C:9]([F:12])([F:11])[F:10])=[N:3]1.[OH-].[K+].Cl[CH:16]([F:18])[F:17].O>CC(O)C>[F:17][CH:16]([F:18])[O:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:9]([F:11])([F:10])[F:12])[C:5]=1[CH3:8]
Reactant: Cc1c(C(F)(F)F)nn(C)c1O
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1c(C(F)(F)F)nn(C)c1OC(F)F
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Into 78.6 g (436.4 mmol) of 1,4-dimethyl-5-hydroxy-3-trifluoromethyl-1H-pyrazole in 500 ml of 2-propanol was added 153.1 g (2728.6 mmol) of powdery potassium hydroxide at room temperature, followed by stirring. Furthermore, an excess amount of chlorodifluoromethane was introduced into the reaction solution under stirring. Thereafter, the reaction temperature once rose to 70° C. by exothermic heat and then returned to room temperature after 2 hours. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was distilled to obtain 88.9 g (yield: 88.5%) of 5-difluoromethoxy-1,4-dimethyl-3-trifluoromethyl-1H-pyrazole as a colorless transparent liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=1.CC1C=C(NC2C3C(=CC=CC=3F)N=CN=2)C=CC=1O>>[Cl:21][C:16]1[CH:15]=[C:14]([NH:13][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[CH:4][N:3]=2)[CH:19]=[CH:18][C:17]=1[OH:20]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: Fc1cccc2ncnc(Cl)c12
Agent: Cc1cc(Nc2ncnc3cccc(F)c23)ccc1O
Product: Oc1ccc(Nc2ncnc3cccc(F)c23)cc1Cl
Yield: 85 %

Procedure:
4-Chloro-5-fluoroquinazoline was reacted with 4-amino-2-chlorophenol using an analogous process to that described in Example 3 for the preparation of 2-methyl-4-[(5-fluoroquinazolin-4-yl)amino]phenol, to give 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol in 85% yield; NMR spectrum (DMSO-d6) 6.97 (d, 1H), 7.38 (dd, 1H), 7.42 (dd, 1H), 7.59 (d, 1H), 7.73 (d, 1H), 7.81 (dd, 1H), 8.51 (s, 1H), 9.03 (d, 1H), 10.07 (bs, 1H); Mass spectrum MH+ 290.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1>CCO>[CH:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[N:19]=1)([CH3:8])[CH3:1]
Reactant: CC(C)C(=O)CC#N
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-n2nc(C(C)C)cc2N)cc1
Temperature: 80 °C
Yield: 48 %

Procedure:
Using the procedure described in Example 308A Step 1, to a solution of 4-methyl-3-oxopentanenitrile (514 mg, 4.5 mmol) prepared as described in Example 122A Step 1, in anhydrous EtOH (15 ml) was added (4-methoxyphenyl)hydrazine hydrochloride (524 mg, 3.0 mmol) and the reaction mixture was heated at 80° C. overnight. The residue was purified by silica gel chromatography (DCM/EtOAc 1:1) to afford 3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (333 mg, 48%) as a solid. 1H NMR (300 MHz, CDCl3) δ 1.26 (d, J=7 Hz, 6H), 2.92 (m, 1H), 3.66 (s, 2H), 3.83 (s, 3H), 5.46 (s, 1H), 6.96 (d, J=9 Hz, 2H), 7.44 (d, J=9 Hz, 2H); LC-MS (ESI) m/z 232 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:21][CH2:22][C:23]([OH:25])=O)=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)=[CH:7][CH:6]=1)=[O:4].C(Cl)(=O)C([Cl:29])=O.C1(C)C=CC=CC=1>ClCCl>[Cl:29][C:23](=[O:25])[CH2:22][CH2:21][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(-c2ccc(CCC(=O)O)c3cccnc23)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(CCC(=O)Cl)c3cccnc23)cc1
Reaction time: 0.33 h

Procedure:
A solution of Example 201H (1.65 g, 4.92 mmol) in dichloromethane (15 mL) at room temperature was treated oxalyl chloride (344 mg, 2.71 mmol), stirred for 20 minutes, treated with toluene (25 mL), and concentrated to provide the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[S:19][C:20]([CH:23]=O)=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:11]([CH3:25])=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:28]OS(O)(=O)=O>C(#N)C.O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[S:19][C:20]([C:23]#[N:28])=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:11]([CH3:25])=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NOS(=O)(=O)O
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccc(C=O)s3)cc21
Solvent: CC#N
Solvent: O
Product: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccc(C#N)s3)cc21
Temperature: 65 °C
Yield: 43.8 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-6-(5-formyl-2-thienyl)-1,2-dihydro-2,2,4-trimethylquinoline (12 mg, 0.03 mmol) in acetonitrile/water (10 ml/0.5 ml) was added hydroxylamine-O-sulphonic acid (5 mg, 0.04 mmol). The reaction mixture was heated to 65° C. for 1 h. The reaction was quenched with 10% NaOH (5 mL) and extracted with EtOAc (10 mL). The organic layer was washed with water and brine (3×5 mL each), dried (Na2SO4), and concentrated in vacuo to afford the crude product as a yellow oil. The crude product was purified by prep. TLC (20×20 cm, 250 μm, 25% EtOAc:hexane) to afford 5 mg (40%) of 1-tert-butyloxycarbonyl-6-(5-cyano-2-thienyl)-1,2-dihydro-2,2,4-trimethylquinoline as a yellow oil. This product was dissolved in CH2Cl2 (5 mL) and treated with TFA (0.1 ml) at rt with stirring. After 2 h, the reaction was quenched with 10% NaOH (5 mL). The organic layer was washed with water and brine (3×5 mL each), dried (Na2SO4) and concentrated in vacuo to afford the crude product as a yellow oil. The crude product was purified by prep. TLC (20×20 cm, 250 μm, 25% EtOAc:hexane) to afford 2 mg (60%) of Compound 451 as a yellow oil. Data for Compound 451: Rf 0.3 (silica gel, 25% EtOAc:Hex); 1H NMR(400 MHz, CDCl3) 7.52 (d, J=4.0, 1H), 7.23 (s, 1H), 7.22 (d, J=7.4, 1H), 7.07 (d, J=4.0, 1H), 6.43 (d, J=7.4, 1H), 5.38 (s, 1H), 2.02 (s, 3H), 1.31 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:20]1([CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>CN(C)C=O.O>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C(O)CCCC1CCCCC1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNC(=O)CCCC2CCCCC2)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
2-{[4-(2-Aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (1.51 g) synthesized in Example 7 and 4-cyclohexylbutanoic acid (0.85 g) were dissolved in N,N-dimethylformamide (10 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (1.05 g) and hydroxybenzotriazole (HOBT) monohydrate (0.85 g) were successively added thereto, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) and the reaction mixture was directly purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give 2-({4-[2-(4-cyclohexylbutanoylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (2.2 g) as a colorless oil. The obtained compound (2.2 g) was dissolved in tetrahydrofuran (10 mL), 1 M-borane/tetrahydrofuran complex (19.5 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was ice-cooled, and methanol (30 mL) was added dropwise. After warming to room temperature, the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, piperidine (30 mL) was added, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound (1.2 g) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[C:8]([O:15][CH3:16])=[CH:9][CH:10]=[C:11]([CH2:13][OH:14])[CH:12]=1.O1CCCC1.[H-].[Na+].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>O>[F:24][C:25]([F:34])([F:35])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][O:14][CH2:13][C:11]1[CH:12]=[C:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]([O:15][CH3:16])=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: COc1ccc(CO)cc1-c1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COCc2cccc(C(F)(F)F)c2)cc1-c1ncccn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a 250 ml single neck round bottom flask equipped with a reflux condensor and an argon inlet was added 3.24 gm of the 5-pyrimidyl-4-methoxyphenylcarbinol and 70 ml of anhydrous tetrahydrofuran. The system was cooled to 0° C. and after cooling 0.45 gm of sodium hydride was added. The system was stirred for an additional 20 minutes and 2.8 ml of 3-trifluoromethylbenzylchloride added. The system was allowed to come to room temperature and was then heated to reflux for 20 hours at this time, water was added to the system and the product extracted with methylene chloride. The methylene chloride was washed with water and then dried over sodium sulfate. The methylene chloride was removed by stripping to give 4.13 gm of the 5-pyrimidyl-4-methoxyphenylcarbinol 3-trifluoromethylbenzylether as an orange oil and listed as Compound No. 7 in Table I.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1)[NH2:2].Cl.CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1>C(O)C.C(OCC)C>[O:12]1[CH2:11][CH2:10][N:9]([C:6]2[N:5]=[N:4][C:3]([NH:1][N:2]3[CH:18]=[CH:22][CH:21]=[CH:20]3)=[CH:8][CH:7]=2)[CH2:14][CH2:13]1
Reactant: NNc1ccc(N2CCOCC2)nn1
Reactant: COC1CCC(OC)O1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: c1ccn(Nc2ccc(N3CCOCC3)nn2)c1
Temperature: 60 °C
Yield: 2 %

Procedure:
To 5.85 g (30 m mol) of 3-hydrazino-6-morpholino-pyridazine in 130 ml of ethanol, ethyl ether (45 ml) saturated with hydrogen chloride is added. The suspension of pale yellow precipitate which forms is additioned with 12 g (90 m mol) of 2,5-dimethoxytetrahydrofuran and the mixture is refluxed (60° C.) for 6 hours. The solvent is removed under vacuum and the residue is dissolved in water, brought to pH 8 by addition of a sodium carbonate solution and extracted with four portions (each of 100 ml) of dichloromethane. The organic extracts are pooled together, washed with water (50 ml) and anhydrified over sodium sulfate. Evaporation of the solvent yields an oil which is purified through column chromatography (silicagel, 500 g) using as the eluent a mixture of dichloromethane and ethyl acetate wherein the ratio of ethyl acetate is gradually increased from 20% to 100%. Evaporation of the more polar fraction yields 0.15 g (2%) of the product of the title which melts at 228° C.
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[NH2:21][C:22]1[C:23]([N:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[CH3:53])[CH2:43][CH2:42]2)=[CH:24][C:25]([F:40])=[C:26]([CH:39]=1)[C:27]([NH:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][C:34]1=[O:38])=[O:28].[Cl-].[Li+]>CN(C=O)C>[F:40][C:25]1[C:26]([C:27](=[O:28])[NH:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][C:34]2=[O:38])=[CH:39][C:22]([NH:21][C:9]([C:7]2[N:8]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[O:5][CH:6]=2)=[O:11])=[C:23]([N:41]2[CH2:42][CH2:43][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[CH3:53])[CH2:45][CH2:46]2)[CH:24]=1
Reactant: Cc1ccccc1N1CCN(c2cc(F)c(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Reactant: O=C(O)c1coc(C2CC2)n1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(c2cc(F)c(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2coc(C3CC3)n2)CC1
Reaction time: 0.05 h

Procedure:
To a solution of 2-cyclopropyl-oxazole-4-carboxylic acid 1h (22.8 mg, 0.149 mmol) in DMF (5.0 mL) HATU (75.4 mg, 0.198 mmol) was added and stirred for 3 min. N, N-diisopropylethylamine (0.086 mL, 0.496 mmol) was added to this followed by 5-amino-2-fluoro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 3d (45.0 mg, 0.099 mmol) in DMF (2.0 mL) and the reaction was stirred at room temperature for 16 h. Saturated solution of lithium chloride was added to this and the contents were extracted with ethyl acetate dried on anhydrous sodium sulfate, concentrated and the crude 3e was dissolved in methanol and purified on preparative HPLC using water/methanol as eluent.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([C:30]([F:33])([F:32])[F:31])[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24](F)=[C:25]([CH:28]=3)[C:26]#[N:27])[CH2:17]2)[CH:12]=[C:13]([Cl:15])[CH:14]=1.O>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([C:30]([F:32])([F:33])[F:31])[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)=[C:25]([CH:28]=3)[C:26]#[N:27])[CH2:17]2)[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: N#Cc1cc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1F
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To the solution of 1H-1,2,4-triazole (0.06 g) in DMF was added sodium hydride (0.04 g) while cooling with ice, and the mixture was warmed to room temperature and then stirred for 0.5 hr. To this solution was added the solution of 5-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]2-fluorobenzonitrile (0.30 g) in DMF, and the mixture was heated to reflux for 6 hours. The mixture was cooled to room temperature and then poured into water, which was then extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 5-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.18 g). 1H-NMR (DMSO-d6) δ: 2.62-2.73 (1H, m), 2.95-3.03 (1H, m), 3.49-3.55 (2H, m), 3.90 (1H, d), 4.31 (1H, d), 7.09 (1H, dd), 7.29 (1H, d), 7.61 (1H, d), 7.68 (2H, d), 7.71 (1H, t), 8.26 (1H, s), 8.98 (1H, s)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([O:23][CH3:24])=[CH:21][C:20]([NH2:25])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([O:23][CH3:24])=[CH:21][C:20]([NH:25][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ncc(N)cc3OC)cc2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC1CCC(c2ccc(-c3ncc(Nc4ccccc4)cc3OC)cc2)CC1
Reaction time: 18 h

Procedure:
To a solution of {4-[4-(5-Amino-3-methoxy-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.12 g, 0.3 mmol, 1.0 equiv) and phenyl boronic acid (0.082 g, 0.67 mmol, 2.0 equiv) in 5 Ml dichloromethane was added pyridine (0.054 Ml, 0.67 mmol, 2.0 equiv), copper (II) acetate (0.092 g, 0.50 mmol, 1.5 equiv), and 4 Å molecular sieves. The heterogeneous reaction mixture was allowed to stir open to atmosphere for 18 h. Removal of solvent and purification by silica gel chromatography (40% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.31 (m, 2 H) 1.50 (br. S., 1 H) 1.55 (dd, J=12.51, 2.40 Hz, 2 H) 1.87 (d, J=12.38 Hz, 5 H) 2.31 (d, J=6.57 Hz, 2 H) 3.66 (s, 3 H) 3.86 (s, 3 H) 6.96 (t, J=7.33 Hz, 1 H) 7.20-7.38 (m, 7 H) 7.82 (d, J=8.34 Hz, 2 H) 8.11 (d, J=2.02 Hz, 1 H) 8.53 (s, 1 H); (M+H)+ 431.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][Mg]Br>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])([CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Br)cc1
Temperature: -50 °C
Reaction time: 20 h
Yield: 99.4 %

Procedure:
1-(4-Bromophenyl)ethanone (9.25 g, 46.5 mmol) was dissolved in tetrahydrofuran (200 mL). The solution was cooled in a −50° C. bath. Methylmagnesium bromide (3M in ether, 46.5 mL, 139 mmol) was added over a 15 min period. The reaction was allowed to warm to room temperature and then stirred for 20 h. The reaction was quenched with saturated ammonium chloride and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to give an oil. The oil was purified on a silica gel column (0-20% ethyl acetate in hexanes) to give the product a colorless oil (9.1 g, 46.2 mmol, 91% yield). MS (ESI) m/z 197.1 [M]+, 199.1 [M+2]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[N:10]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[N:8][C:7]=1[CH2:30]O.CN(C=O)C>ClCCl>[Cl:3][CH2:30][C:7]1[N:8]=[CH:9][N:10]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[CH3:5]
Reactant: Cc1c(CO)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of thionyl chloride (1.3 ml) in dry dichloromethane (10 ml) was added over 5 min. to a stirred suspension of 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-methanol (5.0 g) in a mixture of dichloromethane (100 ml) and dry DMF (2 ml) at 0°. The mixture was stirred at 0° for 30 min. and washed consecutively with 8% sodium bicarbonate (2×50 ml), water (50 ml), dried and evaporated in vacuo below 40° to give an oil (5 g). This was dissolved in ether (100 ml) and the resulting solution was filtered through a pad of silica which was further eluted with ether (2×100 ml). The combined filtrates were evaporated below 40° to give a foam which was triturated with cold hexane and filtered to give the title compound (4.2 g) as a solid, m.p. 133°-135°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:11][C:12]1[CH2:13][C:14](=[O:19])[O:15][C:16](=[O:18])[CH:17]=1)(=[O:10])[CH3:9].O>C(O)(=O)C>[C:8]([O:11][C:12]([CH2:13][C:14](=[O:19])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:17][C:16]([OH:18])=[O:15])(=[O:10])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CC(=O)OC1=CC(=O)OC(=O)C1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC(=CC(=O)O)CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
65.7 g (0.705 mol) of aniline are added to a stirred suspension of 120 g (0.705 mol) of 4-acetyloxy-2H,3H-pyran-2,6-dione in 250 ml of acetic acid. The reaction medium is stirred for 1 h at room temperature and is then diluted by adding 500 ml of water. The solid is drained, washed with water and dried in an oven (50° C.) for 24 h. 150 g (81%) of the expected compound, melting point 125°-126° C., are obtained.