Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[B:9]([OH:11])[OH:10].C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[B:9]([OH:10])[OH:11]
Reactant: Cc1cccc(C)c1B(O)O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(CBr)c1B(O)O

Procedure:
2,6-dimethylphenylboronic acid (2.22 g, 14.8 mmol), NBS (1.31 g, 7.36 mmol, 0.5 eq) and AIBN (0.17 g, 1.0 mmol. 0.07 eq) were heated in refluxing CCl4 for 2 hours. The solution was allowed to cool then filtered. The solution was then washed with water (50 mL), dried over Na2SO4 and the solvent evaporated in vacuo. The resulting white powder (1.66 g) was ˜84% pure by HPLC and contained starting material and some di-brominated product. Column chromatography on silica gel 60 (elution conditions 0%-2% methanol in dichloromethane) failed to improve the purity and the crude material was used for the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-methyl-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example B5) (3.40 g, 10.6 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as light gray solid (3.0 g, 97%).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:12]1([CH2:18][OH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O.O>[CH2:18]([O:19][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: FC(F)(F)c1cncc(Cl)c1
Reactant: OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cncc(OCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-5-(trifluoromethyl)pyridine (10.0 g, 55.1 mmol) in N,N-dimethylformamide (DMF) (150 mL) was added dropwise phenylmethanol (5.96 g, 55.1 mmol) under nitrogen at rt. The reaction mixture was stirred at 40° C. for 2 h, diluted with water (300 mL) and extracted with ethyl acetate (300 mL×3). Combined organic parts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude product (100 g) was used into next step without further purification.
Reaction SMILES: CSC.B.COC(=O)[CH:8]([CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:9][C:10]([O:12][C:13](C)(C)C)=[O:11].CO>C1COCC1>[CH:17]1([CH:8]2[CH2:13][O:12][C:10](=[O:11])[CH2:9]2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)C1CCCC1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: O=C1CC(C2CCCC2)CO1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
Borane dimethyl sulfide complex (3.5 mL, 10.0 M in THF) is added to a solution of 2-cyclopentyl-succinic acid 4-tert-butyl ester 1-methyl ester (8.6 g, 35.5 mmol) in 100 mL of THF at 0° C. The mixture is warmed to room temperature overnight, cooled to 0° C., and treated with 50 mL of MeOH. After being warmed to room temperature over 1 hour, the solvents are evaporated, and the oil is dried at room temperature under vacuum for 12 hours. It is taken up in 100 mL of THF containing 0.1 g of pTsOH, and the solution is warmed to reflux for 12 hours. The THF is evaporated under reduced pressure, and remaining oil is taken up in 100 mL of Et2O. The Et2O solution is washed with 2.0N NaOH (3×50 mL) and 50 mL of brine. Drying over MgSO4 followed by evaporation of the solvent gives 4.4 g (80% yield) of 4-cyclopentyl-dihydro-furan-2-one as an oil. NMR (1H, 400 MHz, CDCl3) δ1.1 (2H, m); 1.3-1.8 (7H, m); 2.2 (1H, dd); 1.4 (1H, m); 1.6 (1H, dd); 3.9 (1H, dd); 4.4 (1H, dd).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=O.[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:13]([N:16]1[CH2:21][CH2:20][N:19]([C:1]([C:4]2[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=2)=[O:3])[CH2:18][CH2:17]1)([CH3:15])[CH3:14]
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc(B(O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-carboxyphenylboronic acid (1 eq, 213 mg) in DMF (5 ml) is treated with 1-isopropylpiperazine (1 eq, 155 mg) and the reaction mixture is stirred at RT for 10 minutes. TEA (1.2 eq, 0.202 ml) and HATU (2.4 eq, 1.104 g) are added and the resulting mixture is stirred at RT overnight. The reaction is quenched by addition of water and the mixture is extracted with DCM (2×). The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is dried in vacuo at 50° C. overnight to afford the title compound which is used without further purification [M+H]+=277
Reaction SMILES: [CH2:1]([NH:6][S:7]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[NH2:16])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:17]=O.Cl>C(O)(C)C.C(OCC)(=O)C>[CH2:1]([N:6]1[CH2:17][NH:16][C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[S:7]1(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C=O
Reactant: CCCCCNS(=O)(=O)c1cnccc1N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCCCCN1CNc2ccncc2S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.5 g of N-pentyl-4-aminopyridine-3- sulfonamide (Preparation 9) and 0.5 g of paraformaldehyde in 15 cm3 of isopropanol to which 50 drops of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 48 hours. After this lapse of time, the solvent is removed under partial vacuum. The residue is suspended in 20 cm3 of 0.1N NaOH. After stirring for 1 hour at ambient temperature, the insoluble material is collected on a filter, washed with water and recrystallized twice from a methanol/water (1/2) mixture and then once from CHCl3 /petroleum ether (40°-60° C.) (1/1).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:27](=[O:28])/[CH:26]=[CH:25]/[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([F:30])([F:31])[F:17])[CH:13]=[N:12]1
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Product: CC(=O)CCCCn1cc(NC(=O)/C=C/c2ccccc2C(F)(F)F)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and (E)-3-(2-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C:21]([N:23]3[CH2:28][CH2:27][N:26](CCC#N)[CH2:25][CH2:24]3)=[O:22])[C:11]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=3[O:43][CH2:44][CH3:45])=[N:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[Cl:55][CH2:56][C:57](Cl)=[O:58]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:57](=[O:58])[CH2:56][Cl:55])[CH2:25][CH2:24]3)=[O:22])[C:11]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:41])([F:40])[F:42])=[CH:35][C:34]=3[O:43][CH2:44][CH3:45])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC#N)CC1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)CCl)CC1
Reaction time: 0.5 h
Yield: 46 %

Procedure:
[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (372 mg, 0.63 mmol, example 8A) and diisopropylethylamine (230 uL, 1.32 mmol) were dissolved in methylene chloride (4 mL) and cooled to ice temperature. Chloroacetyl chloride (100 uL, 1.26 mmol) in methylene chloride (1 mL) was added dropwise and this mixture was stirred for 30 min at ice temperature. The reaction was diluted with methylene chloride and washed with water. The organic layers were dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated. Purification of the crude material by flash chromatography using ethyl acetate and hexanes gave 1-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-2-chloro-ethanone (193 mg, 0.29 mmol).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[O:10][C:9]([S:11]([N:14]2[C:18]([C:19]3[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=3)=[C:17]([F:26])[C:16]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:15]2)(=[O:13])=[O:12])=[CH:8][CH:7]=1.Cl>O1CCCC1>[F:26][C:17]1[C:16]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[CH:15][N:14]([S:11]([C:9]2[O:10][C:6]([CH:2]=[O:1])=[CH:7][CH:8]=2)(=[O:12])=[O:13])[C:18]=1[C:19]1[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(C3OCCO3)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2ccc(C=O)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 40 h
Yield: 58.7 %

Procedure:
To a solution of tert-butyl {[1-{[5-(1,3-dioxolan-2-yl)-2-furyl]sulfonyl}-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (1.23 g) in tetrahydrofuran (5 mL) was added 2 mol/L hydrochloric acid (5 mL) at room temperature and the mixture was stirred for 40 hr. A half of the reaction mixture was evaporated under reduced pressure, and extracted with ethyl acetate. The separated organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as a brown oil (yield 661 mg, 59%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7](CC2C=CC=CC=2)[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=1)(=[O:3])[CH3:2].Cl>>[C:1]([O:4][CH2:5][C:6]1[NH:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nc(COC(C)=O)n(Cc2ccccc2)c1C(=O)OCC
Agent: Cl
Product: CCOC(=O)c1nc(COC(C)=O)[nH]c1C(=O)OCC

Procedure:
Following a procedure similar to that described in Preparation 42(iv), but using 2.00 g of diethyl 2-acetoxymethyl-1-benzylimidazole-4,5-dicarboxylate [prepared as described in step (i) above] as a starting material, 1.70 g of the hydrochloride of the title compound were obtained as a syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:15])=[N:11][N:10]=1.[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1.C(N(CC)CC)C>CC(N(C)C)=O>[CH:29]1([CH2:32][N:26]2[CH2:27][CH2:28][N:23]([C:20]3[N:19]=[CH:18][C:17]([NH:16][C:14]([C:12]4[O:13][C:9]([NH:8][C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])=[N:10][N:11]=4)=[O:15])=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[CH2:31][CH2:30]1
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nnc(Nc2ccccc2F)o1
Reactant: BrCC1CC1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(N2CCN(CC3CC3)CC2)nc1)c1nnc(Nc2ccccc2F)o1
Temperature: 110 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
5-[(2-Fluorophenyl)amino]-N-(6-piperazin-1-ylpyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide (Intermediate 41) (120 mg, 0.31 mmol) in DMA (2 mL) was placed in a microwave tube with cyclopropylmethyl bromide (88 mg, 0.62 mmol), and triethylamine (64 mg, 0.62 mmol). The mixture was heated with stirring in the microwave at 110° C. for 60 minutes then transferred directly onto a reverse phase HPLC column and eluted with a gradient of acetonitrile/water containing 0.2%/TFA to give the title compound (125 mg, 91%) as a solid; 1H NMR δ 10.65 (1H, s), 10.40 (1H, bs), 8.20 (1H, s), 7.65 (2H, m), 6.90 (2H, m), 6.80 (1H, m), 6.65 (1H, d), 4.00 (2H, d), 3.25 (2H, d), 2.80 (6H, m), 0.75 (1H, m), 0.30 (2H, m), 0.00 (2H, m); MS m/e MH+ 438.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[N:15][NH:16][C:17]3[C:18]([OH:32])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)[CH:20]=[CH:21][CH:22]=3)[C:11]([CH3:33])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:34]([CH2:36][NH2:37])[OH:35]>O>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[N:10]=[C:11]([CH3:33])/[C:12](=[N:15]/[NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)[C:18]=3[OH:32])/[C:13]2=[O:14])=[CH:3][C:2]=1[CH3:1].[CH2:36]([NH2:37])[CH2:34][OH:35]
Reactant: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=NNc1cccc(-c2cccc(C(=O)O)c2)c1O
Solvent: O
Solvent: NCCO
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)/C1=N\Nc1cccc(-c2cccc(C(=O)O)c2)c1O
Reaction time: 1 h

Procedure:
To a mixture of 3′-{N′-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid (2 g) in water (40 mL), ethanolamine (2.5 g) was added and heated to about reflux temperature for about 2 hours. The mixture was cooled to about 0° C. to about 10° C. and stirred for about 1 hour. The reaction mixture was filtered, washed with water (10 mL) and dried in an oven at about 55° C. to about 60° C. for about 12 hours to get purple solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][NH2:10])=[O:8].[CH2:11]([O:18][CH2:19][C:20](Cl)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][CH2:19][C:20]([NH:10][NH:9][C:7](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNC(=O)c1ccccn1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COCc1ccccc1)NNC(=O)c1ccccn1

Procedure:
Picolinohydrazide (4.55 g) was dissolved in dichloromethane (40 mL) and 2-(benzyloxy)acetyl chloride (6.06 mL) was added slowly with cooling. Triethylamine (5.98 mL) was added slowly with a strong exotherm. Additional dichloromethane (45 mL) was added to aid stirring. The reaction was allowed to stir overnight. The reaction was partitioned between ethyl acetate and sodium hydrogen carbonate aqueous solution. The organic phase was washed with brine, dried and purified by column chromatography using an eluant of 10% ethyl acetate/dichloromethane to provide the title compound (4.1 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([C:17](OC)=[O:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:25])[CH:3]=1.O.[CH3:27][N:28]1CCCCC1=O>>[NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([C:17]([NH:28][CH3:27])=[O:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:25])[CH:3]=1
Reactant: CN1CCCCC1=O
Reactant: COC(=O)c1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OC
Solvent: O
Product: CNC(=O)c1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OC
Temperature: 40 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
Compound 39b (100 mg) was dissolved in N-methylpiperidin-2-one (250 μL), and 40% methylaminemethanol solution (250 μL) was added thereto, followed by stirring at 40° C. for 16 hours. Subseuqntly, water was added to the reaction mixture, and the precipitate was filtrated, to thereby yield compound 46a (63.7 mg, yield: 64%).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH3:30])[CH2:13][C:14]2[CH:19]=[N:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:16][N:15]=2)=[CH:8][C:7]=1[CH3:31].[Li+].[OH-]>C1COCC1.C(O)C>[CH3:31][C:7]1[CH:8]=[C:9]([N:12]([CH3:30])[CH2:13][C:14]2[CH:19]=[N:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:24][CH:25]=3)=[CH:16][N:15]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:32])=[O:2]
Reactant: COC(=O)COc1ccc(N(C)Cc2cnc(-c3ccc(C(F)(F)F)cc3)cn2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(N(C)Cc2cnc(-c3ccc(C(F)(F)F)cc3)cn2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 110 mg (0.25 mmol) (2-methyl-4-{methyl-[5-(4-trifluoromethyl-phenyl)-pyrazin-2-ylmethyl]-amino}-phenoxy)-acetic acid methyl ester in 0.75 ml of THF and 0.75 ml ethanol was treated at 0° C. with 0.74 ml 1N LiOH and stirred for 45 min at RT. The reaction was extracted with with aqueous 10% KHSO4/Et2O (3×). The organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated. The product was crystallized from ether to give pure (2-methyl-4-{methyl-[5-(4-trifluoromethyl-phenyl)-pyrazin-2-ylmethyl]-amino}-phenoxy)-acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[CH:19]=[C:18]([CH:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[CH3:26])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.O1CCOC[CH2:34]1.C[Mg]Br>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22]([OH:24])([CH3:34])[CH3:23])[CH:19]=[C:18]([CH:25]([O:27][CH2:28][C:29]([F:30])([F:31])[F:32])[CH3:26])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: C1COCCO1
Reactant: COc1cc(Nc2nc(C(C)=O)cc(C(C)OCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(C(C)OCC(F)(F)F)cc(C(C)(C)O)n2)ccc1-n1cnc(C)c1
Reaction time: 0.17 h
Yield: 64 %

Procedure:
1-(2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-(1-(2,2,2-trifluoroethoxy)-ethyl)pyrimidin-4-yl)ethanone (120 mg, 0.27 mmol) was coevaporated with dioxane and dissolved in THF (5 mL). The mixture was added slowly to a vigorously stirred solution of methylmagnesium bromide (0.712 mL of 3M solution, 2.14 mmol). The mixture was stirred for 10 minutes. The mixture was cooled in an ice bath and slowly quenched with a saturated solution of ammonium chloride in water (10 mL). The mixture was extracted with ethyl acetate (2×20 mL). The organic phase was separated, dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC to give the title compound as a solid 81 mg (64%).
Reaction SMILES: C(O[C:4]1[CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:8][N:9]=1)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:25]([NH:27][NH2:28])=O)=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[C:32]([O:31][C:30]([NH:29][CH:24]([C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)[C:25]1[N:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:5][C:4]2=[N:28][N:27]=1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC1=NCCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)NC(C(=O)NN)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(c1ccc(Cl)cc1)c1nnc2n1CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
A solution of tert-butyl 3-ethoxy-5,6-dihydropyrazine-1(2H)-carboxylate (0.762 g, 3.34 mmol) and tert-butyl 1-(4-chlorophenyl)-2-hydrazinyl-2-oxoethylcarbamate (1.00 g, 3.34 mmol) in toluene (6.67 mL, 3.34 mmol) was heated to reflux and stirred at this temperature for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was dried and concentrated to give a residue that was purified by reverse phase chromatography (Biotage SP4, 40+M, C18, 10% to 100% ACN/H2O) to afford tert-butyl 3-((tert-butoxycarbonylamino)(4-chlorophenyl)methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (0.92 g, 60%). LCMS (APCI+) M+H+: 463 (25%), 464 (90%), 466 (25%), 467 (5%); rt=3.56 minutes. 1H NMR (400 MHz, CDCl3) δ □7.33 (d, J=8.6 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.12 (d, J=7.8 Hz, 1H), 5.87 (d, J=7.8 Hz, 1H), 4.84 (d, J=17.6 Hz, 1H), 4.75 (d, J=17.6 Hz, 1H), 3.93 (m, 1H), 3.80 (m, 1H), 3.73 (m, 1H), 3.49 (m, 1H), 1.47 (s, 9H), 1.41 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:16]#[CH:17])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C#CCCCCCC.Br[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([C:42]34[CH2:51][CH:46]5[CH2:47][CH:48]([CH2:50][CH:44]([CH2:45]5)[CH2:43]3)[CH2:49]4)[CH:35]=2)=[CH:30][CH:29]=1.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:42]12([C:36]3[CH:35]=[C:34]([C:31]4[CH:32]=[CH:33][C:28]([C:17]#[C:16][C:8]5([NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]5)=[CH:29][CH:30]=4)[CH:39]=[CH:38][C:37]=3[O:40][CH3:41])[CH2:49][CH:48]3[CH2:47][CH:46]([CH2:45][CH:44]([CH2:50]3)[CH2:43]1)[CH2:51]2
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Reactant: COc1ccc(-c2ccc(Br)cc2)cc1C12CC3CC(CC(C3)C1)C2
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: COc1ccc(-c2ccc(C#CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 35 %

Procedure:
When tert-butyl-5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 1-octyne and the product of Step A was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 35% yield, as pale paste. 1H-NMR (CDCl3) 1.47 (s, 3H); 1.48 (s, 9H); 1.5 (s, 3H); 1.77 (broad s, 6H); 2.07 (broad s, 3H); 2.12 (s, 6H); 3.86 (s, 3H); 4.00 (d, 2H, J=11.38 Hz); 4.10 (d, 2H, J=11.45 Hz); 5.20 (s, 1H); 6.9 (d, 1H, J=8.46 Hz); 7.28-7.5 (s, 6H).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH3:15])[CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([OH:14])[CH:10]=[N:9]2.Cl[CH:17]([F:19])[F:18].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[Br:3][C:4]1[CH:5]=[C:6]([CH3:15])[CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([O:14][CH:17]([F:19])[F:18])[CH:10]=[N:9]2
Reactant: FC(F)Cl
Reactant: Cc1cc(Br)c2nc(O)cnc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Br)c2nc(OC(F)F)cnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
Tetrabutylammonium bromide (689 mg, 2.14 mmol) and sodium hydroxide (17.1 g of a 50% aqueous solution, 214 mmol) were added to a solution of the title compound of Step D (5.11 g, 21.4 mmol) in dioxane (250 mL) at room temperature. Chlorodifluoromethane was condensed with a cold finger trap and added to the reaction mixture until the mixture was saturated. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was slowly poured into water. The resulting mixture was extracted with ethyl acetate three times. The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to give a dark-brown oil. Flash chromatography of this brown oil on silica gel, eluting with 1:25 ethyl acetate/hexane afforded the title compound of Step E as a light yellow solid melting at 86°-87° C. (3.23 g, 52%). 1H NMR (CDCl3): δ2.57 (s,3H), 7.75 (t, 1H), 7.84 (s, 1H), 7.92 (s, 1H), 8.58 (s, 1H).