Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([CH2:9]O)[NH:8][C:4]=2[N:3]=[CH:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:9][C:7]1[NH:8][C:4]2[N:3]=[CH:2][S:1][C:5]=2[CH:6]=1
Reactant: OCc1cc2scnc2[nH]1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2scnc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a solution of (4H-pyrrolo[2,3-d]thiazol-5-yl)methanol (3.5 g, 22.7 mmol) in anhydrous dichloromethane (50 mL) was added triethylsilane (5.23 g, 45.4 mmol) dropwise below 0° C., trifluoroacetic acid (5.18 g, 45.4 mmol) was added dropwise followed below 0° C. The resulting reaction system was warm to the ambient temperature and allowed to stir for 2 hours at room temperature. The reaction mixture was poured into saturated sodium bicarbonate, extracted with dichloromethane (50 mL×3), the combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel eluted with (petrol ether/acetic ester 15:1→8:1) to give the title compound (2.5 g, 80%) as a yellow solid. LCMS (M+H+) m/z: calc'd. 138.03. found 138.9.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.N1C=CC=CC=1.FC(F)(F)C(O[C:32]1[C:37]([F:38])=[C:36]([F:39])[C:35]([F:40])=[C:34]([F:41])[C:33]=1[F:42])=O>CC(N(C)C)=O.CCOC(C)=O>[F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([O:15][C:32]2[C:33]([F:42])=[C:34]([F:41])[C:35]([F:40])=[C:36]([F:39])[C:37]=2[F:38])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: Cn1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (894 mg, 2.30 mmol) and pyridine (909 mg, 11.5 mmol) were dissolved in DMA (15 mL). To this mixture was added pentafluorophenyl trifluoroacetate (3.22 g, 11.5 mmol) then the solution was allowed to stir at R.T. for 2 h. The DMA solution was diluted with EtOAc (150 mL), which was washed sequentially with 1 M HCl (2×100 mL), water (100 mL), sat. NaHCO3 (2×100 mL), and brine (100 mL). The EtOAc fraction was then dried (Na2SO4) and the solvent removed under reduced pressure to yield a viscous oil which was purified by column chromatography on silica gel (50% EtOAc/PE as eluant). This afforded 2,3,4,5,6-pentafluorophenyl-4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate as a cream foam (1.22 g, 96%) which was used directly in subsequent steps. 1H NMR [(CD3)2SO, 400 MHz] δ 9.03 (s, 1H), 8.70 (s, 1H), 7.79 (dd, J=10.1, 1.9 Hz, 1H), 7.62 (br dd, J=8.4, 1.0 Hz, 1H), 7.29 (t, J=8.4 Hz, 1H), 5.36 (d, J=1.6 Hz, 1H), 3.45 (s, 3H). LCMS (APCI+) calcd for C19H9F6N2O3 555 (MH+), found 555.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[O:16][CH3:17])([CH3:7])[CH3:6])[CH3:2].Cl[CH:20]([C:22]1[C:23]([CH3:38])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1)[CH3:21]>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:20]([C:22]2[C:23]([CH3:38])=[N:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH3:21])=[CH:11][C:10]=1[O:16][CH3:17])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1OC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(OC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1OC

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 2-(4-hydroxy-2-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester (example 90A]) was reacted with [rac]-3-(1-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 17C]) to give [rac]-2-(2-methoxy-4-{1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.O>CN(C)C=O>[F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[N:4]1[C:14](=[O:15])[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]1=[O:16]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc(N)c(F)c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)c3ccccc3C2=O)c(F)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A suspension of 2-fluoro-4-methoxyaniline (2.22 g) and phthalic anhydride (2.33 g) in N,N-dimethylformamide (16 mL) was stirred at 120° C. for 1 hour. The reaction mixture was cooled to room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residual crystals were suspended in ethyl acetate (5 mL), and the suspension was stirred at room temperature for 10 minutes. To the suspension was added n-hexane (25 mL), and the crystals were collected by filtration. The collected crystals were dried under reduced pressure to give 3-fluoro-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)anisole (3.35 g). This material was suspended in 1,2-dichloroethane (12.4 mL). To the suspension was added chlorosulfonic acid (1.81 mL) in a dropwise manner under ice-cooling, and the mixture was heated at reflux for 1 hour. The reaction mixture was cooled to room temperature. To the reaction mixture were added thionyl chloride (4.5 mL) and N,N-dimethylformamide (0.048 mL), and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate. To the mixture was added water, and the organic layer was separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residual crystals were suspended in ethyl acetate (10 mL). To the suspension was added n-hexane (30 mL), and the crystals were collected by filtration. The collected crystals were washed with n-hexane, and dried under reduced pressure to give the title compound (3.6 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13](=[O:25])[CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH3:11].[Sn](Cl)(Cl)(Cl)Cl>>[CH2:10]([O:12][C:13]([C:14]1[C:15](=[O:16])[O:9][C:3]2[C:4]([C:20]=1[OH:21])=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=2[CH3:1])=[O:25])[CH3:11]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: Cc1cccc(O)c1C
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CCOC(=O)c1c(O)c2ccc(C)c(C)c2oc1=O
Temperature: 200 °C
Yield: 0.7 %

Procedure:
A mixture of 2,3-dimethyl-phenol (1.17 g, 9.57 mmol), 2-ethoxycarbonyl-malonic acid diethyl ester (4.1 mL, 19.1 mmol), and tin tetrachloride (23 μL, 0.19 mmol) was heated in a 200° C.-oil bath for 10 min; then cooled, the reaction mixture was directly purified on silica gel column chromatography (eluent: ethyl acetate in dichloromethane: 20% to 80%) to give the desired title product (18 mg). ESI (m/z): 263 (M+H)+.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.[CH3:12][O:13][C:14]([C:16]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15].CCN(CC)CC>CN(C=O)C.O>[CH3:12][O:13][C:14]([C:16]1([NH:21][CH2:10][C:5]2[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15]
Reactant: COC(=O)C1(N)CCCC1
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C1(NCc2cc(Br)cnc2N)CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To an ice-cold suspension of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (8.64 g, 24.9 mmol) and 1-amino-cyclopentanecarboxylic acid methyl ester (3.56 g, 24.9 mmol) in DMF (100 mL) was added Et3N (5.30 mL, 37.4 mmol) slowly. The mixture was stirred for 2 h and then diluted with H2O. The solid was collected by filtration to give the title compound (3.55 g, 43%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=2.3 Hz, 1H), 7.37 (d, J=2.3 Hz, 1H), 5.49 (s, 2H), 3.76 (s, 3H), 3.52 (s, 2H), 2.12-2.05 (m, 2H), 1.79 (br s, 7H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>C(Cl)CCl>[F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccc(I)cc1F
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(I)cc1F
Yield: 66.8 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 2-fluoro-4-iodobenzamide (0.500 g, 1.8 mmol), oxalyl chloride (0.285 g, 2.2 mmol) and EDC (10 mL) to afford 0.350 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC>CN(C=O)C.O>[CH2:17]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(N)c1
Reactant: BrCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc(NCc2ccccc2)c1
Reaction time: 48 h
Yield: 30.3 %

Procedure:
A stirred solution of the starting tert-butyl 3-aminobenzylcarbamate (0.925 g, 4.16 mmol, 1 eq, derived from 3-(aminomethyl)aniline (TCI America)) in 10 ml anhydrous DMF under Ar was treated with benzyl bromide (0.54 ml, 0.78 g, 4.58 mmol, 1.1 eq) and Et3N (0.75 ml, 0.55 g, 1.3 eq). After stirring for 48 h the reaction was diluted with water and extracted with EtOAc (×2). The combined organics were washed with water (×4), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.3937 g (1.26 mmol, 30% yield) of tert-butyl 3-(benzylamino)benzylcarbamate.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:7][CH2:6][CH:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([CH3:32])[N:13]=[C:14]([CH2:17][N:18]4[CH2:23][C@@H:22]5[CH2:24][C@H:19]4[CH2:20][N:21]5C(OC(C)(C)C)=O)[C:15]=3[N:16]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C@H:19]12[CH2:24][C@H:22]([NH:21][CH2:20]1)[CH2:23][N:18]2[CH2:17][C:14]1[C:15]2[N:16]=[C:8]([CH:5]3[CH2:6][CH2:7][C:2]([CH3:33])([CH3:1])[CH2:3][CH2:4]3)[S:9][C:10]=2[N:11]=[C:12]([CH3:32])[N:13]=1
Reactant: Cc1nc(CN2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)c2nc(C3CCC(C)(C)CC3)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(CN2C[C@@H]3C[C@H]2CN3)c2nc(C3CCC(C)(C)CC3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To tert-butyl (1S,4S)-5-{[2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]methyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (476 mg) and DCM (10 mL) was added trifluoroacetic acid (2.0 mL), followed by stirring at room temperature for 2 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column to obtain 7-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylmethyl]-2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidine (332 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([N:18]1[CH2:22][C:21](=[O:23])[C@H:20]([CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:27])[CH2:19]1)=[O:17].[BH4-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([N:18]1[CH2:22][C@H:21]([OH:23])[C@H:20]([CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:27])[CH2:19]1)=[O:17]
Reactant: O=C(NC[C@@H]1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1=O)c1ccc(Cl)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NC[C@@H]1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1O)c1ccc(Cl)s1
Reaction time: 1.5 h

Procedure:
To a solution of (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-oxo-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide (example 81.3; 50 mg) in 2 ml of THF was added at 22° C. 12 mg of NaBH4 and stirring was continued for 1.5 h. The mixture was partitioned between 1 N HCl and AcOEt, the organic layer was washed with brine, dried and evaporated to give (3R,4R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-hydroxy-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. White solid. MS491.3 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[C:18]([F:19])=[C:17]([F:20])[C:16]([C:21]([F:24])([F:23])[F:22])=[C:15]([F:25])[C:14]=2[F:26])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+:28]>C(O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[C:14]([F:26])=[C:15]([F:25])[C:16]([C:21]([F:24])([F:23])[F:22])=[C:17]([F:20])[C:18]=2[F:19])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[K+:28]
Reactant: O=C(O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1O
Temperature: 10 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)benzoic acid (10 g, 0.261 mole), as prepared in Example 3, was added to anhydrous ethanol (500 ml) and then the temperature was allowed to rise to 50° C. for complete dissolution. The resulting solution was cooled to 10° C. The pH of the solution was adjusted to 6.8-7.0 using a separately prepared solution of 85%-potassium hydroxide (17.22 g, 0.261 mole) and anhydrous ethanol (30 ml). The reaction mixture was stirred for 2 hours at room temperature and then the precipitated crystals were filtered and dried to give 100.8 g (0.239 mole, 91.7% yield) of potassium 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)benzoate as the desired compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].CN(C)C=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49]2[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=2)=[CH:44][C:43]=1[O:56][CH3:57]>>[CH3:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[C:11]([NH:53][C:52]1[CH:51]=[CH:50][C:49]([O:48][C:45]2[CH:46]=[CH:47][C:42]([CH3:41])=[C:43]([O:56][CH3:57])[CH:44]=2)=[CH:55][CH:54]=1)=[O:13]
Reactant: COc1cc(Oc2ccc(N)cc2)ccc1C
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cc2)ccc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a solution of N-{[(1,1-dimethylethyl)oxy]carbonyl}-D-alanine (182 mg, 0.960 mmol) in dry N,N-Dimethylformamide (DMF) (4 mL) DIPEA (0.305 mL, 1.745 mmol) and then TBTU (336 mg, 1.047 mmol) were added and the reaction mixture was stirred for 15 minutes at r.t. 4-{[4-methyl-3-(methyloxy)phenyl]oxy}aniline (Intermediate 20, 200 mg) was then added and the reaction mixture was stirred for 1 hour at the same temperature. The reaction was quenched with water (2 mL), diluted with brine (10 mL) and extracted with ethyl acetate (2 times 20 mL). Organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system, 10 g SNAP column) using as eluent a gradient cyclohexane/ethyl acetate from 100/0 to 80/20 to afford the title compound as a yellow pale solid (304 mg).
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:15][N:16]([C:24](=[O:39])[C@@H:25]([CH2:37][OH:38])[NH:26]C(OCC1C=CC=CC=1)=O)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.FC1C=CC(C(OC(C)(C)C)=O)=CC=1CN(C(=O)[C@@H](C)NC(OCC1C=CC=CC=1)=O)C>>[CH2:17]([N:16]1[CH2:15][C:3]2[CH:4]=[C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])[CH:13]=[CH:14][C:2]=2[NH:26][C@H:25]([CH2:37][OH:38])[C:24]1=[O:39])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)c1ccc(F)c(CN(Cc2ccccc2)C(=O)[C@@H](CO)NC(=O)OCc2ccccc2)c1
Agent: C[C@@H](NC(=O)OCc1ccccc1)C(=O)N(C)Cc1cc(C(=O)OC(C)(C)C)ccc1F
Product: CC(C)(C)OC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C(=O)[C@@H](CO)N2
Yield: 34 %

Procedure:
According to the procedure of Preparation 4 (d), except substituting tert-butyl (R)-4-fluoro-3-[[[N-(benzyloxycarbonyl)serinyl]benzylamino]methyl]benzoate (1.58 g, 3 mmole) for the tert-butyl (R)-4-fluoro-3-[[[N-(benzyloxycarbonyl)alaninyl]-methylamino]methyl]benzoate, the title compound (0.39 g, 34%) was prepared as an off-white solid following recrystallization from EtOAc/hexanes: MS (ES) m/e 383.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([C:16]([O:18]C)=[O:17])[C:3]=1[Cl:20].[OH-].[Na+].Cl>CO.O>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([C:16]([OH:18])=[O:17])[C:3]=1[Cl:20]
Reactant: COC(=O)c1nc(Oc2ccccc2)c(Cl)c(N)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1c(Cl)c(Oc2ccccc2)nc(C(=O)O)c1Cl
Yield: 90 %

Procedure:
To a solution of methyl 4-amino-3,5-dichloro-6-phenoxypyridine-2-carboxylate in methanol (10 mL) and water (100 mL) was added sodium hydroxide (0.5 g excess) and the solution heated under reflux for 3 hr. The solution was cooled and concentrated hydrochloric acid (2 mL) added. The solid was collected to give 4-amino-3,5-dichloro-6-phenoxypyridine-2-carboxylic acid (1.1 g, 90%); mp 158-60° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:8](OC(OCC)CBr)[CH3:9].Br.[OH-].[Na+]>C(O)C.CC(O)C.C(Cl)Cl>[N:1]1[CH:8]=[CH:9][N:3]2[CH:4]=[CH:5][N:6]=[CH:7][C:2]=12
Reactant: Nc1cnccn1
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: CC(C)O
Product: c1cn2ccnc2cn1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of aminopyrazine (5 g, 53 mol, 1 eq.) in ethanol (212 ml) was added bromoacetaldehyde diethylacetal (12 ml, 80 mol, 1.5 eq.) and HBr (48%, 26.5 ml). The mixture was heated at 70–80° C. for 17 hours. The mixture was then cooled to rt (room temperature), then a mixture of 1N NaOH (200 ml) and 20% IPA/DCM (isopropyl alcohol/Dichloromethane) was added to the reaction mixture. The combined organic layer was dried over sodium sulfate and concentrated to afford 5.9 g of brown solid of imidazo[1,2-a]pyrazine (yield 94%).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C.CS(C)=O.CO.CO>[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:61]=[C:60]4[C:56]([CH:57]=[N:58][NH:59]4)=[C:55]([NH:62][C:4]([C:3]4[C:2]([CH3:1])=[N:10][CH:9]=[CH:8][CH:7]=4)=[O:6])[CH:54]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: Cc1ncccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cc1ncccc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 25.9 %

Procedure:
To a solution of 2-methylnicotinic acid (55 mg, 0.40 mmol) in DMF (2 ml) was added HATU (150 mg, 0.40 mmol) and DIPEA (0.211 ml, 1.21 mmol). The mixture was stirred at room temperature for 20 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.20 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was added to the top of a 20 g aminopropyl cartridge that had been pre-conditioned with MeOH. The reaction mixture remained on the cartridges for 3 h before being eluted with MeOH. The solvent was removed in vacuo to give a crude residue that was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method E). The sample was further purified using Mass Directed Automated Preparative HPLC (Method E) and product-containing fractions were dried under a stream of nitrogen to give the title compound (19 mg) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]=[CH:6][CH2:5]1.CC(C)([O-])C.[K+].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>C(O)CCC>[CH:4]1([CH2:3][CH2:2][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH2:9][CH2:8][CH:7]=[CH:6][CH2:5]1
Reactant: c1c[nH]cn1
Reactant: ClCCC1CC=CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCO
Product: C1=CCC(CCn2ccnc2)CC1

Procedure:
1-Chloro-2-(cyclohex-3-enyl)ethane (38.0 g, 0.265 mol) was added dropwise to a stirred, boiling solution of potassium tert-butoxide (30.0 g, 0.27 mol) and imidazole (18.0 g, 0.265 mol) in dry butan-1-ol. Following the addition, the reaction mixture was stirred and heated under reflux for 4 h.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40](S(C)(=O)=O)[N:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40]([O:20][CH2:19][CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][N:11]([C:9]3[CH:8]=[C:7]([CH:21]4[CH2:24][CH2:23][CH2:22]4)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:10]=3)[CH2:16][CH2:15]2)[N:39]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CS(=O)(=O)c1nccc(OCc2ccccc2)n1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCO)CC2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCOc3nccc(OCc4ccccc4)n3)CC2)n1
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
0.9 g of 3-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-propan-1-ol (2.71 mmol) were dissolved in 20 ml of tetrahydrofuran. 2.75 ml of n-butyllithium (15% in hexane) were added at 0° C. The reaction mixture was stirred for 30 min. 0.79 g of 4-benzyloxy-2-methanesulfonyl-pyrimidine (3.0 mmol) dissolved in 10 ml of tetrahydrofuran were then added. The reaction mixture was stirred overnight at room temperature and for an additional 6 h at 60° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (1.5%) as eluent to yield 0.75 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24]Cl>>[Cl:19][C:18]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:24][C:23]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:21]([Cl:20])[CH:22]=3)[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=3)=[N:6][C:5]=2[CH:17]=1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Product: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3n2Cc2ccc(Cl)c(Cl)c2)cc1

Procedure:
5,6-Dichloro-1-(3,4-dichlorobenzyl)-2-(4-formylphenyl)benzimidazole was prepared from 5,6-dichloro-2-(4-formylphenyl)benzimidazole obtained in Example 13 and 3,4-diclorobenzyl chloride by following General Procedure 3.