Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]4[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[N:26]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2ccnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.4 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.08 g) in dichloromethane (2 ml) was added TFA (2 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.036 g, 15%). MS (ISP) 472.2 [(M+H)+]; mp 255° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[C:17]([CH2:20]O)[S:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[I-].[Na+].[CH3:36][O:37][C:38]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CC(C)=O.COCCOC.C(O)C.O>[CH3:36][O:37][C:38](=[O:39])[C:40]1[CH:45]=[CH:44][C:43]([CH2:20][C:17]2[S:18][CH:19]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:16]=2)=[CH:42][CH:41]=1
Reactant: OCc1nc(-c2ccccc2OCc2ccccc2)cs1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cc2nc(-c3ccccc3OCc3ccccc3)cs2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.7 %

Procedure:
To a solution (8 mL) of the compound (1.2 g, 4.0 mmol) obtained in Example 191a in tetrahydrofuran were added triethylamine (0.73 mL, 5.3 mmol) and methanesulfonylchloride (0.38 mL, 4.8 mmol), and the mixture was stirred at room temperature for 3 hr. The resulting salt was filtered and removed, and the solvent was evaporated under reduced pressure. To a solution (40 mL) of the residue in acetone was added sodium iodide (1.8 g, 12 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. To a mixed solution of the residue, 4-methoxycarbonylphenylboronic acid (870 mg, 4.8 mmol) and 2M aqueous sodium carbonate solution (2.4 mL, 4.8 mmol) in 1,2-dimethoxyethane/ethanol (v/v=3/1, 12 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (330 mg, 0.40 mmol), and the mixture was stirred at 90° C. overnight. The resulting salt was filtered and removed, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=85/15) to give the title compound (360 mg, 21% in 3 steps) as colorless crystals.
Reaction SMILES: O=C1NCCN1C1SC(C([O-])=O)=CN=1.[O:15]=[C:16]1[NH:20][CH2:19][CH2:18][N:17]1[C:21]1[S:22][C:23]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=1.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1>>[F:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][N:20]2[CH2:19][CH2:18][N:17]([C:21]3[S:22][C:23]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=3)[C:16]2=[O:15])=[CH:38][CH:39]=1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C(F)(F)F
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])c1cnc(N2CCNC2=O)s1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C(F)(F)F
Yield: 94 %

Procedure:
Following the procedure as described in Example 24, making variations as required to replace 2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(2-oxoimidazolidin-1-yl)-4-(trifluoromethyl)thiazole-5-carboxylate to react with 1-(bromomethyl)-4-fluorobenzene, the title compound was obtained as a colorless solid in 94% yield: 1H NMR (300 MHz, CDCl3) δ 7.28-7.25 (m, 2H), 7.06-7.01 (m, 2H), 4.46 (s, 2H), 4.33 (q, J=7.1 Hz, 2H), 4.13-4.07 (m, 2H), 3.50-3.44 (m, 2H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 418.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([N:17]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)C(=O)C(F)(F)F)[CH:9]=2)[CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>O1CCCC1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:16]=[CH:15][C:11]([CH2:12][OH:13])=[C:10]([NH:17][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(C(=O)O)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2ccc(CO)c(NC3CCOCC3)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
500 mg (1.060 mmol) of 4-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzoic acid dissolved in 5 ml of tetrahydrofuran is added at 0° C. to a suspension of 201 mg (5.30 mmol) of LiAlH4 in 9 ml of tetrahydrofuran. The reaction mixture is stirred at 0° C. for 1 hour and then at room temperature for 3 hours. The reaction mixture is cooled at 0° C. and then, drop by drop, 200 μl water, then 200 μl of soda solution (15% by weight) and finally 1 ml of water are added. The reaction mixture is stirred at room temperature for 2 hours and then filtered and rinsed with tetrahydrofuran. The filtrate is concentrated to yield 250 mg (yield=77%) of (4-(4-methylpiperazine-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl)methanol in the form of a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]3[CH:17]=[CH:18][S:19][C:15]=3[CH:14]=[C:13]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[N:12]=2)[CH2:7][CH2:6]1)[CH3:4].Br[CH:28]([SiH](C1C=CC=CC=1)C1C=CC=CC=1)[CH:29]([O:31]C(C)(C)C)[CH3:30].O>CCCCCC.CN(C=O)C>[CH2:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]3[CH:17]=[CH:18][S:19][C:15]=3[CH:14]=[C:13]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:28][CH:29]([OH:31])[CH3:30])=[CH:22][CH:21]=3)[N:12]=2)[CH2:7][CH2:6]1)[CH3:4]
Reactant: CCN1CCN(c2nc(-c3ccc(O)cc3)cc3sccc23)CC1
Reactant: CC(OC(C)(C)C)C(Br)[SiH](c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCN(c2nc(-c3ccc(OCC(C)O)cc3)cc3sccc23)CC1
Reaction time: 0.75 h
Yield: 90 %

Procedure:
66% sodium hydride (0.26 g, 1.2 equivalents) was washed with n-hexane and was then suspended in DMF of 1 ml, and the mixture was stirred under ice-cooling. To the resulting mixture was added 4-(4-ethylpiperazin-1-yl)-6-(4-hydroxyphenyl)thieno[3,2-c]pyridine of 2.00 g (5.88 mmol) dissolved in DMF of 20 ml, followed by the agitation at room temperature for 45 min. To the resulting product was added 1-bromo-O-(t-butyl)diphenylsilyl-2-propanol of 4.44 g (2.0 equivalents) dissolved in DMF of 15 ml, which was stirred in nitrogen atmosphere at 50° C. for 18 hr. Water was added to the resulting mixture, and then extracted with ethyl acetate. The organic layer was washed sequentially with water (three times) and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by NH-silica gel column chromatography (eluent solvent/ethyl acetate system), to give the title compound as a pale yellow oil (3.38 mg, yield; 90%).
Reaction SMILES: [Na:1].COC1OCC([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])CO1.[CH3:31][C:32]1([CH3:41])[O:37][CH2:36][CH:35]([CH2:38]CO)[CH2:34][O:33]1>>[Na:1].[CH3:31][C:32]1([CH3:41])[O:37][CH2:36][CH:35]([CH2:38][CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])[CH2:34][O:33]1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Reactant: CC1(C)OCC(CCO)CO1
Agent: [Na]
Product: Cc1c(OCCC2COC(C)(C)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 2 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using 2-(2,2-dimethyl-1,3-dioxan-5-yl)ethanol obtained in the step (28a) to obtain the title compound (58 mg, total yield: 2.0%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1([F:31])[CH2:17][CH2:16][CH:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([CH:15]1[CH2:14][CH2:13][C:12]([F:31])([F:11])[CH2:17][CH2:16]1)[C:21]1[CH:26]=[N:25][C:24]([C:27]([F:28])([F:29])[F:30])=[N:23][CH:22]=1)=[O:6]
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=448.1, tR (minutes, Method F)=2.95
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:12])=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+]>O1CCCC1.CO>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[CH:23][N:22]=[C:21]([N:18]2[CH2:17][CH2:16][CH:15]([CH2:14][NH:13][C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=3)=[O:12])[CH2:20][CH2:19]2)[N:26]=1
Reactant: COC(=O)c1ccc(C(=O)NCC2CCN(c3nccc(C(F)(F)F)n3)CC2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(NCC1CCN(c2nccc(C(F)(F)F)n2)CC1)c1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.4 %

Procedure:
To a suspension of methyl-5-{[({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)amino]carbonyl}pyridine-2-carboxylate (272 mg, 0.643 mmol) in tetrahydrofuran, methanol, and water (5 ml, in a ratio of 3:2:1, respectively) was added lithium hydroxide (108 mg, 2.57 mmol). The reaction was stirred at ambient temperature for 18 h and then concentrated in vacuo to afford the title compound as a white solid (230 mg). Mass spectrum (ESI) 410 (M+1). 1H NMR (500 MHz, CD3OD) δ 8.96 (s, 1H), 8.54 (d, 1H, J=4.8 Hz), 8.24 (d, 1H, J=8.3 Hz), 8.05 (d, 1H, J=8 Hz), 6.81 (d, 1H, J=4.8 Hz), 4.70-5.0 (m, 2H), 2.94-3.01 (m, 2H), 1.97-2.03 (m, 1H), 1.88 (d, 2H, J=12.8 Hz), 1.21-1.34 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:66]1([CH2:72][SH:73])[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:72]([S:73][C:2]1[C:3]([F:14])=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: O=C1CCCN1c1cccc(Br)c1F
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCN1c1cccc(SCc2ccccc2)c1F
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Intermediate 98 (1.48 g, 5.73 mmol) in dioxane (50 ml) was stirred under argon. DIPEA (2 ml, 11.47 mmol), xantphos (0.2 g, 0.34 mmol) and Pd2(dba)3 (0.157 g, 0.17 mmol) were added and the reaction was heated to 100° C. Phenyl-methanethiol (0.64 ml, 5.45 mmol) was slowly added and the reaction stirred for 1 h. The reaction was quenched by the addition of 50 ml of H2O. After extraction with ethyl acetate (three times) the combined organic layers were washed with water, dried with Na2SO4, evaporated to dryness and the product was purified by silica gel chromatography.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[CH:16]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:21]([CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[O:22])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: O=C(Cl)C1CCCC1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)C1CCCC1

Procedure:
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and cyclopentanecarbonyl chloride (66 mg; 0.50 mmol; 2.0 eq.) as a white powder (64.1 mg, 86%). HPLC, Rt: 3.11 min. (purity 82.7%). LC/MS, M+(ESI): 297.4, M−(ESI): 295.3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([CH:24]=[CH2:25])[O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:24][CH3:25])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(CN1CCN(Cc2ccccc2)CC1)Oc1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCC(CN1CCN(Cc2ccccc2)CC1)Oc1ccc(F)cc1
Reaction time: 8 h

Procedure:
1-Benzyl-4-[2-vinyl-2-(4-fluorophenoxy)ethyl]piperazine 919 mg was dissolved in ethanol 20 ml, and palladium hydroxide/carbon 50 mg, 51.5% wet was added thereto, and the mixture was reduced for 8 hours under hydrogen pressure at about 3 kg/cm3. After the insolubles were filtered off, the filtrate was evaporated, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound, 717 mg, 77%, was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[NH:13][C:12]([CH3:15])=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Cl.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19][N:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:14]=2[N:13]=[C:12]1[CH3:15]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1cccc2nc(C)[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2c1nc(C)n2Cc1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 16 h
Yield: 25.5 %

Procedure:
A mixture of 1.61 g of 4-ethoxycarbonyl-2-methylbenzimidazole, 3.08 g of 2,4-dichlorobenzyl chloride, 1.51 g of potassium iodide, 1.05 g of potassium carbonate and 4 ml of N,N-dimethylformamide was stirred at 80° C. for 16 hours. The reaction mixture was extracted with chloroform and with water. The chloroform layer was washed with water, dried, and concentrated. The residue was purified through silica-gel column chromatography (eluent: a mixture of hexane and ethyl acetate at a ratio of 2:8) to give 0.730 g of 1-(2,4-dichlorobenzyl)-4-ethoxycarbonyl-2-methylbenzimidazole (297).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:9]3[CH:10]=[C:11]([CH2:20][OH:21])[CH:12]=[CH:13][C:14]=3[N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)=[N:8][C:4]=2[CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=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>[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:27]=[CH:26][C:5]3[N:6]([C:22]([CH3:23])([CH3:25])[CH3:24])[C:7]([C:9]4[CH:10]=[C:11]([CH2:20][OH:21])[CH:12]=[CH:13][C:14]=4[N:15]4[CH:19]=[N:18][CH:17]=[N:16]4)=[N:8][C:4]=3[CH:3]=2)=[CH:31][N:30]=1
Reactant: CC(C)(C)n1c(-c2cc(CO)ccc2-n2cncn2)nc2cc(Br)ccc21
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
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: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)n1c(-c2cc(CO)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 110 °C
Yield: 61.9 %

Procedure:
To a sealed vial is added [3-(5-bromo-1-tert-butyl-1H-benzoimidazol-2-yl)-4-[1,2,4]triazol-1-yl-phenyl]methanol (47 mg, 0.11 mmol) in DMF (2 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (29 mg, 0.13 mmol) and tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.011 mmol) and 2M aqueous Na2CO3 (0.25 mL, 0.5 mmol). The reaction mixture is heated under argon at 110° C. for 2 hours. The residue is diluted with EtOAc (10 mL), washed with brine (10 mL), and dried under anhydrous Na2SO4 (500 mg). The mixture is filtered and is concentrated. The residue is purified by silica gel flash chromatography with 0-10% 2M NH3 in MeOH/CH2Cl2 as the eluent. The product fractions are collected and concentrated to afford the title compound (30 mg, 62%). LCMS (ESMS): m/z 441.32 (M++1)
Reaction SMILES: C([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=O)C1C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>>[CH2:20]([N:12]1[C:13]2[C:18](=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:10]([OH:9])([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[C:11]1=[O:22])[CH3:21]
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: COc1ccc(CCl)cc1
Product: CCN1C(=O)C(O)(Cc2ccc(OC)cc2)c2cc(C)ccc21

Procedure:
This compound was made in an analogous fashion to 11-ethyl-3-hydroxy-5-methyl-3-(3,4,5-trimethoxybenzyl)indolin-2-one using 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate: and 4-methoxy benzyl chloride (purchased from Fisher Scientific). 1H-NMR δ 7.11 (s, 1H), 7.05 (dd, 1H), 6.83 (d, 2H), 6.65 (d, 2H), 6.56 (d, 1H), 3.72 (s, 3H), 3.64 (m, 1H), 3.40 (m, 1H), 3.24 (d, 1H), 3.12 (d 1H), 2.34 (s, 3H), 2.0 (bs, OH), 0.94 (t, 3H). Calculated mass for C19H21NO3, 311.15. Observed 334.1 (M+Na).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([S:12]([NH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)(=[O:14])=[O:13])=[CH:7][C:6]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])=[CH:5][C:4]=2[N:3]=1.[CH:28]1([CH2:31][NH2:32])[CH2:30][CH2:29]1>CN(C=O)C>[CH:16]1([NH:15][S:12]([C:8]2[C:9]3[CH:10]=[CH:11][C:2]([NH:32][CH2:31][CH:28]4[CH2:30][CH2:29]4)=[N:3][C:4]=3[CH:5]=[C:6]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:7]=2)(=[O:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NCC1CC1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(Cl)nc2c1
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(NCC3CC3)nc2c1
Temperature: 110 °C

Procedure:
A mixture of 2-chloro-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide (23 mg, 0.057 mmol), cyclopropylmethyl amine (0.2 mL) and DMF (0.5 mL) was heated at 110° C. for 1 hour. The reaction mixture was purified by preparative HPLC to give the desired product, N-cyclopentyl-2-((cyclopropylmethyl)amino)-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[NH2:17].C(N(C(C)C)C(C)C)C.[F:27][C:28]([F:46])([F:45])[C:29]1[CH:30]=[C:31]([C:39]([CH3:44])([CH3:43])[C:40](Cl)=[O:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>C(Cl)Cl>[F:27][C:28]([F:45])([F:46])[C:29]1[CH:30]=[C:31]([C:39]([CH3:43])([CH3:44])[C:40]([NH:17][C:9]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[O:41])[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccccc1-c1ccc([N+](=O)[O-])cc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccc([N+](=O)[O-])cc1NC(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 89 %

Procedure:
A solution of 925 mg (4.05 mmol) 2′-methyl-4-nitro-biphenyl-2-ylamine and 1.03 ml (6.08 mmol) N-ethyldiisopropylamine in 9 ml CH2Cl2 was cooled in an ice bath and a solution of 1.42 g (4.46 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 1 ml CH2Cl2 was added dropwise. The reaction mixture was kept at room temperature for 2 hrs. After addition of CH2Cl2, the organic layer washed with 1 N NaOH solution and 1 N HCl solution, dried (MgSO4) and evaporated to give 1.84 g (89%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-(2′-methyl-4-nitro-biphenyl-2-yl)-isobutyramide as yellow crystals, MS (ISP): 511.3 (M+H)+.
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:19](I)[CH3:20].[H-].[Na+].O>C1COCC1>[C:9]([N:1]([CH2:19][CH3:20])[C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: CCI
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(C(=O)OCc1ccccc1)[C@H](C(=O)O)C(C)C
Temperature: 60 °C
Reaction time: 12 h
Yield: 52.7 %

Procedure:
To a solution of Z-Val-OH (50 g) in THF (500 ml), ethyl iodide (127.3 ml, 1592 mmol) was added under cooling with ice and then sodium hydride (60% in oil) (23.88 g, 597 mmol) was added slowly, followed by stirring at 60° C. for 12 hours. The reaction mixture was mixed with water and washed with ether. The thus obtained aqueous layer was rendered acidic by the addition of dilute hydrochloric acid and extracted with ethyl acetate. The resultant was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (H:EA:AcOH=100:50:1), giving Z-N-Et-Val-OH (V2) (29.29 g, 53%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[O:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].CC1OC=CC=1CCO.Cl[Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24].N1C=CN=C1>ClCCl.O>[CH:23]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[O:9][CH2:8][C:7]1[CH:6]=[CH:5][O:4][C:3]=1[C:2]([F:1])([F:10])[F:11])([CH3:25])[CH3:24]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCc1ccoc1C(F)(F)F
Agent: Cc1occc1CCO
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)[Si](OCc1ccoc1C(F)(F)F)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the (2-trifluoromethyl-furan-3-yl)-methanol from (i) in dry dichloromethane (180 ml) was treated with chloro-tri-isopropyl-silane (2.6 g, 13.4 mmoles) and imidazole (1.45 g, 21.3 mmoles) and the mixture was stirred overnight at room temperature. Further aliquots of chloro-tri-isopropyl-silane (0.9 g, 4.64 mmoles) and imidazole (0.5 g, 7.34 mmoles) were added and the mixture was stirred for 3 h. The reaction mixture was diluted with water, the organic phase separated and washed sequentially with 0.1M aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, water and brine. After drying, evaporation of the solvents afforded a colourless oil. The oil was distilled under reduced pressure (0.05 torr) in a Kugelruhr apparatus collecting the fraction boiling at an oven temperature of 125±20° C. to afford compound 88 as a colourless oil.