Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:44])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:29]3[N:30]=[C:31]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[O:32][C:33]=3[C:34]([F:37])([F:36])[F:35])=[O:28])=[CH:22][N:21]=2)=[CH:16][CH:15]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>>[C:38]1([C:31]2[O:32][C:33]([C:34]([F:35])([F:36])[F:37])=[C:29]([C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([C:17]4[CH:18]=[CH:19][C:14]([C:13]([N:9]5[CH2:10][CH2:11][CH2:12][C@@H:8]5[C:6]([OH:7])=[O:5])=[O:44])=[CH:15][CH:16]=4)=[N:21][CH:22]=3)=[O:28])[N:30]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)c1ccc(-c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(-c2ccc(C(=O)N3CCC[C@@H]3C(=O)O)cc2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
(R)-1-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (37 mg) from above was treated with 2 mL of trifluoroacetic acid and stirred at room temperature for one hour. The reaction was concentrated and the product was lyophilized to give 27 mg of (R)-1-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoyl)-pyrrolidine-2-carboxylic acid as a white powder. LCMS calcd for C28H21F3N4O5 (m/e) 550, obsd 551 (M+H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[C:9]([C:12]1[CH:13]=[C:14]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:15]=[C:16]([S:18]([F:23])([F:22])([F:21])([F:20])[F:19])[CH:17]=1)(=[O:11])[CH3:10]>C(COC)OC>[C:9]([C:12]1[CH:13]=[C:14]([N:24]([CH3:1])[C:25](=[O:30])[C:26]([F:29])([F:27])[F:28])[CH:15]=[C:16]([S:18]([F:22])([F:23])([F:21])([F:20])[F:19])[CH:17]=1)(=[O:11])[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Agent: [K+]
Solvent: CI
Solvent: COCCOC
Product: CC(=O)c1cc(N(C)C(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Temperature: 100 °C

Procedure:
In a microwave insert, N-(3-acetyl-5-pentafluorosulfanylphenyl)-2,2,2-trifluoroacetamide (O3.075; 0.25 g) was dissolved in absolute dimethoxyethane (7.5 ml), powdered potassium carbonate was added and the mixture was admixed with iodomethane (80 μl). Subsequently, the mixture was heated in the microwave to 100° C. for 40 min. Once further N-(3-acetyl-5-pentafluorosulfanylphenyl)-2,2,2-trifluoroacetamide (4×250 mg) had been converted in the manner described, the five batches were worked up together, by decanting from potassium carbonate into 1 N hydrochloric acid with ice cooling. After repeatedly washing the potassium carbonate residue with dimethoxyethane, the aqueous phase was extracted five times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (met. A). The product-containing fractions were combined, freed of the acetonitrile and extracted five times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 1.03 g of the desired compound were obtained. LC-MS rt: 1.62 min [M+H]+: 372.0 (met. a)
Reaction SMILES: C(=[N:14][NH:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([C:23]1[N:27](COCC2C=CC=CC=2)[C:26]2[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:25]=2[N:24]=1)=O)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C(O)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.CCCCCCC>[CH3:42][O:41][C:38]1[CH:39]=[CH:40][C:25]2[N:24]=[C:23]([C:21]3[C:17]4[S:18][CH:19]=[CH:20][C:16]=4[NH:15][N:14]=3)[NH:27][C:26]=2[CH:37]=1
Reactant: COc1ccc2nc(C(=O)c3sccc3NN=C(c3ccccc3)c3ccccc3)n(COCc3ccccc3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCCC
Solvent: CCO
Product: COc1ccc2nc(-c3n[nH]c4ccsc34)[nH]c2c1
Temperature: 75 °C
Reaction time: 4.33 h

Procedure:
A mixture of [3-(N′-benzhydrylidene-hydrazino)-thiophen-2-yl]-(1-benzyloxymethyl-6-methoxy-1H-benzoimidazol-2-yl)-methanone (300 mg, 0.553 mmol, Example 2C), concentrated hydrochloric acid (4 mL), and ethanol (12 mL) is heated at 75° C. with stirring for 260 minutes. The reaction is allowed to cool to ambient temperature, diluted with water (40 mL), and basified with 5% aqueous potassium carbonate. The mixture is extracted with ethyl acetate and the combined extracts washed with water and brine successively. The organic layer is dried over potassium carbonate and concentrated under reduced pressure to give a brown solid. The solid is chromatographed on silica. Step gradient elution with 70% ethyl acetate/heptane, 80% ethyl acetate/heptane, and 90% ethyl acetate/heptane provided an orange solid. Trituration with ethyl acetate/heptane gave 6-methoxy-2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-benzoimidazole as a beige powder: TLC Rƒ0.28 (silica, 75% ethyl acetate/heptane); LC/MS: M+H 241.0, RT=2.15 minutes; 1H NMR [(CD3)2SO), 300 MHz]: two species observed (ca. 60:40), presumed to be slowly exchanging imidazole tautomers, with chemical shifts of resolved resonances reported as major (minor); δ 13.48 (13.51) brs (1H; NH of benzimidazole), 12.79 brs (1H; NH of pyrazole), 7.77 d (1H, J=5 Hz; H-α of thiophene), 7.57 (7.35) d (1H, J=8.5 Hz; H-7 of benzimidazole), 7.20 d (1H, J=5 Hz; H-β of thiophene), 6.96 (7.25) d (1H, J=2 Hz; H-4 of benzimidazole), 6.82 m (1H; H-6 of benzimidazole), 3.80 (3.32) s (3H; methoxy). Chemical shifts are referenced to internal dimethyl sulfoxide-D5 (δ 2.50).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:8]2=[N:9][CH:10]=1)=O.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[C:17]1([S:14]([N:11]2[C:8]3=[N:9][CH:10]=[C:5]([CH2:3][OH:2])[CH:6]=[C:7]3[CH:13]=[CH:12]2)(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2cc(CO)cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a stirred solution of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (prepared as in Example 1, 8 g, 25.3 mmol) in dry tetrahydrofuran (100 mL) was added diisobutylaluminum hydride (126 mL, 126 mmol) at −78° C. The mixture was warmed to room temperature and stirred for 1 h. The mixture was cooled to 0° C. and quenched with a saturated aqueous potassium sodium tartrate solution, and then stirred for 30 min. The resulting mixture was filtered, washed with tetrahydrofuran (300 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford (1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-methanol (6.5 g, 89.2%) as a light yellow solid: LC/MS m/e calcd for C14H12N2O3S [M+H]+ 289.33, observed 289.1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:12]([C:14]1([NH:17][C:18]([C@@H:20]2[CH2:24][C@@H:23]([S:25]([C:28]3[CH:33]=[CH:32][C:31](F)=[CH:30][C:29]=3[C:35]([F:38])([F:37])[F:36])(=[O:27])=[O:26])[CH2:22][N:21]2[C:39]2[N:40]([CH:45]3[CH2:48][CH2:47][CH2:46]3)[N:41]=[C:42]([CH3:44])[CH:43]=2)=[O:19])[CH2:16][CH2:15]1)#[N:13].C(OC(C)=O)(C)C>CC(N(C)C)=O>[C:12]([C:14]1([NH:17][C:18]([C@@H:20]2[CH2:24][C@@H:23]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:30][C:29]=3[C:35]([F:36])([F:38])[F:37])(=[O:26])=[O:27])[CH2:22][N:21]2[C:39]2[N:40]([CH:45]3[CH2:48][CH2:47][CH2:46]3)[N:41]=[C:42]([CH3:44])[CH:43]=2)=[O:19])[CH2:16][CH2:15]1)#[N:13]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)OC(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(-n4cccn4)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Yield: 20 %

Procedure:
Pyrazole (5 mg, 67 umol; CAS Reg. No. 288-11-9) and cesium carbonate (18 mg, 56 umol) were added to a solution of (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (30 mg, 56 umol; example 388 g) in DMA (0.9 ml) under an argon atmosphere. The mixture was heated for 48 h to 90° C. and for additional 4 h to 120° C. in a shaking reactor. Ice water/brine 1/1 and iPrOAc were added and the layers were separated. The aqueous layer was extracted one more time with iPrOAc. The combined extracts were washed with ice water/brine 1/1, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to give a brown oil which was purified by preparative HPLC to give the title compound (6.5 mg, 11 umol; 20%) as colorless oil. MS (ESI): m/z=588.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:11][C:10]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:33][CH2:34][O:35][CH:36]([CH3:38])[CH3:37])(=O)=O)=CC=1.O>CC#N.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:11]([CH2:33][CH2:34][O:35][CH:36]([CH3:38])[CH3:37])[C:10]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=c1cc(Cl)nc2n1CC1(CCCC1)N2
Reactant: Cc1ccc(S(=O)(=O)OCCOC(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)OCCN1c2nc(Cl)cc(=O)n2CC12CCCC2
Temperature: 65 °C
Yield: 61.5 %

Procedure:
0.200 g of 7′-chlorospiro[cyclopentane-1,2′-imidazo[1,2-a]pyrimidin]-5′-one are suspended in 7 mL of CH3CN, 0.70 g of cesium carbonate and 0.55 g of 2-isopropoxyethyl 4-methylbenzenesulfonate are added. The mixture is heated to 65° C. for 36 h. Water, ethyl acetate are added and then after decantation, the organic phase is dried with magnesium sulfate and then evaporated. The crude is purified by flash chromatography on silica gel (CH2Cl2/MeOH, 99/1). 0.17 g (yield=47%) of 7′-chloro-1′-(2-isopropoxyethyl)-spiro[cyclopentane-1,2′-imidazo[1,2-a]pyrimidin]-5′-one are obtained as a brown powder and including the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH:10](=O)[CH2:11][CH2:12][CH3:13]>>[CH2:10]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([Cl:1])[CH:3]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCC=O
Reactant: Cc1ccc(N)cc1Cl
Product: CCCCNc1ccc(C)c(Cl)c1
Yield: 97 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 3-chloro-p-toluidine (Aldrich, 430 μL, 3.53 mmol) and butyraldehyde (320 μL, 3.13 mmol) were converted to the title compound (600 mg, 79%). 1H NMR (CDCl3) δ 7.06-6.93 (m, 1H), 6.62 (d, J=2.4 Hz, 1H), 6.43 (dd, J=8.1, 2.4 Hz, 1H), 3.56 (br s, 1H), 3.08 (t, J=7.2 Hz, 2H), 2.26 (s, 3H), 1.66-1.50 (m, 2H), 1.49-1.33 (m, 2H), 1.00-0.89 (m, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]=[CH:10][CH2:11][NH:12][C:13](=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH:9]=[CH:10][CH2:11][NH:12][C:13](=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCC=CCNC(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC=CCNC(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{4-[6,6-Bis-(4-fluoro-phenyl)-hexanoylamino]-but-2-enyl}-carbamic acid tert-butyl ester (1.6 g, 4.3 mmol) was dissolved in dry CH2Cl2 (50 ml) followed by addition of TFA (20 ml). The resulting solution was stirred at room temperature for 2 hrs. The solution was concentrated under reduced pressure. The resulting residue was dissolved in water (20 ml) and pH of the solution was adjusted to 10. The water phase was extracted with CH2Cl2 (100 ml), and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the desired product in almost quantitative yield.
Reaction SMILES: CS([O:5][C:6](=O)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=O)=O.[Br-:29].[Mg+2].[Br-]>CCOCC>[C:6]([Br:29])(=[O:5])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: [Br-]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)OS(C)(=O)=O
Agent: [Mg+2]
Solvent: CCOCC
Product: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)Br
Reaction time: 8 h

Procedure:
A mixture of docosahexaenoyl methane sulfonate (2.0 g, 5.1 mmol) and magnesium bromide (4.3 g, 23 mmol) in anhydrous ether (100 mL) was stirred under argon overnight. The resulting suspension was filtered and the solid washed with ether (2×30 mL). The filtrate and wash were combined and solvent evaporated. The resulting residual was purified by column chromatography on silica gel (230-400 mesh, 40 mL) eluted with hexanes. This gave 2.2 g of docosahexaenoyl bromide (II) as colourless oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH3:17])[N:5](COCC[Si](C)(C)C)[C:6]=1[CH:7]=[O:8].Cl>C(O)C>[Br:1][C:2]1[NH:3][C:4]([CH3:17])=[N:5][C:6]=1[CH:7]=[O:8]
Reactant: Cc1nc(Br)c(C=O)n1COCC[Si](C)(C)C
Agent: Cl
Solvent: CCO
Product: Cc1nc(C=O)c(Br)[nH]1
Yield: 83.7 %

Procedure:
4-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)imidazole-5-carbaldehyde (18.5 g) was dissolved in ethanol (80 ml) and 6N hydrochloric acid (80 ml) was added. The mixture was refluxed under heating for 1 hr. The solvent was evaporated under reduced pressure and saturated aqueous sodium hydrogencarbonate solution was added under ice-cooling until the mixture assumed weak alkalinity. The precipitated crystals were collected by filtration, and the crystals were washed with methanol and heat-dried under reduced pressure to give 5-bromo-2-methylimidazole-4-carbaldehyde (9.17 g) as white crystals.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1[O:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]=1.Cl>CCOCC>[C:10]([NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16])(=[O:15])[CH3:9]
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1nc2ccccc2c(=O)o1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)Nc1ccccc1C(=O)C1CCCCC1
Temperature: -10 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
Cyclohexylmagnesium bromide (240 ml of a 2M solution in ether, 0.48 mol) in ether (200 ml) was added dropwise to a solution of 2-methyl-4H-3,1-benzoxazin-4-one (100 g, 0.62 mol) in ether (1100 ml) at -10° C. over 2 h. The mixture was stirred at this temperature for 2 h, then at ambient temperature for 30 min. After cooling to -10° C. the suspension was treated with 2M HCl (600 ml), keeping the temperature below 0° C. After stirring for 15 rain the layers were separated, and the ethereal layer lo washed sequentially with water (500 ml), 5% sodium hydroxide solution (2×500 ml) and finally water (2×500 ml). The organic layer was separated, dried (MgSO4), evaporated in vacuo and chromatographed on silica using petrol:ethyl acetate (2:1) to give (2-acetamidophenyl) cyclohexyl methanone (28 g, 24%) as a pale yellow solid. mp 66° C. 1H NMR (CDCl3, 360MHz) δ1.25-1.89 (10 H, m), 2.23 (3H, s), 3.33 (1H, m), 7.13 (1H, dt, J=6 and 1Hz), 7.53 (1H, dt, J=6 and 1Hz), 7.92 (1H, d, J=6Hz), 8.76 (1H, d, J =6Hz), 11.73 (1H, brs).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]3[CH3:21])[N:12]=2)=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:22])=[C:11]([CH2:13][CH2:14][N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]4[CH3:21])[N:12]=3)=[CH:4][CH:3]=2)=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCCC1C
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CCN1CCCCC1C
Reaction time: 0.62 h
Yield: 34.3 %

Procedure:
Add 1-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-2-methylpiperidine (0.290 g, 0.798 mmol), Pd(Ph3)4 (0.041 g, 0.035 mmol), 4-methanesulfonylphenylboronic acid (0.240 g, 1.20 mmol), 2N Na2CO3 (1.98 mL), and 1,4-dioxane (1 mL) to a microwave vessel. Microwave at 30 W, 90° C. for 30-45 minutes. Concentrate and purify on silica gel eluting with 10% 2N NH3 in methanol/dichloromethane to give 1-{2-[2-(4′-methanesulfonyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl}-2-methylpiperidine (0.120 g, 34%).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH2:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32]>>[CH3:32][C:31]([OH:33])([CH3:34])[CH2:30][NH:29][CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2
Reactant: CC(C)(O)CN
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCC(C)(C)O)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 1-amino-2-methylpropan-2-ol via General Procedure E to give 8.1 mg of 292 following reverse phase purification. MS (Q1) 451.2 (M)+
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[C:9]([NH:21][C:22]([NH2:24])=[S:23])=[N:10][CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:26][CH:27]=O>CN(C=O)C>[CH:1]1([CH2:6][O:7][C:8]2[C:9]([NH:21][C:22]3[S:23][CH:26]=[CH:27][N:24]=3)=[N:10][CH:11]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NC(=S)Nc1ncc(Oc2ccccc2)cc1OCC1CCCC1
Reactant: O=CCCl
Solvent: CN(C)C=O
Product: c1ccc(Oc2cnc(Nc3nccs3)c(OCC3CCCC3)c2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
(3-Cyclopentylmethoxy-5-phenoxy-pyridine-2-yl)-thiourea (0.68 mmol) is dissolved in DMF (3 ml) and chloro-acetaldehyde (1.0 eq., 55% in water) is added and stirred three hours at 100° C. After cooling to room temperature the suspension is pored into ice-water and extracted with methyl-tert.-butyl ether. The combined organic phases are washed with brine and dried over MgSO4. The solvent is removed in vacuo. (3-Cyclopentylmethoxy-5-phenoxy-pyridine-2-yl)-thiazole-2-yl-amine (“A29”) is obtained after reversed phase column chromatography (acetonitrile/water+0.1% TFA) as yellow solid in a yield of 43%. HPLC (method C): 2.03 min; LC-MS (method A): 2.22 min, 368.15 (MH+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 7.705 (d, 1H, J=2.1 Hz), 7.509 (d, 1H, J=3.9 Hz), 7.387 (t, 2H, J=7.9 Hz), 7.32 (d, 1H, J=2.1 Hz), 7.143-7.119 (m, 2H), 7.029 (d, 2H, J=7.9 Hz), 3.992 (d, 2H, J=7.1 Hz), 3.787 (br, 1H), 2A49-2.389 (m, 1H), 1.853-1.829 (m, 2H), 1.619-1.547 (m, 4H), 1.371-1.320 (m, 2H).
Reaction SMILES: I[C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C(N(CC)CC)C.O1CCCC1.[Cu]I.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:3]([NH2:12])=[N:4][CH:5]=1
Reactant: Nc1ncc(C(F)(F)F)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(C(F)(F)F)cnc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
3-Iodo-5-trifluoromethyl-pyridin-2-ylamine (52.5 g, 180 mmol) was dissolved in a mixture of triethylamine (76 mL) and tetrahydrofuran (300 mL) and the solution was degassed and purged with nitrogen. Trimethylsilyl acetylene (38 mL, 270 mmol), copper(I) iodide (0.7 g, 3.6 mmol) and bis(triphenylphosphino) palladium (II) chloride (2.53 g, 3.6 mmol) were added. The mixture was degassed and purged with nitrogen one more time. The mixture was stirred at ambient temperature for 16 h and a solution containing a white precipitate resulted. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 15%-35% ethyl acetate in hexanes) to afford 5-trifluoromethyl-3-trimethylsilanylethynyl-pyridin-2-ylamine (43.8 g, 92%) as a yellow solid: LC/MS m/e calcd for C11H13F3N2Si [M+H]+ 259.32, observed 258.9.
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[N:9]=[C:8]([SH:10])[NH:7][C:6]=2[CH:11]=1.Cl.[CH3:19][C:20]1[C:21]([CH2:32]Cl)=[N:22][CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]([F:31])([F:30])[F:29].[OH-].[Na+]>C(O)C>[CH3:19][C:20]1[C:21]([CH2:32][S:10][C:8]2[NH:7][C:6]3[CH:11]=[C:2]([F:1])[C:3]([N:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)=[CH:4][C:5]=3[N:9]=2)=[N:22][CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]([F:31])([F:29])[F:30]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CCl
Reactant: Fc1cc2[nH]c(S)nc2cc1N1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2cc(N3CCCCC3)c(F)cc2[nH]1
Yield: 49.5 %

Procedure:
The title compound (0.45 g, 50%) was prepared by the general procedure using 6-fluoro-5-(piperidin-1-yl)-2-mercapto-1H-benzimidazole (0.5 g, 2.0 mmol) (obtained in preparation 3), 3-methyl-4-(2,2,2,-trifluoroethoxy)-2-chloromethylpyridine hydrochloride (0.47 g, 2.0 mmol), sodium hydroxide (0.16 g, 4.0 mmol) and ethanol (10 mL). mp 160-161° C.; 1R (KBr) 3122, 1585, 1432 cm-1 ; 1H NMR (CDCl3) δ 1.60 (m, 2H, CH2), 1.80 (m, 4H, (CH2)2), 2.38 (s, 3H, CH3), 3.00 (m, 4H, N(CH2)2), 4.40 (s, 2H, SCH2), 4.46 (q, J=7.8 Hz, 2H, OCH2CF3), 6.74 (d, J=5.5 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.26 (d, J=10.0 Hz, 1H), 8.42 (d, J=5.5 Hz, 1H), 12.50 (s, 1H, NH); Mass (m/z) 454 (M+).
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:35])[C@@H:10]([NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOC(C)=O>[Cl:33][C:27]1[C:26]([CH3:34])=[C:25]([NH:24][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=3)=[N:14][N:15]=2)[C@@H:9]([OH:8])[CH3:35])[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -40 °C

Procedure:
To a 25 mL round bottom flask equipped with a magnetic stirrer and a septum was added 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (9.98 g, 19.6 mmol), followed by anhydrous THF (245 mL) under an atmosphere of nitrogen. The reaction mixture was cooled to −40° C. via a CO2/acetone bath. To this was added tetrabutylammonium fluoride as a 1M solution in THF (22.54 mL, 22.54 mmol) producing an instant color change to yellow. This was allowed to warm to room temperature for a period of 4 h. The solvent was then removed under reduced pressure to yield a black residue. This residue was taken up in EtOAc (200 mL) and washed with water (2×250 mL), brine (1×200 mL) and dried over Na2SO4. The solution was then filtered and concentrated under reduced pressure using rotary evaporation to reveal a yellow solid. This was purified via silica gel chromatography eluted with hexanes-EtOAc (20:80) the title compound as a white solid (5.23 g, 68%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.10 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 5.27 (d, J=8.0 Hz, 1H), 4.80 (dd, J=2.8, 8.4 Hz, 1H), 4.62-4.65 (m, 1H), 2.91 (br s, 1H), 2.37 (s, 3H), 1.46 (d, J=6.4 Hz, 3H).