Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[N:5]=[C:4]([S:16][CH3:17])[N:3]=1.[H][H]>[Pt].CO>[CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)[N:5]=[C:4]([S:16][CH3:17])[N:3]=1
Reactant: CSc1nc(C)n(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: CSc1nc(C)n(-c2ccc(N)cc2)n1
Yield: 68 %

Procedure:
A mixture of 2.5 parts of 5-methyl-3-(methylthio)-1-(4-nitrophenyl)-1H-1,2,4-triazole and 120 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and petroleumether. The product is filtered off and dried, yielding 1.5 parts (68%) 4-[5-methyl-3-(methylthio)-1H-1,2,4-triazol-1-yl]benzenamine; mp. 130°-136° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][N:45]1[CH:49]=[C:48]([NH2:50])[CH:47]=[N:46]1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:50][C:48]3[CH:47]=[N:46][N:45]([CH3:44])[CH:49]=3)=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Reactant: Cn1cc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)CN2C[C@@H]3COCCN3c3nc(Cl)ncc32)cn1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), 1-methyl-1H-pyrazol-4-amine (26 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C15H18ClN7O2, 364.13; found 364.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[CH:13]([OH:17])[NH:14][C:15](=O)[CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[SiH](C)C>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:15][NH:14][C:13](=[O:17])[CH:11]2[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(O)C2CN(Cc3ccccc3)CC12
Agent: C[SiH](C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCC2CN(Cc3ccccc3)CC12
Temperature: 3 °C
Reaction time: 16 h

Procedure:
5-Benzyl-3-hydroxyhexahydropyrrolo[3,4-c]pyrrole-1-one, (7 g; 30 mmol) in suspension in dichloromethane (50 ml) is placed in a 1000 ml three-necked flask and is then cooled in an ice bath. Trimethylsilane (7.1 g; 60 mmol) is run in slowly at 3° C. The reaction mixture is homogeneous and is left to react at 25° C. for 10 minutes, and is then cooled to 3° C. in order to run in trifluoroacetic acid (50 ml). The reaction mixture is agitated at 20° C. for 16 hours and then evaporated under reduced pressure. The residue is taken up in a mixture of ethyl acetate (100 ml) and 4 N aqueous sodium peroxide (50 ml), separated by settling out and washed with water (100 ml). After drying over magnesium sulfate and evaporation under reduced pressure, a yellow-colored oil is isolated, which is purified by chromatography on silica gel (silica: 40-63 μm, eluent: 90/10 ethyl acetate/methanol). The fractions containing the expected compound are combined and then evaporated under reduced pressure, giving 5-benzyl-hexahydropyrrolo[3,4-c]pyrrole-1-one, (7.2 g) which is used directly in the following step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:5]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[CH:7]=1.[Li+].CC([N-]C(C)C)C.[O:32]=[C:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.[Cl-]>C1COCC1>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][C:33]([OH:32])([C:11]2[S:12][C:8]([C:6]3[CH:5]=[C:4]([NH:13][C:14]4[N:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][N:15]=4)[CH:3]=[C:2]([CH3:1])[CH:7]=3)=[CH:9][N:10]=2)[CH2:34][CH2:35]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)s2)c1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
At −78° C., INTERMEDIATE 4 (200 mg, 0.595 mmol) in THF (3.0 mL) was added to LDA (892 μL, 1.784 mmol) and the reaction aged for 10 min followed by addition of tert-butyl 4-oxo-piperidine-1-carboxylate (474 mg, 2.379 mmol). The reaction was allowed to slowly warm to −20° C. over 4 hrs. To the mixture was added saturated aqueousammonium chloride solution and the product was extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layer was dried, filtered and solvent reduced by rotovap. The residue was purified by column chromatography on silica gel (0-50% ethyl acetate in DCM) to give 260 mg (0.485 mmol, 82%) tert-butyl-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate as off-white solid. MS ESI: [M+H]+ m/z 536.2. 1H NMR (600 MHz, CDCl3): δ 8.60 (d, J=4.8 Hz, 1H); 7.81 (appr s, 2H); 7.74 (br s, 1H); 7.28 (s, 1H); 7.02 (s, 1H); 7.00 (d, J=4.8 Hz, 1H); 4.0 (br s, 2H); 3.28 (br s, 2H); 2.34 (s, 3H); 2.09 (m, 2H); 1.88 (m, 2H); 1.41 (s, 9H). rhSYK=+++
Reaction SMILES: [Mg].Br[C:3]1[C:8]2[S:9][CH:10]=[C:11]([CH2:12][CH3:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1.CI.[C:16](=[O:18])=[O:17].Cl>CCOCC>[C:16]([C:3]1[C:8]2[S:9][CH:10]=[C:11]([CH2:12][CH3:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1)([OH:18])=[O:17]
Reactant: O=C=O
Reactant: CCc1csc2c(Br)cccc12
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Product: CCc1csc2c(C(=O)O)cccc12
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
Magnesium (2.67 g) was stirred in ether (15 ml) at room temperature. A solution of 7-bromo-3-ethylbenzo[b]thiophene (4.40 g) and methyl iodide (7.76 g) in ether (50 ml) were added dropwise over 30 min. Then, refluxing was conducted for 50 min and the reaction mixture was cooled in ice water bath. Using a separate reaction vessel, pulverized dry ice was stirred in ether, and the Grignard reagent prepared above was transferred to the vessel for about 5 min. To the reaction mixture was added 2N hydrochloric acid to acidify the solution, and the ether layer was separated. The solution was made alkaline with a 5% aqueous sodium hydroxide solution. The separated aqueous layer was acidified with 2N hydrochloric acid. After extraction with ether, the extract was dried over sodium sulfate and concentrated to give the objective compound (3.22 g) as crystals.
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.[OH-].[K+].[CH:6]1C=CC=C[CH:7]=1.C=C[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Cl)[CH:15]=1>O>[CH:6]([CH:2]1[CH2:3][N:1]1[CH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[CH:14][CH:15]=1)=[CH2:7]
Reactant: C1CN1
Reactant: C=Cc1cccc(CCl)c1
Reactant: c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=CC1CN1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a 1-liter, 3-necked flask equipped with a mechanical stirrer, reflux condenser and dropping funnel was charged 86 g. (2.0 mole) of aziridine, 66 g. of 85% powdered KOH (1.0 mole) and 400 ml. of benzene. The mixture was stirred and heated to reflux and 76.25 g. (0.5 mole) of ar-vinylbenzyl chloride containing 0.1% by weight of p,p'-diphenylphenylene diamine inhibitor was added over 15 minutes. The ar-vinylbenzyl chloride was an isomeric mixture consisting of approximately 60-70% meta isomer and 40-30% para isomer. The reaction mixture was then stirred rapidly under reflux for four hours, cooled to room temperature, filtered through a filter cell and the filtrate concentrated at reduced pressure to give 72.4 g. (91.1%) of crude product. This crude product was distilled at reduced pressure to give 63.1 g. (79.4%) of water-white N-ar-vinylbenzylaziridine b.p. 72°-73°/0.6 mm. whose identity was established by IR and NMR. Its purity was found to be greater than 99% by vapor phase chromatography on a G.E. silicone column (10 ft. × 1/4 in.) at 200° C. and 60 ml./min. helium flow rate.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N:13]2[N:17]=[CH:16][CH:15]=[N:14]2)[C:3]=1[C:4]([OH:6])=O.[CH3:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][NH:21][C@@H:20]1[CH2:25][N:26]1[C:34](=O)C2C(=CC=CC=2)C1=O.ClC1[N:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=1>>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N:13]2[N:17]=[CH:16][CH:15]=[N:14]2)[C:3]=1[C:4]([N:21]1[CH2:22][CH2:23][CH2:24][C@@H:19]([CH3:18])[C@H:20]1[CH2:25][NH:26][C:34]1[N:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=1)=[O:6]
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: COc1ccc(-n2nccn2)c(C(=O)O)c1F
Product: COc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)c1F

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 2-fluoro-3-methoxy-6-(2H-1,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 494 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.75-6.95 (m, 7H), 5.00-2.70 (m, 8H), 2.00-0.65 (m, 8H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:48])[CH2:18][C:17]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[CH:24]3)[CH:21]=[CH:22][C:16]=2[O:15]1>C(OCC)(=O)C>[CH3:13][C:14]1([CH3:48])[CH2:18][C:17]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:3][C:4](=[O:7])[O:5][N:44]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[CH:24]3)[CH:21]=[CH:22][C:16]=2[O:15]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1ncn(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1ncn(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.95 g), sodium hydrogen carbonate (1.35 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.76 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.29 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.46 g, 53%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:16][C:17](=[O:19])[CH3:18])[CH:7]=[C:8]([S:10]([F:15])([F:14])([F:13])([F:12])[F:11])[CH:9]=1)(=[O:3])[CH3:2].[Br-:20].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.S(=O)(=O)(O)O>CO.C1COCC1>[Br:20][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([NH:16][C:17](=[O:19])[CH3:18])[CH:7]=[C:8]([S:10]([F:11])([F:12])([F:13])([F:14])[F:15])[CH:9]=1)=[O:3]
Reactant: CC(=O)Nc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(C(=O)CBr)cc(S(F)(F)(F)(F)F)c1
Temperature: 40 °C
Yield: 76.5 %

Procedure:
N-[3-Acetyl-5-(pentafluorosulfanyl)phenyl]acetamide (859 mg, for synthesis see example 1) was dissolved in a mixture of methanol (10 ml) and THF (10 ml) and phenyltrimethylammonium tribromide (1.065 g) was added in portions while stirring. After stirring at RT for 2 h, the mixture was heated to 40° C. for a further 3 h. After cooling, the reaction mixture was added to 2 N sulfuric acid and the aqueous phase was extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. The crude product was purified using silica gel with ethyl acetate/heptane as the eluent. 480 mg of the desired compound were obtained. LC-MS rt: 1.47 min [M+H]+: 382.0 (met. a)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][N+:9]([O-])=[C:8]([CH3:13])[C:7]=1[CH3:14])[CH2:2][CH2:3][CH3:4].[C:15]([O:18]C(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:18][CH2:13][C:8]1[C:7]([CH3:14])=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:11]=[CH:10][N:9]=1)(=[O:17])[CH3:16]
Reactant: CCCCOc1cc[n+]([O-])c(C)c1C
Reactant: CC(=O)OC(C)=O
Product: CCCCOc1ccnc(COC(C)=O)c1C
Yield: 45.8 %

Procedure:
To 24.1 g of 4-butoxy-2,3-dimethylpyridine-1-oxide, 44.0 g (4.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 4 hours at 90° C. Acetic anhydride was distilled off, and then the resulting concentrated residue was purified on a silica gel column, to obtain 13.4 g of 2-acetoxymethyl-3-methyl-4-butoxy-pyridine as an oily matter.
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)(=[O:3])[NH2:2].[ClH:21].O>C(OCC)(=O)C>[ClH:21].[ClH:21].[N:8]1([CH2:7][CH2:6][O:5][CH2:4][C:1]([NH2:2])=[O:3])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOCC(N)=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)COCCN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
1.4 g (0.005 mol) of tert-butyl 4-(2-carbamoylmethoxyethyl)piperazine-1-carboxylate prepared in Example I.4.1. and 14 ml of a 3M solution of hydrochloric acid in ethyl acetate are introduced into a 50 ml three-necked round-bottomed flask fitted with a water-cooled condesner and a mechanical stirrer. The mixture is stirred at room temperature for 2 hours. The precipitate is filtered off and is washed with ethyl acetate. 1.3 g (100%) of 2-(1-piperazinyl)ethoxyacetamide dihydrochloride are obtained. NRM: δ: 3.4 (2H, t, 4.7 Hz); 3.49-3.66 (8H, m); 3.81 (2H, t, 4.7 Hz); 3.87 (2H, s); 6.2 (5H exchangeable, bm); 7.2-7.7; 10.2. Mass spectrum: 188 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH2:20][CH:21]([CH3:23])[CH3:22].[F:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Br>>[F:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27][O:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:13]2)=[O:7])=[CH:4][C:3]=1[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1O
Reactant: Fc1ccc(CBr)c(F)c1
Product: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1OCc1ccc(F)cc1F
Yield: 74.8 %

Procedure:
As in the case of Example 18, 1-(4-hydroxy-3-isobutylbenzoyl)-4-isobutylpiperazine (1.60 g) was benzylated with 2,4-difluorobenzyl bromide (1.24 g), thereby yielding 1.67 g of the aimed compound.
Reaction SMILES: CC([O-])(C)C.[K+].[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[NH:16][C:17]1[C:22]([S:23][CH2:24][CH2:25][C:26](OC)=O)=[CH:21][CH:20]=[CH:19][N:18]=1.FC1C=C[C:34]([C:35]#[N:36])=[CH:33][CH:32]=1.C(OCC)(=O)C>CS(C)=O>[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[NH:16][C:17]1[C:22]([S:23][C:24]2[CH:32]=[CH:33][C:34]([C:35]#[N:36])=[CH:26][CH:25]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: COC(=O)CCSc1cccnc1Nc1nc2cccnc2s1
Reactant: N#Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Sc2cccnc2Nc2nc3cccnc3s2)cc1
Reaction time: 0.25 h
Yield: 32.5 %

Procedure:
Added potassium 2-methylpropan-2-olate (0.097 g, 0.87 mmol) to a solution of methyl 3-(2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)propanoate (100 mg, 0.289 mmol) in DMSO (1 mL). Stirred 15 minutes, added 4-fluorobenzonitrile (0.105 g, 0.866 mmol) and stirred overnight. Partitioned between ethyl acetate and water. Washed the organic layer with water, brine, dried, and concentrated. Purified by MPLC eluting with 3:2 hexane:ethyl acetate to afford the title compound (0.034 g, 33% yield) as a white powder: 1H NMR (CDCl3) δ 7.10-7.15 (m, 3H), 7.32 (dd, 1H), 7.52 (d, 2H), 7.87 (d, 1H), 7.96 (d, 1H), 8.42 (d, 1H), 8.58 (d, 1H), 9.10 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)=O>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:27]=[C:28]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3ccc4ccccc4c3)nc2-c2ccc(Cl)cc2)cc1
Yield: 53.7 %

Procedure:
To a mixture of 4-chloro-N-(4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (400 mg, 1.29 mmol) and sodium bicarbonate (216 mg, 2.59 mmol) in isopropanol (30 mL), 2-bromo-2′-acetonaphthone (970 mg, 3.89 mmol) was added. After heating the reaction mixture at 80–85° C. for 20 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (1.2 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 2-(4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl]-4-(2-naphthyl)-1H-imidazole (318 mg, 54%) as a pale yellow solid: mp 204–206° C. Anal Calc'd. for C26H19N2SO2Cl: C, 68.04; H, 4.17; N, 6.10; S, 6.99. Found: C, 67.65; H, 4.19; N, 5.96; S, 7.10.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([C:23]#N)=[CH:22][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].C([Al+]CC(C)C)C(C)C.C1C[O:40]CC1>O.CC(=O)OCC>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([CH:23]=[O:40])=[CH:22][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C1CCOC1
Reactant: CCCCCCCOc1ccc(Cc2nc3cc(C#N)ccc3[nH]2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCOc1ccc(Cc2nc3cc(C=O)ccc3[nH]2)cc1
Reaction time: 1 h
Yield: 46 %

Procedure:
To a stirred solution of 2-(4-(heptyloxy)benzyl)-1H-benzo[d]imidazole-5-carbonitrile INT-46 (1.22 g, 3.51 mmol) in THF (20 mL) at 0° C. was added diisobutylaluminum hydride (12.3 mL, 12.3 mmol, 1 M in toluene). After 2 h the reaction mixture was poured onto Rochelle's salt (7.91 g, 28.0 mmol) in water (100 mL) and EA (50 mL) and stirred for 1 h. The layers were split and the aqueous layer was further extracted with EA (2×30 mL). The combined organics were washed with brine (20 mL) dried over MgSO4 and evaporated. The crude material was purified by chromatography (EA/isohexanes) to afford 571 mg (46%) of 2-(4-(heptyloxy)benzyl)-1H-benzo[d]imidazole-5-carbaldehyde INT-47 as a brown oil. LCMS-ESI (m/z) calculated for C22H26N2O2: 350; found 351 [M+H]−, tR=2.34 min (Method 5).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ON1C2C=[CH:54][CH:55]=[CH:56][C:51]=2[N:50]=N1.C(N(C(C)C)CC)(C)C.N1CCCC1>CN(C)C=O>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:50]4[CH2:51][CH2:56][CH2:55][CH2:54]4)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Solvent: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCCC2)CC1
Reaction time: 2 h
Yield: 89.2 %

Procedure:
To a suspension of {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid (75.0 mg, 0.112 mmole) in dimethylformamide (6 mL) were added successively 1-hydroxybenzotriazole (23.0 mg, 0.169 mmole, Chem-Impex), N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate (64.0 mg, 0.169 mmole, Aldrich) and diisopropylethylamine (58 mg, 0.448 mmole). The mixture was stirred for 15 min before pyrrolidine (12.0 mg, 0.169 mmole, Aldrich) was added. The reaction mixture was allowed to stir for 2 h before concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1 N sodium hydroxide, brine, dried and concentrated. The crude residue was purified by flash column chromatography (silica gel, eluting with a gradient of 1-10% methanol in methylene chloride) to give the title compound (71.8 mg, 89% yield). HR-MS (ES, m/z) calculated for C40H50Cl2N5O3 [(M+H)+] 718.3285, observed 718.328.
Reaction SMILES: C(Cl)Cl.[F:4][C:5]1[N:10]=[C:9]([F:11])[C:8]([F:12])=[C:7](F)[C:6]=1[F:14].[CH3:15][NH:16][CH3:17]>O>[CH3:15][N:16]([CH3:17])[C:7]1[C:6]([F:14])=[C:5]([F:4])[N:10]=[C:9]([F:11])[C:8]=1[F:12]
Reactant: CNC
Reactant: Fc1nc(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O
Product: CN(C)c1c(F)c(F)nc(F)c1F
Reaction time: 0.5 h

Procedure:
To methylene chloride (50 mL) cooled in an ice bath was added pentafluoropyridine (2.0 g, 11.8 mmol) and dimethylamine (2.97 mL of a 40% solution in water, 24 mmol). After stirring for 30 minutes the solution was washed with water, and dried over basic alumina. The solvent was removed in vacuo to give 4-dimethylamino-2,3,5,6-tetrafluoropyridine; NMR (CDCl3) 3.13 (m,6) ppm.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[P:5](Cl)([O:10][CH2:11][CH3:12])([O:7][CH2:8][CH3:9])=[O:6].[CH:14]([C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:18]=1[NH2:19])([CH3:16])[CH3:15]>CC(C)=O>[CH3:25][CH:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:17]([CH:14]([CH3:16])[CH3:15])[C:18]=1[NH:19][C:2]([NH:3][P:5](=[O:6])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:1])[CH3:26]
Reactant: CCOP(=O)(Cl)OCC
Reactant: N#C[O-]
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=O)(NC(=O)Nc1c(C(C)C)cccc1C(C)C)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
To a suspension of potassium cyanate (0.82 g, 10.1 mmol) in acetone (10 mL) is added diethyl chlorophosphate (1.3 mL, 9.2 mmol). The mixture is heated at reflux for 90 minutes. After cooling to room temperature, 2,6-diisopropylaniline (1.7 mL, 9.2 mmol) is added. The mixture is stirred at room temperature for 2 hours, then heated at reflux for 2 hours. After cooling, the mixture is filtered. The filtrate is diluted with ethyl acetate, washed twice with brine, dried over magnesium sulfate, and concentrated. Flash chromatography (3:2 ethyl acetate/hexane) provides 1.3 g of the product as a white solid. Recrystallization from ethyl acetate/hexane provides an analytical sample; mp 157°-158° C.