Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:23]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[CH:20][C:4]=1[O:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:9]=[CH:8][N:7]=1.Br[CH2:29][C:30](=[O:33])[CH2:31][CH3:32].C(N(CC)CC)C>CN(C=O)C>[F:2][C:3]1[CH:23]=[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=[CH:20][C:4]=1[O:5][C:6]1[N:7]=[CH:8][N:9]=[C:10]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:29][C:30](=[O:33])[CH2:31][CH3:32])[CH2:16][CH2:15]2)[C:11]=1[CH3:12]
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Reactant: CCC(=O)CBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)CN1CCC(Oc2ncnc(Oc3ccc(S(C)(=O)=O)cc3F)c2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine hydrochloride salt (42 mg, 0.1 mmol), 1-bromo-butan-2-one (0.1 mmol, 1 eq), and triethylamine (0.2 mmol, 2 eq) were dissolved in DMF (1 mL) and then stirred at room temperature overnight. The crude was filtered and then purified via prep-LCMS 5-95% to provide Compound C93 as an oil (39.6 mg, 88%). Exact mass calculated for C21H26FN3O5S 451.2, found 452.3 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][C:22]=2[CH3:31])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].[F:32][C:33]([F:53])([F:52])[C:34]1[CH:35]=[C:36]([C@H:44]2[O:49][C:48](=[O:50])[NH:47][C@@H:46]([CH3:51])[CH2:45]2)[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[F:53][C:33]([F:32])([F:52])[C:34]1[CH:35]=[C:36]([C@H:44]2[O:49][C:48](=[O:50])[N:47]([CH2:2][C:3]3[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=3[C:13]3[CH:14]=[C:15]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][C:22]=4[CH3:31])[CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[C@@H:46]([CH3:51])[CH2:45]2)[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CBr)c2)c(C)c1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)C[C@@H]3C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 2″-(bromomethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (78.5 mg; 0.159 mmol) and (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazinan-2-one (43.4 mg; 0-133 mmol) in DMF (1 mL) was added potassium tert-butoxide (14.9 mg; 0.133 mmol). The reaction was stirred at room temperature for 2 h, quenched with sat. NH4Cl, and partitioned between EtOAc (10 mL) and sat. NH4Cl (10 mL). The aqueous layer was extracted with EtOAc (4×25 mL) and the combined extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-100% EtOAc/hexanes gradient) to afford methyl 2″-({(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazinan-3-yl}methyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate as a colorless glass. LCMS=740.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.89-7.82 (m, 3H), 7.71-7.66 (m, 2H), 7.59 (s, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.41-7.38 (m, 1H), 7.30 (d, J=8 Hz, 1H), 7.22 (d, J=2.2 Hz, 1H), 7.16 (d, J=8 Hz, 1H) 7.11-7.07 (m, 1H), 5.38 (d, J=15.6 Hz, 1H), 4.65 (d, J=11.5 Hz, 1H), 4.32 (d, J=15.8 Hz, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.30-3.25 (m, 1H), 2.34 (s, 3H), 2.17-2.12 (m, 1H), 1.73-1.65 (m, 1H), 1.08 (d, J=6.2 Hz, 3).
Reaction SMILES: [B][B][B][B][B][B][B][B][B][B].[NH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:19]=2[N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[N:14]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[N:13]=1.[CH3:49][O:50][C:51]1[CH:64]=[CH:63][C:54]([CH2:55][N:56]2[CH2:60][C:59](=O)[CH2:58][C:57]2=[O:62])=[CH:53][CH:52]=1>CO.C(Cl)Cl>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:14]2[C:15]3=[N:16][CH:17]=[C:18]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:19]([N:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]4)=[C:20]3[C:12]([NH:11][CH:59]3[CH2:58][C:57](=[O:62])[N:56]([CH2:55][C:54]4[CH:53]=[CH:52][C:51]([O:50][CH3:49])=[CH:64][CH:63]=4)[CH2:60]3)=[N:13]2)=[CH:46][CH:45]=1
Reactant: COc1ccc(CN2CC(=O)CC2=O)cc1
Reactant: COc1ccc(Cn2nc(N)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN2CC(Nc3nn(Cc4ccc(OC)cc4)c4ncc(-c5ccccc5)c(N5CCN(C(=O)OC(C)(C)C)CC5)c34)CC2=O)cc1
Temperature: 48 °C
Reaction time: 20 h
Yield: 71.4 %

Procedure:
Decaborane (0.014 g, 0.12 mmol) was added to a solution of tert-butyl 4-(3-amino-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.20 g, 0.39 mmol) and 1-(4-methoxybenzyl)pyrrolidine-2,4-dione (0.10 g, 0.47 mmol) in MeOH (3 mL) and DCM (0.5 mL) and stirred at 48° C. (oil bath) for 20 hours. The solvent was removed. The resulting residue was dissolved in ethyl acetate (20 mL), washed with saturated NaHCO3 (10 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane:ethyl acetate=1:1) to give tert-butyl 4-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-5-oxopyrrolidin-3-ylamino)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.20 g, 70%) as a solid. LCMS (APCI+) m/z 718(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=3[CH3:34])[C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl.N1C=CC=CC=1>[Si:17]([O:16][C@H:14]([CH3:15])[C@H:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:37])[CH3:36])=[CH:7][CH:6]=2)=[N:9][N:10]=1)[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:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(N)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@@H](C)O[Si](C)(C)C(C)(C)C)o2)cc1
Yield: 100 %

Procedure:
To a solution of 4-((1R,2R)-1-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2-chloro-3-methylbenzonitrile (intermediate 69d) (311 mg, 0.62 mmol) in CH2Cl2 (10 mL) and pyridine (1.5 mL) was added acetylchloride (62 μL, 0.87 mmol) at room temperature. The resultant solution stirred for 89 hours and quenched with 2N aq. HCl (15 mL). The mixture was further partitioned between H2O (40 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (35 mL). The combined organic extracts were washed with sat. aq. NaHCO3 (2×45 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a colourless oil (335 mg, 100%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.49 (s 1H), 7.93 (dm, J=8.8 Hz, 2H), 7.83 (dm, J=8.8 Hz, 2H), 7.50 (d, J=8.6 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 5.74 (d, J=9.0 Hz, 1H), 5.03 (dd, J=6.4, 9.0 Hz, 1H), 4.65 (pentet, J=6.4 Hz, 1H), 2.34 (s, 3H), 2.12 (s, 3H), 1.44 (d, 6.1 Hz, 3H), 0.81 (s, 9H), 0.09 (s, 3H), −0.02 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([CH3:13])[NH:8]2.[CH:14]1([N:17]2[CH:21]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:19]=[N:18]2)[CH2:16][CH2:15]1>>[C:3]([N:8]1[C:9]2[C:4](=[C:3]([O:2][C:1]3[CH:10]=[CH:9][CH:4]=[CH:5][C:6]=3[C:7]#[N:8])[C:12]([C:20]3[CH:19]=[N:18][N:17]([CH:14]4[CH2:15][CH2:16]4)[CH:21]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:6][C@@H:7]1[CH3:13])(=[O:2])[CH3:12]
Reactant: COc1cccc2c1CC[C@H](C)N2
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(Oc3ccccc3C#N)c2CC[C@@H]1C

Procedure:
(S)-2-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile was synthesized according to the procedures described above for Example 36, with the following changes: (1) in Step 2, 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used in place of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (3) Step 3 (removal of the Boc-protecting group) was eliminated. 1H NMR (300 MHz, CD3OD) δ ppm 0.92-1.05 (m, 4H), 1.16 (d, J=6.30 Hz, 3H), 1.35-1.52 (m, 1H), 2.10-2.40 (m, 5H), 2.58-2.80 (m, 1H), 3.55-3.65 (m, 1H), 4.68-4.8 9 (m, 1H), 6.40-6.55 (m, 1H), 7.05-7.15 (m, 1H), 7.30-7.52 (m, 2H), 7.55-7.65 (m, 1H), 7.70-7.80 (m, 2H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z 413 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH2:2][CH:3]=[CH2:4].ClC1C=C(C=CC=1)C(OO)=[O:21]>ClCCl>[O:21]1[CH2:4][CH:3]1[CH2:2][CH2:1][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: C=CCCN1C(=O)c2ccccc2C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCC1CO1
Temperature: 25 °C
Reaction time: 10 h
Yield: 92.9 %

Procedure:
To a mixture of 2-(but-3-en-1-yl)isoindoline-1,3-dione obtained in step 1 (0.65 g, 3.22 mmol) in dichloromethane (10 ml), was added m-chloroperoxybenzoic acid (1.11 g, 6.44 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 10 hours. After the reaction complete, the reaction mixture thus obtained was filtered through a plug of Celite. The filtrate was washed with 1 N sodium hydroxide solution and brine. The organic phase thus separated was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.65 g). The compound was used for the next step without further purification.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C@H:28]([CH3:32])[C:29]([OH:31])=[O:30])[CH:22]=[CH:21]2.[OH:33][CH2:34][C:35]([CH2:37]O)=[O:36]>CC(C)=O>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C@H:28]([CH3:32])[C:29]([O:31][CH2:37][C:35](=[O:36])[CH2:34][OH:33])=[O:30])[CH:22]=[CH:21]2
Reactant: O=C(CO)CO
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(C)=O
Product: COc1ccc2cc([C@H](C)C(=O)OCC(=O)CO)ccc2c1

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (2.84 g, 13.8 mmol) in acetone (40 mL) was added, drop-wise, to a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 3.14 g, 13.6 mmol), 1,3-dihydroxy-acetone (3.11 g, 34.5 mmol) and N,N-dimethylaminopyridine (DMAP, 1.4 g, 11.5 mmol) in acetone (100 mL) and stirred at ambient temperature overnight. The byproduct, dicyclohexyl urea was removed by filtration. The filtrate was concentrated and the residue was dissolved in CH2Cl2 (150 mL), washed with 3N HCl (150 mL), water (150 mL×3), brine, and dried over Na2SO4, filtered and concentrated. The product was separated by silica gel column chromatography eluting with ethyl acetate/hexane (1:2, Rf=0.13) to obtained a mixture of the title compound and its dimer. The reaction mixture was treated with ethyl ether and the dimer was removed by filtration. The filtrate was concentrated and dried under vacuum to give the title compound as a sticky oil (1.59 g). The resulted material was use in the next step without further purification. Mass spectrum (API-TIS) m/z 303 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:14])[C:8]=2[CH:7]=1)=[O:5])[CH3:2].CN(C=O)C.[H-].[Na+].[CH3:23][Si:24]([CH2:27][CH2:28][O:29][CH2:30]Cl)([CH3:26])[CH3:25]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:15]([CH2:30][O:29][CH2:28][CH2:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:14])[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(Cl)ncnc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(Cl)ncnc2n1COCC[Si](C)(C)C
Temperature: 0 °C
Yield: 82.4 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.13 g, 0.58 mmol, 1.0 eq.) and DMF (3 ml). The mixture was cooled to 0° C. followed by the addition of NaH (0.028 g, 0.70 mmol, 1.2 eq) with stirring. After stirring for 10 minutes SEM-CL (0.106 g, 0.64 mmol, 1.1 eq) was added and the reaction was allowed to warm to room temperature with stirring for 1 hour. The reaction was diluted with ethyl acetate (50 ml), washed (2×) water, (1×) NaHCO3, (2×) 5% LiCl, (1×) brine, and dried over sodium sulfate, and concentrated in vacuo to give 4-chloro-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester as a cream solid (0.17 g, 84%). MS (ESI) for C15H22ClN3O3Si: 356 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11]OC=S.[CH2:15](Br)C#C.CN(C)CCN>C(O)C.C1COCC1.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9][CH2:10][C:11]#[CH:15]
Reactant: Cc1ccc(Br)c(SCCOC=S)c1
Reactant: C#CCBr
Agent: CN(C)CCN
Solvent: CCO
Solvent: C1CCOC1
Product: C#CCSc1cc(C)ccc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94.2 %

Procedure:
To a solution of (2-bromo-5-methylphenylthio)ethoxymethane-1-thione (80.23 g, 275 mmol) in ethanol-THF (2/1) (420 ml), a solution of propargyl bromide (49.13 g, 413 mmol) in ethanol (140 ml) was slowly added dropwise in an ice bath and stirred in an ice bath for 20 minutes. Furthermore, while keeping the mixture in the ice bath, a solution of N,N-dimethylethylenediamine (48.48 g, 550 mmol) in ethanol (275 ml) was added dropwise over 15 minutes. The mixture was kept in the ice bath for 20 minutes, and removed from the ice bath and left at room temperature for 1 hour, followed by further stirring at 30° C. in an oil bath for 2 hours. To a separatory funnel that contained 2N aqueous hydrochloric acid (600 ml) and hexane (500 ml), the reaction mixture was added and extracted as it was. The aqueous phase was extracted with hexane (300 ml), and the organic phase combined was washed with 1N aqueous hydrochloric acid (200 ml). Then, after washing with water (200 ml×2 times), it was dried on magnesium sulfate. The solvent was evaporated to obtain 1-bromo-4-methyl-2-(prop-2-inylthio)benzene (62.35 g, 259 mmol). The yield was 94%.
Reaction SMILES: [Na].O[C:3]([CH3:10])([CH3:9])[C:4]([O:6]CC)=O.[NH2:11][C:12]([NH2:14])=[O:13]>C(O)C>[CH3:9][C:3]1([CH3:10])[NH:14][C:12](=[O:13])[NH:11][C:4]1=[O:6]
Reactant: NC(N)=O
Reactant: CCOC(=O)C(C)(C)O
Agent: [Na]
Solvent: CCO
Product: CC1(C)NC(=O)NC1=O
Temperature: 100 °C
Reaction time: 18 h
Yield: 52.7 %

Procedure:
In a 5-liter three neck distillation flask were placed 1.5 l of ethanol, 92 g of metallic sodium, 472 g of ethyl α-hydroxyisobutyrate (4 mole), and 240 g of urea (4 mole). The mixture was heated and stirred on hot oil bath at 100° C. for 18 hours. After ethanol and methanol were distilled off from the reaction mixture and then 2 l of water was added therefor, the mixture was made acid with aqueous hydrochloric acid solution and then extracted twice with ethyl acetate. The extract was dried with Glauber's salt, and then filtered. The solvent was distilled off from the extract to obtain 270 g of 5,5-dimethylhydantoin having a melting point of 75° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][OH:19])=[CH:15][CH:16]=2)[N:11]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[CH:10]=1)=[O:8].N[C:25]1SC(C)=CN=1>>[CH3:25][C:5]1[S:1][C:2]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][OH:19])=[CH:15][CH:16]=3)[N:11]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:10]=2)=[O:8])=[N:3][CH:4]=1
Reactant: O=C(Nc1nccs1)c1cn(CC2CC2)c2cc(CO)ccc12
Reactant: Cc1cnc(N)s1
Product: Cc1cnc(NC(=O)c2cn(CC3CC3)c3cc(CO)ccc23)s1

Procedure:
The compound was prepared according to the procedure given for 1-Cyclopropylmethyl-6-hydroxymethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide using 2-amino-5-methyl-thiazole.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1.[CH2:14]([O:19][C:20]1[C:25]([C:26]2[C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=[C:28]([C:38]#[N:39])[CH:27]=2)=[CH:24][C:23]([C:40]#[N:41])=[CH:22][CH:21]=1)[CH2:15][CH2:16][CH2:17][CH3:18].O>CS(C)=O>[C:40]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:25]([C:26]2[C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=[C:28]([C:38](=[NH:39])[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=3)[CH:27]=2)[CH:24]=1)#[N:41]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCCCCOc1ccc(C#N)cc1-c1cc(C#N)ccc1OCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCOc1ccc(C#N)cc1-c1cc(C(=N)Nc2cccc(C(F)(F)F)c2)ccc1OCCCCC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A slurry of sodium hydride (50% in oil, 1.76 g), m-aminobenzotrifluoride (5.91 g) and 6,6'-dipentyloxy[1,1'-biphenyl]-3,3'-dicarbonitrile (6.9 g; additional material is added to the batch of part A) in 50 ml of anhydrous dimethylsulfoxide is stirred at room temperature for 3 days. The reaction mixture is poured into water and the resultant precipitate collected by filtration. The dried material is chromatographed on 1 liter of silica gel eluting with (1) dichloromethane and (2) 1% methanol/dichloromethane to yield 5'-cyano-2',6-bis(pentyloxy)-N-[3-(trifluoromethyl)-phenyl][1,1'-biphenyl]-3-carboximidamide (melting point 74°-75° C after two recrystallizations from cyclohexane). The column is next eluted with 2% methanol/dichloromethane to yield 1.3 g of the desired product. Two recrystallizations of this material from 1% hydrochloric acid/methanol yields 900 mg of the title compound, melting point 207°-2l0° C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6][CH:5]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[B-](F)(F)(F)[F:24].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C1COCC1.CN(C=O)C>[F:24][C:5]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:4](=[O:3])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
NaH (2.66 g, 105 mmol) was suspended in THF (300 mL) and cooled to 0° C., and 1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (30 g, 105 mmol) was added as THF solution (550 mL) using an addition funnel over 30 minutes. The mixture was stirred for 30 minutes and then diluted with DMF (200 mL). Selectfluor (41.0 g, 116 mmol) was added as a DMF solution (200 mL). The mixture was warmed to ambient temperature and stirred for 2 hours. The mixture was then concentrated to remove THF and diluted with 1N KHSO4 (300 mL), water (300 mL) and EtOAc (750 mL). The organic layer was washed with brine (2×250 mL). The combined aqueous layers were washed with EtOAc (200 mL) and this organic layer was washed with brine (200 mL). The combined organic layers were then dried over Na2SO4, filtered and concentrated. The crude product was passed through a silica gel plug (1 kg, 20 to 40% EtOAc/hexanes) to provide 23.6 g (74%) of the product as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:15])=[N:6][C:7]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:16]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:16][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH2:15])=[N:6][C:7]=1[C:10]1[O:11][CH:12]=[CH:13][N:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(-c2ncco2)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2ncco2)c(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 101.8 %

Procedure:
To a stirred solution of 3-nitro-6-(1,3-oxazol-2-yl)pyridin-2-amine (0.127 g, 0.62 mmol) in dimethylformamide (3 mL) at 0° C. was added N-bromosuccinimide (0.115 g, 0.65 mmol) and the mixture was warmed to room temperature. After 3 days, further N-bromosuccinimide (0.058 g, 0.33 mmol) was added and stirring was continued for 3 hours. The solution was poured into water and the precipitate was filtered, washed with water and dried to give the title compound (0.18 g, 70%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:12][CH3:13])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:22]=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:13])[S:27]([C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)(=[O:29])=[O:28])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CNc1cc(C(=O)OC)cc(Cl)n1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(Cl)nc(N(C)S(=O)(=O)c2cccnc2)c1
Temperature: 50 °C
Reaction time: 36 h
Yield: 91.6 %

Procedure:
To a solution of methyl 2-chloro-6-(methylamino)isonicotinate (2.00 g, 9.97 mmol) in 3:1 CH2Cl2:pyridine (100 mL total) was added 3-pyridine sulfonyl chloride hydrochloride (6.40 g, 29.9 mmol) and dimethylaminopyridine (0.609 g, 4.98 mmol). Reaction heated to reflux at 50° C. After 36 h, reaction cooled to rt. Reaction diluted with CH2Cl2 (200 mL) and washed with 1N HCl (150 mL) solution. The aqueous solution was extracted with CH2Cl2 (100 mL×2). The combined organics were washed with brine (100 mL), dried over Mg2SO4, filtered, and concentrated in vacuo. Purification by normal-phase chromatography (20->40% EtOAc/hexanes) yielded 3.12 g (92%) of methyl 2-chloro-6-[methyl(pyridin-3-ylsulfonyl)amino]isonicotinate as a yellow residue. 1H NMR (CDCl3, 400 MHz) 8.95 (d, J=0.64 Hz, 1H); 8.82 (m, 1H); 8.03 (m, 2H); 7.67 (m, 1H); 7.45 (m, 1H); 3.99 (s, 3H); 3.39 (s, 3H); LC/MS [M+H]+=341.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[N:18]=[C:17]([C:19](=O)[CH3:20])[CH:16]=[CH:15][CH:14]=1)[CH3:12].[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH2:27])([CH3:24])[CH3:23]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([C:19](=[N:27][C:26]2[C:28]([CH:32]([CH3:33])[CH3:34])=[CH:29][CH:30]=[CH:31][C:25]=2[CH:22]([CH3:24])[CH3:23])[CH3:20])[N:18]=1)[CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Solvent: C1CCOC1
Product: CC(=Nc1c(C)cc(C)cc1Cl)c1cccc(C(C)=Nc2c(C(C)C)cccc2C(C)C)n1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
18.80 g of 1-{6-[1-(2-chloro-4,6-dimethylphenylimino)-ethyl]pyridin-2-yl}ethanone (0.0625 mol), 22.16 g of 2,6-diisopropylaniline (0.125 mol) and 20.0 g of Sicapent were heated under reflux under argon in 300 ml of tetrahydrofuran for 17 h. A further portion of Sicapent (10.0 g) was added and the mixture was heated under argon for a further 4 h and then cooled to room temperature. It was filtered and the residue on the filter was washed with 50 ml of tetrahydrofuran. The solvent was distilled off completely from the combined filtrates and the residue was stirred with 50 ml of methanol. The precipitate formed was filtered off, washed twice with methanol, stirred with 100 ml of hot methanol and then filtered. 17.84 g (0.0388 mol) of 2-[1-(2-chloro-4,6-dimethylphenylimino)ethyl]-6-[1-(2,6-diisopropylphenylimino)ethyl]pyridine were obtained in a yield of 62%.