Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[F:18].[Al+3].[Cl-].[Cl-].[Cl-].Cl.CCOC(C)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[F:18]
Reactant: COc1ccc(C(=O)c2ccc(Br)c(F)c2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C(c1ccc(O)cc1)c1ccc(Br)c(F)c1
Temperature: 25 °C
Yield: 112.1 %

Procedure:
To a stirred solution of (4-bromo-3-fluorophenyl)[4-(methyloxy)phenyl]methanone (185) (3.20 g, 10.4 mmol) in benzene (80 mL) was slowly added AlCl3 (5.91 g, 44.2 mol., 4.3 eq) via a powder addition funnel under a nitrogen atmosphere at room temperature. The stirred reaction mixture was heated at reflux for 3 h under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and then poured onto a mixture of 1 N HCl (150 mL) and ice (300 g). The quenched reaction mixture was transferred to a separatory funnel and EtOAc (200 mL) added. The organic phase was separated and the aqueous phase was extracted with EtOAc. The organic phase was washed with brine (200 mL), dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give 3.44 g of a brown solid. Crystallization from toluene yielded 2.68 g (88%) of the title compound 186 as a brown crystalline solid. 1H NMR (400 MHz, DMSO-d6): δ 6.91 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.2 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.69 (d, J=8.7 Hz, 2H), 7.89 (t, J=7.1 Hz, 1H), 10.54 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C@:11]1([CH3:32])[C@H:16]([CH2:17][CH2:18][OH:19])[S:15](=[O:21])(=[O:20])[C:14]([CH3:23])([CH3:22])[C:13]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:12]1.[H-].[Na+]>C1COCC1.CN(C=O)C>[CH3:23][C:14]1([CH3:22])[S:15](=[O:20])(=[O:21])[CH:16]2[CH2:17][CH2:18][O:19][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=3[C@@:11]2([CH3:32])[N:12]=[C:13]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)[C@H](CCO)S(=O)(=O)C1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OCCC2S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.8 %

Procedure:
A solution of crude tert-butyl ((5R,6S)-5-(2-fluoro-5-nitrophenyl)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (250 mg, 0.528 mmol) in THF (5 ml) and DMF (0.5 ml) was treated portionwise with NaH (60% suspension in mineral oil) (52.8 mg, 1.320 mmol). After initial gas evolution the reaction mixture became dark red. The mixture was stirred at RT for 10 min. The mixture was quenched with NH4Cl solution and diluted with EtOAc. Water was added to dissolve solids, and the organic layer was separated, washed with brine and concentrated. The residue was purified by FC on 12 g RedSep Gold column using 10-100% EtOAc in heptane. All the fractions containing both epimers were combined and concentrated to afford tert-butyl ((11bR)-3,3,11b-trimethyl-10-nitro-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (196 mg, 0.432 mmol, 82% yield) as a mixture of epimers at C4. Ratio by NMR 2:1 favoring trans-isomer.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:21][C:15]3[N:16]=[CH:17][N:18]=[C:19](O)[C:14]=3[CH:13]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:19]1[C:14]2[CH:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[NH:21][C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc(-c2cc3c(O)ncnc3[nH]2)cc1
Product: CCOC(=O)c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1

Procedure:
Analogously to Step 8.3,1.45 g of 6-(4-ethoxycarbonyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol in 15 ml of phosphorus oxychloride are heated under a protective gas for 2 hours and worked up, yielding the title compound; m.p.: 250° C. (decomp.): TLC-Rf =0.63 (ethyl acetate/hexane [1:1]); FAB-MS: (M+H)+ =302.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:24])([CH3:23])[C:19]([NH:21][CH3:22])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[CH:41][C:42]([NH2:45])=[N:43][CH:44]=2)O1>>[NH2:45][C:42]1[N:43]=[CH:44][C:39]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([CH3:24])([CH3:23])[C:19]([NH:21][CH3:22])=[O:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:40][CH:41]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CNC(=O)C(C)(C)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CNC(=O)C(C)(C)N1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-[4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N-methyl-isobutyramide was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine in General Procedure A. Purification on silica yielded 171. (400 MHz CDCl3): 1.21 (6H, s, ar), 2.56 (8H, b, CH2), 2.80 (3H, d (J=5.03), CH3), 3.82 (2H, s, ar), 3.87-3.89 (4H, m, CH2), 4.01-4.04 (4H, m, CH2), 4.61 (1H, s, NH), 6.56 (1H, d (J=8.40), ar), 7.15 (1H, d, ar), 8.45-8.47 (1H, m, ar), 9.15 (1H, s, ar). MH+ 511.52
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.NCC1C=NC(CSCC(C)(C)C)=CC=1>O1CCOCC1>[CH2:10]1[C:4]2[CH:3]=[CH:2][CH:18]=[CH:17][C:5]=2[CH2:6][CH2:7][NH:8][CH2:9]1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: CC(C)(C)CSCc1ccc(CN)cn1
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCNCC2
Yield: 99.2 %

Procedure:
Use a method similar to the General Procedure 1-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (586 mg, 1.37 mmol) with 3-aminomethyl-6-[(2,2-dimethylpropyl)thiomethyl]-pyridine (340 mg, 1.51 mmol) in 1,4-dioxane (15 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1, 5:1 and 3:1) followed by SCX chromatography eluting with DCM and DCM/2M ammonia in methanol (1:1). Concentrate in vacuo to obtain 7-chloro-6-{6-[(2,2-dimethyl-propylthiomethyl)-pyridin-3-ylmethyl]-amino}trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (0.2 g, 29%).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[F:10][C:11]1[CH:29]=[CH:28][C:14]2[C:15]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[N:16][O:17][C:13]=2[CH:12]=1.[Cl-].[NH4+]>BrC(Br)C.CCOCC.O1CCCC1>[F:10][C:11]1[CH:29]=[CH:28][C:14]2[C:15]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][C:24]([C:3]4[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=4)([OH:27])[CH2:25][CH2:26]3)=[N:16][O:17][C:13]=2[CH:12]=1
Reactant: O=C1CCN(CCCc2noc3cc(F)ccc23)CC1
Reactant: Fc1ccc(Br)cc1
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)CCN(CCCc2noc3cc(F)ccc23)CC1
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To a suspension of 1.1 g of magnesium shavings and a few drops of dibromoethane in 30 ml of ether was added a solution of 7.9 g of p-bromofluorobenzene in 20 ml of ether at a rate to maintain reflux of the mixture. After the addition was complete, the mixture was slowly diluted with 30 ml of tetrahydrofuran and then a solution of 5 g of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone in 30 ml of tetrahydrofuran was slowly added. After one hr, the mixture was diluted with ether, poured into 400 ml of saturated ammonium chloride solution and extracted with ether. The organic extracts were washed with water (2×), saturated sodium chloride solution and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was recrystallized from hexanes/ether to give 3.6 g (54%) of product, mp 100°-101° C.
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5](N(C(OC(C)(C)C)=O)NC(OC(C)(C)C)=O)[CH:4]=1)#[N:2].C(C1SC([N:31]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=CC=1)=O>>[C:1]([C:3]1[S:7][C:6]([N:31]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1csc(C#N)c1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc(C=O)s1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc(C#N)s1
Yield: 75 %

Procedure:
Following the same procedure as described for compound 12 (step 2, scheme 2, example 1c) except using 19 (935 mg, 2.73 mmol) instead of 11 to provide compound 20 (692 mg, 75%) as a yellow solid. LRMS (ESI): calc. 339.1; found 340.2 (MH)+.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=O)=[CH:16][CH:15]=2)[N:11]=1)(=[O:5])=[O:4])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:39])[NH:37][NH2:38].O>O1CCCC1>[CH2:1]([S:3]([NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([NH:38][NH:37][C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:23])=[CH:18][CH:19]=2)[N:11]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)Nc1nc(CCc2ccc(CC(=O)O)cc2)cs1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)Nc1nc(CCc2ccc(CC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 42.5 °C
Reaction time: 1 h

Procedure:
To a suspension of [4-(2-{2-[(ethylsulfonyl)amino]-1,3-thiazol-4-yl}ethyl)phenyl]acetic acid (700 mg, 1.98 mmol) in anhydrous tetrahydrofuran (5 ml) was added 1,1′-carbonyldiimidazole (480 mg, 2.96 mmol), and the mixture was stirred at 40-45° C. for 1 hr. After cooling to 0° C., tert-butyl carbazate (914 mg, 6.91 mmol) was added, and the mixture was stirred at room temperature for 4 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The combined organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to give tert-butyl 2-{[4-(2-{2-[(ethylsulfonyl)amino]-1,3-thiazol-4-yl}ethyl)phenyl]acetyl}hydrazinecarboxylate (989 mg, quantitatively) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C:19]3[CH:40]=[CH:39][C:22]4[O:23][CH:24]([CH2:27]OS(C5C=CC(C)=CC=5)(=O)=O)[CH2:25][O:26][C:21]=4[CH:20]=3)=[N:14][CH:15]=2)[N:10]([CH3:41])[C:9]1=[O:42].[CH3:43][NH:44][CH3:45]>CN1C(=O)CCC1.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C:19]3[CH:40]=[CH:39][C:22]4[O:23][CH:24]([CH2:27][N:44]([CH3:45])[CH3:43])[CH2:25][O:26][C:21]=4[CH:20]=3)=[N:14][CH:15]=2)[N:10]([CH3:41])[C:9]1=[O:42]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3cc(Nc4ncc5c(n4)N(C)C(=O)N(c4ccccc4Br)C5)ccc3O2)cc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CN(C)CC1COc2cc(Nc3ncc4c(n3)N(C)C(=O)N(c3ccccc3Br)C4)ccc2O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
90 mg of the tosylate from example 4 in 8 ml NMP were treated with 0.62 ml 2 M dimethylamine in THF and stirred at room temperature for 3 d. The mixture was heated to 50° C. for 4 hrs, then to 65° C. for another 2 hrs. Stirring was continued at 45° C. over night. Separation by HPLC-MS yielded crude product contaminated by NMP, which was further purified by dissolving in CHCl3 and washing with water.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[C:8]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:17][C:18]([NH:24][C:25]([O:27][CH3:28])=[O:26])=[N:19][C:20]([O:22][CH3:23])=[O:21])=[O:2].[OH:29]O>C(OC(=O)C)(=O)C>[CH:1]([NH:3][C:4]1[CH:9]=[C:8]([S:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:29])[CH:7]=[CH:6][C:5]=1[NH:17][C:18]([NH:24][C:25]([O:27][CH3:28])=[O:26])=[N:19][C:20]([O:22][CH3:23])=[O:21])=[O:2]
Reactant: COC(=O)N=C(NC(=O)OC)Nc1ccc(Sc2ccccc2)cc1NC=O
Reactant: OO
Solvent: CC(=O)OC(C)=O
Product: COC(=O)N=C(NC(=O)OC)Nc1ccc(S(=O)c2ccccc2)cc1NC=O
Reaction time: 4 h

Procedure:
10.9 g of N-(2-formamido-4-phenylthiophenyl)-N',N"-bis(carbomethoxy)guanidine (Example 1) are dissolved in 200 ml of acetic anhydride. 25.8 ml of hydrogen peroxide (30% strength) are added and the mixture is stirred for 4 hours at 20° and is then concentrated in vacuo, and the residue is recrystallized from ethyl acetate to yield N-(2-formamido-4-phenylsulfinylphenyl)-N',N"-bis(carbomethoxy)guanidine (7.37 g), m.p. 168° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[N:3]=1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1.CO>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[N:3]=1)=[O:21]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CN1CCC(C(=O)c2cccc(N)n2)CC1
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccccc3Cl)n2)CC1
Yield: 85.2 %

Procedure:
Mix 2-Amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.223 g) and 2-chlorobenzoyl chloride (0.175 g) in 1,4-dioxane (10 mL) and heat at reflux for 1 hour. Dilute with methanol (10 mL) and load on a SCX column (10 g). Wash the column with methanol, elute the product with 2 M NH3 in methanol, evaporate and purify the product on a silica gel column (CH2Cl2 with 2 M NH3 in methanol) to obtain 0.305 g (84%) of the title compound: mass spectrum (electric spray) m/z=358 (M+1) and 360 (M+2+1); 1H NMR (CDCl3): 8.60 (br s, 1H), 8.54 (d, 1H), 7.90 (dd, 1H), 7.81 (d, 1H), 7.76 (dd, 1H), 7.45 (m, 3H), 3.63 (m, 1H), 2.90 (m, 2H), 2.29 (s, 3H), 2.07 (m 2H), 1.85 (m, 4H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.CC(C)([O-])C.[Na+].[Cl-].[NH4+]>C(O)(C)(C)C>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:37]4[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4ccc(C#N)nc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)(C)O
Product: Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(-c2ccc(C#N)nc2)s1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 50.9 %

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene (597 mg) obtained in Example 159-(1) was dissolved in N-methyl-2-pyrrolidone (10 ml) and added thereto were tri-n-butyl(2-cyano-5-pyridyl)tin (590 mg), dichlorobis(triphenylphosphine)palladium(II) (70 mg) and copper(I) iodide (19 mg). The mixture was heated under stirring at 100° C. for 4 hours. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was washed with water and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)-4-methylbenzene (351 mg) as colorless powder. APCI-Mass m/Z 621 (M+H). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)-4-methylbenzene (62 mg) was dissolved in a mixture of tert-butanol (3 ml)tetrahydrofuran (3 ml) and added thereto was sodium tert-butoxide (48 mg). The mixture was stirred at room temperature for 3.5 hours. Sodium tert-butoxide (19 mg) was further added thereto, and the mixture was stirred at room temperature for 1 hour. To the mixture was added a saturated aqueous ammonium chloride solution at 0° C., and the mixture was extracted with ethyl acetate twice. The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=19:1) to give the desired 1-(β-D-glucopyranosyl)-3-(5-(2cyano-5-pyridyl)-2-thienylmethyl)-4-methylbenzene (23 mg) as colorless powder. APCI-Mass m/Z 470 (M+NH4).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([C:50]([F:53])([F:52])[F:51])[CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:54][C:55]1[CH:60]=[CH:59][C:58]([Br:61])=[CH:57][N:56]=1>C(Cl)Cl>[Br:61][C:58]1[CH:59]=[CH:60][C:55]([NH:54][C:35](=[O:36])[CH:34]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([C:50]([F:51])([F:53])[F:52])[CH:39]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:56][CH:57]=1
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1ccc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A solution of triphenylphosphine (213 mg, 0.84 mmol) in methylene chloride (12 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (144 mg, 0.84 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with the 3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionic acid (prepared in Example 7, 150 mg, 0.4 mmol). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was then treated with 2-amino-5-bromopyridine (122 mg, 1.22 mmol), and the resulting suspension was stirred for 15 h at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (30 mL) and water (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×20 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionamide (90 mg, 42%) as an amorphous white solid: EI-HRMS m/e calcd for C22H22BrF3N6O (M+) 522.0991, found 522.0989.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:26])[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19](=O)[CH2:18]1>[Zn].Cl[Ti](Cl)(Cl)Cl.C1COCC1>[C:10]1([C:8](=[C:19]2[CH2:20][C:21]([CH3:24])([CH3:23])[CH2:22][C:17]([CH3:26])([CH3:16])[CH2:18]2)[C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccccc2)c2ccc(O)cc2)CC(C)(C)C1
Yield: 94.2 %

Procedure:
The McMurry procedure described for 9 (example 5, step 1) was utilized using (4-hydroxyphenyl)(phenyl)methanone (2.97 g, 14.9 mmol), 3,3,5,5-tetramethylcyclohexanone (6.25 g, 44.9 mmol), Zn (9.69 g, 149 mmol), TiCl4.2THF complex (25 g, 7.5 mmol), and THF (200 mL). Standard work-up followed by purification gave 4.50 g (91%) of the title product 32 as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.28-7.24 (m, 2H), 7.18-7.15 (m, 3H), 7.04 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.4 Hz, 2H), 1.98 (s, 2H), 1.95 (s, 2H), 1.28 (s, 2H), 0.93 (s, 6H), 0.92 (s, 6H).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.O>CN(C=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])=[CH:16][CH:15]=1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1ccc(F)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C1CCN(c2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of 6,6-dimethyl-5,7-dioxaspiro[2,5]-octane-4,8-dione (1.02 g, 6.0 mmol, Aldrich) in 3 mL of DMF was added 4-fluorobenzenamine (666 mg, 6.0 mmol, Aldrich). The reaction mixture was stirred at rt overnight. The reaction mixture was poured into cold water (10 mL). The precipitate that formed was collected by filtration, washed with water, and dried under vacuum to afford the desired product (980 mg, 73%) as a tan solid. MS(ESI+) m/z 224.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:5]=[C:4]([NH:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[N:3]=1.[NH3:27].O1CCOCC1>>[NH2:27][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:5]=[C:4]([NH:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[N:3]=1
Reactant: N
Reactant: Cc1cc(C)c(Nc2nc(Cl)nc(Nc3ccc(C#N)cc3)n2)c(C)c1
Solvent: C1COCCO1
Product: Cc1cc(C)c(Nc2nc(N)nc(Nc3ccc(C#N)cc3)n2)c(C)c1
Temperature: 100 °C
Yield: 61.4 %

Procedure:
A mixture of 4-[[4-chloro-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]-amino]benzonitrile (*A9c) (0.00137 mol) and NH3 in 1,4-dioxane (0.5 M; 0.00548 mol) was heated in a pressure vessel at 100° C. for 6 days. The solvent was evaporated and the residue was dissolved in CH2Cl2, washed with a saturated aqueous NaHCO3 solution, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0, 99/1 and 98/2). The desired fractions were collected and the solvent was evaporated. The residue was recrystallized from toluene. The precipitate was filtered and dried, yielding 0.29 g (61.4%) of 4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]-benzonitrile. b) As an alternative for the preparation of this compound, a mixture of 4-[[4-chloro-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile (0.0230 mol) in NH3 in 2-propanol (2.0 M; 60 ml) and NH3 in 1,4-dioxane (0.5 M; 20 ml) was heated at 95° C. for 21 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate, washed with 1 N NaOH, water and brine, dried, filtered and the filtrate was evaporated. The residue was recrystallized with acetonitrile, yielding 5.25 g (66.1%) of 4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile.