Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH:7]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:8][NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C>[N:28]([CH2:6][CH:7]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:8][NH:9][C:10](=[O:11])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N+:29]=[N-:30]
Reactant: CC(C)(C)OC(=O)NC(CNC(=O)OCc1ccccc1)COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CN=[N+]=[N-])CNC(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 3-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]propyl methanesulfonate (20.0 g, 49.7 mmol) in DMF (400 mL) was added sodium azide (8.0 g, 120 mmol). The reaction mixture was heated to 50° C. After 24 hours, the reaction mixture was cooled to ambient temperature and extracted with ethyl acetate. The organic layers were concentrated under reduced pressure to afford benzyl tert-butyl (3-azidopropane-1,2-diyl)biscarbamate. The material was used without purification. MS ESI calc'd. for C16H24N5O4 [M+H]+ 350. found 350.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH:13]=[CH:12][C@@H:11]1/[CH:16]=[CH:17]/[C@@H:18]([OH:28])[CH2:19][CH2:20][C:21]1[S:22][C:23]([CH3:27])=[C:24]([Br:26])[CH:25]=1.N1C(C)=CC=CC=1C.[Si:38](OS(C(F)(F)F)(=O)=O)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH:13]=[CH:12][C@@H:11]1/[CH:16]=[CH:17]/[C@@H:18]([O:28][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:19][CH2:20][C:21]1[S:22][C:23]([CH3:27])=[C:24]([Br:26])[CH:25]=1
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C=C[C@@H]1/C=C/[C@@H](O)CCc1cc(Br)c(C)s1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)C=C[C@@H]1/C=C/[C@H](CCc1cc(Br)c(C)s1)O[Si](C)(C)C(C)(C)C
Reaction time: 1.5 h
Yield: 90.3 %

Procedure:
A dichloromethane (6 mL) solution of 6 (497 mg, 1.03 mmol) was treated with 2,6-lutidine (143 μL, 1.22 mmol) and TBSOTf (0.26 mL, 1.13 mmol). After 1.5 h, 50 mL saturated NaHCO3 was added and the resulting mixture was extracted with 25 mL CH2Cl2. The CH2Cl2 layer was washed with 50 mL 1 M HCl and 50 mL brine. The CH2Cl2 solution was then dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (8% ethyl acetate/hexanes→10%) gave 7 (553 mg, 0.93 mmol, 90%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3]1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C1COCC1>[O:1]=[C:2]1[N:6]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C@@H:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OCc1ccccc1

Procedure:
9.1 Reaction of 1.0 g of ethyl(R)-5-oxopyrrolidine-2-carboxylate, 949.8 μl of benzyl chloroformate, 6.9 ml of bis(trimethylsilyl)lithium amide (in THF) in 25 ml of THF under standard conditions and work-up gives 730 mg of ethyl(R)-5-oxo-N-benzyloxycarbonylpyrrolidine-2-carboxylate (“17”).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)(O)[O-].[Na+].Cl[C:35]1[N:40]=[CH:39][C:38]2[N:41]=[C:42]([C:44]3[CH:49]=[C:48]([CH3:50])[C:47]([O:51][CH3:52])=[C:46]([CH3:53])[CH:45]=3)[O:43][C:37]=2[CH:36]=1>CN(C)C=O.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:35]1[N:40]=[CH:39][C:38]2[N:41]=[C:42]([C:44]3[CH:45]=[C:46]([CH3:53])[C:47]([O:51][CH3:52])=[C:48]([CH3:50])[CH:49]=3)[O:43][C:37]=2[CH:36]=1
Reactant: Oc1ccccc1F
Reactant: COc1c(C)cc(-c2nc3cnc(Cl)cc3o2)cc1C
Agent: [Cu]I
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1c(C)cc(-c2nc3cnc(Oc4ccccc4F)cc3o2)cc1C
Temperature: 200 °C
Yield: 10.6 %

Procedure:
In a microwaveable vessel, 0.65 g of 6-chloro-2-(4-methoxy-3,5-dimethylphenyl)oxazolo[4,5-c]pyridine were dissolved in 12 ml of absolute N,N-dimethylformamide, and 0.25 g of 2-fluorophenol, 0.88 g of cesium carbonate, 21 mg of copper (I) iodide and 40 mg of 1,10-phenanthroline were added. In a microwave reactor, the reaction was heated at 200° C. for 1 h. For work-up, the mixture was added to saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium bisulaite solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by means of preparative HPLC, giving 86 mg (10%) of product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[SH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
The product from Example 4a (11.22 g, 39.3 mmol) and 4-mercaptophenol (4.96 g, 39.3 mmol) in 100 mL of EtOH was treated with Na2CO3 and heated overnight under efflux. Cooled to room temperature and quenched with water. Extracted with EtOAc. Dried over MgSO4, filtered and concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 25% EtOAc/hexane giving a red oil (8.65 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[OH:9])=[C:6]([F:16])[C:5]([C@H:17]([NH:20][CH3:21])[CH2:18][CH3:19])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.ClCCCl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:17]([NH:20][CH3:21])[CH2:18][CH3:19])=[C:6]([F:16])[C:7]=1[C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: CC[C@@H](NC)c1ccc(Cl)c(C(O)c2cccnc2)c1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: CC[C@@H](NC)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Temperature: 100 °C

Procedure:
Step 3 A stirred suspension of {6-chloro-2-fluoro-3-[(1R)-1-(methylamino)propyl]-phenyl}(pyridin-3-yl)methanol (0.123 g, 0.398 mmol) and manganese(IV) oxide (0.693 g, 7.97 mmol) in toluene (1.99 mL) and 1,2-dichloroethane (1.99 mL) was heated at 100° C. for 2.5 hours. Upon cooling, the mixture was filtered; the residual solids were washed with DCM (×2) and concentrated. Preparative HPLC gave [(1R)-1-{4-chloro-2-fluoro-3-[(pyridin-3-yl)carbonyl]phenyl}propyl](methyl)amine which was converted to the HCl salt, 0.012 g, 9%.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][C@H:33]([CH3:36])[CH2:34][OH:35]>>[CH3:31][N:2]([CH3:1])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][C@H:33]([CH3:36])[CH2:34][OH:35])=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: C[C@@H](N)CO
Product: C[C@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-2-amino-1-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as an off-white solid: 1H NMR (d6-DMSO) δ 10.23 (1H, d, J=8 Hz), 8.50 (1H, s), 7.77 (1H, s), 7.32 (2H, dd, J=8.6, 6 Hz), 7.12 (2H, t, J=8.6 Hz), 5.12 (2H, m), 5.00 (1H, br), 4.11 (2H, s), 4.03 (1H, m), 3.44 (2H, m), 3.12 (3H, s), 2.82 (3H, s), 1.15 (3H, d, J=7 Hz); HRMS calcd for C23H25FN4O5+H+: 457.1887. Found: 457.1881.
Reaction SMILES: [Br-].[CH2:2]([N+:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.C(=O)(O)[O-].[Na+].[C:31](#[N:34])[CH:32]=[CH2:33]>CN(C)C=O>[C:3]([C:2]1[N:11]2[C:16]([CH:15]=[CH:14][CH:13]=[CH:12]2)=[C:32]([C:31]#[N:34])[CH:33]=1)(=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=CC#N
Reactant: O=C(C[n+]1ccccc1)c1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)c2ccccc2)n2ccccc12

Procedure:
The title compound was prepared from 1-(phenacyl)-pyridinium bromide (101 mg, 0.362 mmol), tetrapyridinecobalt(II) dichromate (246 mg, 0.403 mmol), sodium bicarbonate (84.9 mg, 1.01 mmol), acrylonitrile (120 μL, 1.82 mmol), and N,N-dimethylformamide (2.0 mL), similar to Example 1b, and yielded 30.5 mg (34%) as a white solid. 1H NMR (CDCl3): 9.96 (dd, J=6.05, 1.10 Hz, 1H), 7.82 (m, 3H), 7.61 (m, 2H), 7.52 (m, 3H), 7.17 (td, J=7.00, 1.29 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[CH2:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17].CCN(C(C)C)C(C)C>ClCCl>[CH2:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[C:12]([F:15])([F:14])[F:13])[CH2:20][CH2:19]1)[CH3:17]
Reactant: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CCN1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
1-(Bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (34 g, 120 mmol) obtained in Step (1) above was stirred in a solvent of dichloromethane (300 mL). The reaction solution was added with 1-ethylpiperazine (15.97 mL, 126 mmol) and DIPEA (27.2 mL, 156 mmol), followed by stirring for about 3 hours at room temperature. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (21.7 g, 57%).
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][N: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].[CH:47]([O:50][CH2:51][CH2:52][NH:53][CH2:54][CH2:55][O:56][CH:57]([CH3:59])[CH3:58])([CH3:49])[CH3:48]>>[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][N:37]([CH2:40][C:41]([N:53]([CH2:52][CH2:51][O:50][CH:47]([CH3:49])[CH3:48])[CH2:54][CH2:55][O:56][CH:57]([CH3:58])[CH3:59])=[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:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: CC(C)OCCNCCOC(C)C
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(CCOC(C)C)CCOC(C)C)CC1

Procedure:
In a manner analogous to the method described in example 99, {4-[(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]-piperazin-1-yl}-acetic acid was coupled with bis-(isopropoxy-ethyl)-amine (TCI-US) to give the title compound. HR-MS (ES, m/z) calculated for C45H62Cl2N6O5 [(M+H)+] 837.4232, observed 837.4231.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:18])[CH2:13]2)=[N:4][N:3]=1.[C:19]([O:23][C:24](=O)[O:25]C(C)(C)C)([CH3:22])([CH3:21])[CH3:20].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[C@@H:14]([CH3:18])[CH2:13]2)=[N:4][N:3]=1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccccc23)CCN1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2nnc(Cl)c3ccccc23)CCN1C(=O)OC(C)(C)C

Procedure:
(S)-1-chloro-4-(3-methylpiperazin-1-yl)phthalazine (1.50 g, 5.71 mmol) and di-t-butylcarbonate (1.73 g, 6.56 mmol) were dissolved in DMF (12 mL) and N,N-diisopropylethylamine (2 mL) and stirred at rt for 4 hours. The reaction was taken up in ethyl acetate (150 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-40% ethyl acetate gave an off-white solid. MS (M+H)+=363.1.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23](O)[CH2:24][CH3:25])=[CH:4][CH:3]=1>ClCCl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([N:7]2[CH:6]=[CH:10][N:9]=[CH:8]2)[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: ClCCl
Product: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)n1ccnc1
Temperature: 50 °C
Reaction time: 22 h
Yield: 187.7 %

Procedure:
A mixture of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (150 mg, 0.326 mmol) and N,N′-carbonyldiimidazole (119 mg, 0.734 mmol) in dichloromethane (2.0 mL) was stirred at 50° C. for 22 hr. The mixture was concentrated in vacuo, diluted with 1N hydrochloric acid and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (141 mg, 0.306 mmol, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:37])(=[O:36])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:17][CH:16]=3)[C:10]([CH2:38][CH2:39][CH2:40][CH3:41])=[N:9]2)=[C:4]([C:42]([F:45])([F:44])[F:43])[CH:3]=1.[C:46](Cl)(=[O:49])[CH2:47][CH3:48].[H-].[Na+]>C1COCC1>[C:32]([O:31][C:29]([NH:28][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[C:10]([CH2:38][CH2:39][CH2:40][CH3:41])=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:46](=[O:49])[CH2:47][CH3:48])=[CH:3][C:4]=3[C:42]([F:43])([F:44])[F:45])[C:12]2=[O:13])=[CH:20][CH:19]=1)(=[O:36])=[O:37])=[O:30])([CH3:34])([CH3:35])[CH3:33]
Reactant: CCC(=O)Cl
Reactant: CCCCc1nn(-c2ccc(N)cc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nn(-c2ccc(NC(=O)CC)cc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1

Procedure:
This material is prepared from 2-[4-amino-2-(trifluoromethyl)phenyl]-4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]biphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 22) and propionyl chloride in the presence of sodium hydride in THF. The crude product is flash chromatographed over silica gel to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B1OC(C)(C)C(C)(C)O1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1)[CH3:27]
Reactant: CCOC(=O)Cc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(CC(C)Nc2c(C)noc2-c2ccc(Br)cc2)cc1
Product: CCOC(=O)Cc1ccccc1-c1ccc(-c2onc(C)c2NC(C)Cc2ccc(OC)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amine and [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]acetic acid ethyl ester.
Reaction SMILES: CCO.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:23]#[N:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:13](F)[CH:12]=1.O>C(COC)OC>[Cl:10][C:11]1[CH:16]=[C:15]2[NH:24][CH2:23][C:17]3([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:14]2=[CH:13][CH:12]=1
Reactant: N#CC1(c2ccc(Cl)cc2F)CCNCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: Clc1ccc2c(c1)NCC21CCNCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
HCl (4.0 N in dioxane, 10 mL, 40 mmol, 7.1 equiv) was added to a solution of 1,1-dimethylethyl 4-(4-chloro-2-fluorophenyl)-4-cyano-1-piperidinecarboxylate (1.9 g, 5.6 mmol, 1 equiv) in 1,4-dioxane (25 mL) at 23° C. The resulting solution was warmed to 45° C. and stirred for 1 hour (white precipitation formed). The suspension was concentrated to afford 4-(4-chloro-2-fluorophenyl)-4-piperidinecarbonitrile as a pale-yellow solid. EtOH (1.6 mL, 38.1 mmol, 6.8 equiv) was slowly added to a suspension of lithium aluminium hydride (LAH) (1.15 g, 30.3 mmol, 5.4 equiv) in glyme (16 mL) at 0° C. The resulting suspension was heated to reflux and stirred for 5 min. A suspension of the newly prepared 4-(4-chloro-2-fluorophenyl)-4-piperidinecarbonitrile in glyme (10 mL) was added in portions. The resulting brown suspension was refluxed for 1 h, then cooled to 0° C. Water (8 mL) was added slowly at 0° C. and the resulting suspension was warmed to room temperature and stirred for 30 min. The suspension was filtered through Celite pad and the solid was rinsed with CH2Cl2 (200 mL). The filtrate was dried over anhydrous potassium carbonate. The dried solution was concentrated. The residue was purified by reverse phase C18 column to afford 6-chloro-1,2-dihydrospiro[indole-3,4′-piperidine] as a white powder (1.2 g, 5.4 mmol, 96%). MS (ES) m/e 223 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]2[N:19]=[C:18]3[N:10]([C:11](=[O:24])[N:12]([CH2:20][CH2:21][CH2:22][CH3:23])[C:13]4[N:14]=[CH:15][NH:16][C:17]=43)[N:9]=2)=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.CCOC(C)=O.Br[Pd](Br)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:20]([N:12]1[C:13]2[N:14]=[CH:15][NH:16][C:17]=2[C:18]2=[N:19][C:8]([CH2:7][O:6][C:5]3[CH:25]=[CH:26][C:2]([C:30]4[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=4)=[CH:3][CH:4]=3)=[N:9][N:10]2[C:11]1=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: OB(O)c1ccncc1
Reactant: CCCCn1c(=O)n2nc(COc3ccc(Br)cc3)nc2c2[nH]cnc21
Agent: Br[Pd](Br)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(=O)n2nc(COc3ccc(-c4ccncc4)cc3)nc2c2[nH]cnc21
Temperature: 120 °C
Yield: 30.1 %

Procedure:
8-[(4-bromophenoxy)methyl]-4-butyl-1,4-dihydro-5H-[1,2,4]triazolo[5,1-i]purin-5-one (100 mg, 0.24 mmol) and 4-pyridinylboronic acid (32 mg, 0.26 mol) were dissolved in N,N-dimethylformamide (3 mL) in a microwave tube. After the solution was degassed with N2 for 5 minutes, dibromo[bis(triphenylphosphoranyl)]-palladium (20 mg, 0.02 mmol) and a solution of sodium carbonate in water (2 M, 1 mL) were added. The reaction mixture was heated on a microwave reactor at 120° C. for 20 minutes. After cooling down to room temperature, the reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated. The residue was dissolved in DMSO/acetonitrile and purified by preparative LCMS (method A) to yield the desired product as white powder (30 mg, 24% yield). LCMS calculated for C22H22N7O2 (M+H): 416.2. found: 417.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([NH:18][C:19](=[O:21])[CH3:20])[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12][CH2:11]2)=[CH:4][CH:3]=1.[CH:22]([C:24]1[S:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23].C(=O)([O-])O.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:22]([C:24]1[S:28][C:27]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]3([NH:18][C:19](=[O:21])[CH3:20])[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12][CH2:11]3)=[CH:4][CH:3]=2)=[CH:26][CH:25]=1)=[O:23]
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CC(=O)NC1(CCc2ccc(Br)cc2)COC(C)(C)OC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: O
Solvent: COCCOC
Product: CC(=O)NC1(CCc2ccc(-c3ccc(C=O)s3)cc2)COC(C)(C)OC1
Yield: 21.5 %

Procedure:
A mixed solution of N-{5-[2-(4-bromophenyl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (1.07 g) of Reference Example 5, 5-formyl-2-thiopheneboronic acid (0.56 g), sodium hydrogen carbonate (1.51 g), palladium(II) acetate (33.7 mg) and 2-(di-t-butylphosphino)biphenyl (89.5 mg) in 1,2-dimethoxyethane (12 mL)-water (4 mL) was stirred at 65° C. for 9 hr under a nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.25 g) as brown crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]2[N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[CH:12][C:8]=2[S:7][C:6]=1[CH3:24])=[O:4].CO.O.[Li+].[OH-]>C1COCC1.CC(O)=O>[CH3:24][C:6]1[S:7][C:8]2[CH:12]=[CH:11][N:10]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=3)[C:9]=2[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(C)sc2ccn(Cc3ccc(C(F)(F)F)cc3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1sc2ccn(Cc3ccc(C(F)(F)F)cc3)c2c1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.3 %

Procedure:
A mixture of 0.35 g of the product of Step 6 was dissolved in 15 ml THF, 10 ml of MeOH and 5 ml of water, followed by 5 ml of 1N aqueous LiOH solution. After stirring for 5 h at room temperature, 1 ml of AcOH was added and the mixture was extracted with 50 ml of EtOAc. The organic layer was washed with 25 ml of brine and dried over Na2SO4, filtered, and concentrated to give 0.30 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][O:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:31](O)=[O:32])=[N:27][NH:28]2)=[CH:24][CH:23]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:31]([C:26]1[C:25]2[C:29](=[CH:30][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[NH:28][N:27]=1)=[O:32]
Reactant: COc1ccc2c(C(=O)O)n[nH]c2c1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: COc1ccc2c(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)n[nH]c2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 6-methoxy-1H-indazole-3-carboxylic acid. MS: 434.3 (M+H).