Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:11]([CH2:12][CH:13]2[CH2:14][CH2:15][CH:16]([C:19]([OH:21])=[O:20])[CH2:17][CH2:18]2)[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:25][CH:26]=1
Reactant: NCC1CCC(C(=O)O)CC1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C(O)C1CCC(CN(Cc2ccc(F)cc2)S(=O)(=O)c2ccccc2)CC1

Procedure:
Prepared as in example 5-11 from benzenesulfonyl chloride, 4-(aminomethyl)-cyclohexanecarboxylic acid and 1-(bromomethyl)-4-fluorobenzene. MS (M+H, 406); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 0.77 (m, 2H), 0.94 (m, 2H), 0.98 (m, 2H), 1.50 (m, 2H0, 1.75 (m, 2H), 1.77 (m, 1H), 2.80 (d, 2H), 4.28 (s, 2H), 7.20 (m, 2H), 7.38 (m, 2H), 7.62 (m, 2H), 7.70 (m, 1H), 7.88 (m, 2H), 11.93 (br, s, 1H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:19]=[CH:18][C:17]([N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=[O:26])=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH:9]=1)=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[NH2:1][CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:19]=[CH:18][C:17]([N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=[O:26])=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH:9]=1
Reactant: COC(=O)c1cc(-n2ccccc2=O)ccc1-n1cnc(CN=[N+]=[N-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-n2ccccc2=O)ccc1-n1cnc(CN)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(4-(azidomethyl)-1H-imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)benzoate prepared above (25 mg, 0.071 mmol) in THF (1 mL) and H2O (0.025 mL, 1.4 mmol), Ph3P (64 mg, 0.24 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo to give methyl 2-(4-(aminomethyl)-1H-imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)benzoate as a crude mixture, which was then used in the next transformation. MS 325.1 (M+H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Cl[C:9]1[CH:10]=[CH:11][C:12]([N+:28]([O-:30])=[O:29])=[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:14]=1>CN1C(=O)CCC1>[CH:25]([NH:24][C:22]([C@H:19]1[CH2:18][CH2:17][C@@H:16]([NH:15][C:13]2[CH:14]=[C:9]([N:3]3[CH:7]=[N:6][CH:5]=[N:4]3)[CH:10]=[CH:11][C:12]=2[N+:28]([O-:30])=[O:29])[CH2:21][CH2:20]1)=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ccc2[N+](=O)[O-])CC1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(-n3cncn3)ccc2[N+](=O)[O-])CC1

Procedure:
To a suspension of sodium hydride (70.6 mg, 2.94 mmol) and 1H-1,2,4-triazole (203 mg, 2.94 mmol) in NMP (1 mL) was added cis-4-(5-chloro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide (100 mg, 0.294 mmol). The resulting suspension was irradiated in a microwave reactor for 1 hour at 150° C. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layers were then washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide a yellow oil that crystallized upon standing to provide cis-N-isopropyl-4-(2-nitro-5-(1H-1,2,4-triazol-1-yl)phenylamino)cyclohexanecarboxamide as a yellow solid (100 mg, 91% yield).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[P:30](=[O:34])([OH:33])([OH:32])[OH:31]>CO>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[P:30]([O-:34])([O-:33])([O-:32])=[O:31]
Reactant: O=P(O)(O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CO
Product: O=P([O-])([O-])[O-]
Temperature: 30 °C

Procedure:
Sunitinib (1.0 g) was suspended in methanol (152 mL), followed by addition of phosphoric acid (0.24 g) at 25-35° C. over a period of 15 minutes. After the stipulated time period, methanol was completely distilled off under vacuum below 45° C. The residue was treated with acetonitrile (38 mL) and refluxed. The reaction mass was maintained at reflux temperature for 60 minutes. The reaction mass was cooled to 25-35° C. for crystallization. The solid obtained was filtered, washed with acetonitrile, suck dried and dried under vacuum at 60° C. over 4-5 hr period to obtain sunitinib phosphate. (1.18 g; yield: 95%)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4[OH:28])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C=O)C>[CH:37]1([CH2:36][O:28][C:19]2[CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=[CH:23][C:18]=2[C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:11][C:8]3[CH:9]=[C:10]4[C:5]([CH:4]=[CH:3][CH:2]=[N:1]4)=[CH:6][CH:7]=3)[CH:13]=2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: Oc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)c(OCC2CCCCC2)c1
Temperature: 60 °C
Reaction time: 23 h

Procedure:
To a mixture of 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenol, (Example 191), (50 mg, 0.13 mmol) and K2CO3 (54 mg, 0.39 mmol) in DMF (2.0 mL) was added (bromomethyl)cyclohexane (20 μL, 0.14 mmol, Aldrich). The reaction mixture was stirred at 60° C. for 23 h. The resulting mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated in vacuum and purified by silica gel chromatography (gradient: 0% to 3.0% MeOH/CH2Cl2) to provide the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 480 (M+1).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15](SSC2SC3C=C(C)C=CC=3N=2)[N:14]([CH:28]([C:42]([CH3:44])=[CH2:43])[C:29]([O:31][CH2:32][C:33]([C:35]2[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=2)=[O:34])=[O:30])[C:13]1=[O:45])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:46]1([S:52](=[S:65])([O:54]C2SC3C=C(C)C=CC=3N=2)=[O:53])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.O.C1(S([O-])=O)C=CC=CC=1.[Na+]>CC(C)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:54][S:52]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)(=[O:65])=[O:53])[N:14]([CH:28]([C:42]([CH3:44])=[CH2:43])[C:29]([O:31][CH2:32][C:33]([C:35]2[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=2)=[O:34])=[O:30])[C:13]1=[O:45])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C(C(=O)OCC(=O)c1ccc(Br)cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccc(C)cc2s1
Reactant: Cc1ccc2nc(OS(=O)(=S)c3ccccc3)sc2c1
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)C(C(=O)OCC(=O)c1ccc(Br)cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
A 1.23 g quantity of p-bromophenacyl 2-[3-phenoxyacetamido-4-(6-methylbenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 572 mg of 6-methylbenzothiazol-2-yl benzenethiosulfonate were dissolved in 10 ml of acetone. To the solution were added 2 ml of water and then 3 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 5 hours. The precipitated 6-methylbenzothiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving p-bromophenacyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 94%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below shows the data thereof.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:4]=1[CH:5]=O.[C:17]([S:21]([NH2:23])=[O:22])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl.O.[O-]S([O-])(=O)=O.[Cu+2]>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:4]=1/[CH:5]=[N:23]/[S:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22]
Reactant: O=Cc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: CC(C)(C)S(N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)S(=O)/N=C/c1cc(C(F)(F)F)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.3 %

Procedure:
A mixture of 2,5-bis trifluoromethyl benzaldehyde (21.5 g, 88.8 mmol), tert butyl sulfinamide (16.1 g, 133 mmol) and anhydrous CuSO4 (16.5 g, 103 mmol) in DCM (94 ml) was stirred at room temperature for 16 hours and at reflux for 3 days. The fine suspension was diluted with water and extracted with DCM. The extracts were washed with water, dried (MgSO4) and evaporated in vacuo to an off white solid which was purified by chromatography (silica, 4-10% EtOAc/isohexane) to give the desired N-{(1E)-[2,5-bis(trifluoromethyl)phenyl]methylene}-2-methylpropane-2-sulfinamide as a white crystalline solid (14.8 g, 91%); 1H NMR δ (ppm)(CDCl3): 8.98 (1 H, d, J=1.8 Hz), 8.46 (1 H, s), 7.92-7.85 (2 H, m), 1.29 (9 H, s); m/z (ES+) 346 (MH+).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([C:13]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH3:26])[C:14]=1[CH2:15][C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[CH3:12].N>ClCCl.C(N(CC)CC)C>[CH2:11]([C:13]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH3:26])[C:14]=1[CH2:15][C:16]1[NH:17][CH:18]=[CH:19][N:20]=1)[CH3:12]
Reactant: CCc1cccc(CC)c1CC1=NCCN1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cccc(CC)c1Cc1ncc[nH]1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 73.9 %

Procedure:
To a solution of 1.08 g (14 mmol) dimethylsulfoxide in 100 ml dichloromethane cooled to −78° C. was added a solution of 1.82 g (14 mmol) oxalyl chloride in 7 ml dichloromethane. The mixture was stirred for 50 minutes at −78° C. and then a solution of 0.620 g (3 mmol) 2-(2,6-diethyl-benzyl)-4,5-dihydro-1H-imidazole in 80 ml dichloromethane was added and stirring continued at −78° C. for 90 minutes. Then 2.90 g triethylamine were added and the reaction mixture warmed to ambient temperature and stirring continued for 2 hours. Concentrated ammonia was added and the reaction mixture extracted with ethyl acetate, the combined extracts washed with brine, dried over Na2SO4, filtered and evaporated. Purification on silica gel by flash-chromatography with a heptane/ethyl acetate gradient followed by trituration of residue of the collected and evaporated fractions in tert.-butyl methyl ether provided 0.475 g 2-(2,6-diethyl-benzyl)-1H-imidazole as colourless solid: MS (ISP): 215.2 ((M+H)+.).
Reaction SMILES: C(OC(N1CC(OC(=O)C)CC1C[C:21]1[C:29]2[C:24](=[CH:25][C:26](F)=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=O)C1C=CC=CC=1.[C:31](O)([C:33](F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[NH:23]1[C:31]2[C:33](=[CH:29][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:22]1[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][CH2:22]1
Reactant: CC(=O)OC1CC(Cc2c[nH]c3cc(F)ccc23)N(C(=O)OCc2ccccc2)C1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)CCN2c1cc2ccccc2[nH]1
Temperature: 3 °C
Reaction time: 4.75 h

Procedure:
A solution containing 8 (2.9 g, 7.1 mmol) in EtOAc (ca. 5 mL) was cooled in an ice-bath and pre-cooled TFA (20.3 mL) was added in one portion. The resulting yellow-colored solution was stirred at 2-4° C. After 4.75 h, the cold reaction mixture was transferred (via canula) with stirring into a pre-cooled mixture of EtOAc (30 mL), and 25% aq. K2CO3 (80.7 g). The aqueous layer was separated and extracted with EtOAc (3×30 mL) and the combined organic extracts were washed with 10% aq. Na2CO3 (30 g). The organic solution was concentrated in vacuo and azeotropically dried using anhydrous EtOAc to afford 2.95 g of indolylindoline diastereomers as a yellow-colored foam which was used directly in the next reaction. Mass spectrum (ESI), m/z 821.3 [(M)+; calcd for C46H46F2N4O8: 820.9].
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH2:7][CH2:8][CH3:9])[NH:5][CH:6]=1.[N:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH2:7]([C:4]1[NH:5][CH:6]=[C:2]([C:13]2[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=2)[N:3]=1)[CH2:8][CH3:9]
Reactant: OB(O)c1ccncc1
Reactant: CCCc1nc(I)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1nc(-c2ccncc2)c[nH]1
Yield: 37 %

Procedure:
[step 1] 4-Iodo-2-propylimidazole obtained in Reference Example A16 was dissolved in dioxane/water (2 mL/1 mL), 4-pyridineboronic acid (0.108 g, 0.889 mmol), 1,1-bisdiphenylphosphinoferrocene dichloropalladium (0.052 g, 0.064 mmol) and sodium carbonate (0.202 g, 1.91 mmol) were added, and the mixture was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give 2-propyl-4-(4-pyridyl)imidazole (0.044 g, 37%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[C:14]4[O:16][CH2:17][O:18][C:13]4=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[OH-].[Na+].[C:21]([Cl:31])(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[ClH:31].[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([NH:1][CH:2]2[CH2:11][CH:10]3[N:5]([CH2:6][CH2:7][C:8]4[CH:15]=[C:14]5[O:16][CH2:17][O:18][C:13]5=[CH:12][C:9]=43)[CH2:4][CH2:3]2)=[O:30])=[CH:23][CH:24]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NC1CCN2CCc3cc4c(cc3C2C1)OCO4
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC2CCN3CCc4cc5c(cc4C3C2)OCO5)cc1
Product: Cl
Reaction time: 1 h
Yield: 30.4 %

Procedure:
A mixture of 2-amino-1,3,4,6,7,11b-hexahydro-9,10-methylenedioxy-2H-benzo[a]quinolizine (6.5 g, 0.026 mole), 20% NaOH (50 ml) and 200 ml of toluene was cooled in an ice bath and p-anisoyl chloride (4.6 g) was added dropwise. The mixture was stirred in the cold for one hour whereupon the solid was collected and recrystallized from aqueous methanol-DMF. The free base was converted to the HCl salt with hydrogen chloride in a mixture of 2-propanol and ethyl acetate. The resulting solid was collected and twice recrystallized from methanol-ethyl acetate to yield 3.3 g of the desired product, m.p. (decomposed at 228°-30°). This product conforms to Formula II where R1 and R2 combined are ##STR34## R3 is H and R4 is ##STR35##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][C:9]=1[NH2:10])([O-:3])=[O:2].[I:21]I>S([O-])([O-])(=O)=O.[Ag+2].CCO>[I:21][C:8]1[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:9]=1[NH2:10]
Reactant: II
Reactant: Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1c(I)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.1 %

Procedure:
The method of Koradin, C. et al. (Tetrahedron 2003, 59, 1571-1587) was used. 3-Nitro-2′-trifluoromethyl-biphenyl-4-ylamine (752 mg, 2.66 mmol, as prepared in Example 6, step A) was placed in a 40 mL vial equipped with a magnetic stir bar, and anhydrous EtOH (27 mL) was added. Iodine (1.4 eq., 945 mg, 3.72 mmol) was added as a solid to the stirred solution. Silver sulfate (1.4 eq., 1.16 g, 3.72 mmol) was added in one portion as a solid, and the reaction was stirred at RT for 24 h. The reaction was filtered, and the solvent was removed under reduced pressure. The residue was dissolved in DCM (30 mL), washed with 10% aq Na2S2O3 (10 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography using a 40-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 1:4, v/v, yielding 902 mg (83%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 8.17 (d, J=2.0 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.76 (d, J=7.3 Hz, 1H), 7.58 (t, J=7.6 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 6.74 (br. s., 2H).
Reaction SMILES: [CH:1]1([C:7]2[N:15]3[C:10]([C:11](=[O:16])[NH:12][CH:13]=[N:14]3)=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I:17]N1C(=O)CCC1=O>CN(C=O)C.O>[CH:1]1([C:7]2[N:15]3[C:10]([C:11](=[O:16])[NH:12][CH:13]=[N:14]3)=[C:9]([I:17])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1[nH]cnn2c(C3CCCCC3)ncc12
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]cnn2c(C3CCCCC3)nc(I)c12
Temperature: 55 °C
Reaction time: 20 h

Procedure:
To a solution of 7-cyclohexylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (130 mg, 0.6 mmol) in DMF (0.6 mL) was added N-iodosuccinimide (700 mg, 0.003 mol) and the reaction mixture stirred at 55° C. for 20 h. After this time the mixture was diluted with water (50 mL) and extracted with EtOAc (4×40 mL). The organic extracts were washed with water (4×40 mL), treated with sodium thiosulfate and brine, dried over Na2SO4 and concentrated in vacuo to afford 7-cyclohexyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4(3H)-one. 1H NMR (400 MHz-DMSO-d6) δ 1.34-1.37 (m, 3H), 1.52-1.56 (m, 2H), 1.76-1.88 (m, 5H), 3.06-3.08 (m, 1H) 7.87 (s, 1H) 11.78 (s, 1H); MS (ES+): m/z: 344.95 (100) [MH+]. HPLC: tr=2.95 min (OpenLynx: polar—5 min).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1(=O)[NH:11][C:10](=O)[CH:9]2[CH2:13][CH2:14][CH:15]=[CH:16][CH:8]12>C1COCC1>[CH:10]1[NH:11][CH:7]=[C:8]2[C:9]=1[CH:13]=[CH:14][CH:15]=[CH:16]2
Reactant: O=C1NC(=O)C2CCC=CC12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c[nH]cc2c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a suspension of LAH (22.80 g, 600 mmol) in THF (600 mL) at 0° C. was added tetrahydrophthalimide (39.45 g, 260.9 mmol) portionwise. After addition, the reaction mixture was stirred at 60° C. for 18 h, then cooled down to 0° C. and quenched carefully with water (25 mL), followed by 15% KOH aqueous solution (25 mL) and another 75 mL of water. The resulting mixture was stirred at rt for 1 h and filtered through a pad of Celite, then washed with DCM (500 mL). The filtrate was concentrated in vacuo to give isoindole as yellow oil, which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:5]=[CH:6][CH:7]=1.C[O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1>>[C:19]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:37][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][C:29]([OH:39])=[O:28])=[CH:36][CH:35]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])(=[O:20])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Reactant: Cc1cccc2c(-c3cccc(N)c3)c(C(=O)c3ccccc3)cnc12
Product: Cc1cccc2c(-c3cccc(NCc4ccc(CC(=O)O)cc4)c3)c(C(=O)c3ccccc3)cnc12

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-methyl-quinolin-3-yl]-phenyl-methanone and (4-formyl-phenyl)-acetic acid methyl ester according to the procedure of Example 66. MS (ESI) m/z 487; MS (ESI) m/z 485.
Reaction SMILES: [CH:1]12[O:8][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[OH:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: C1CCC2OC2CC1
Product: OC1CCCCCC1Nc1ccccc1

Procedure:
Reaction of the cycloheptene oxide IIIa with an aniline under conditions well known in the art gives the N-(2-hydroxycycloheptyl)aniline IX which when reacted with chlorosulfonic acid in a non-polar organic solvent, e.g., methylene chloride at 20°-30° C. followed by heating with a selected C1 to C3 -monoalkylamine (aqueous) or ammonium hydroxide (aqueous) at 100°-150° C. for 40-55 hours at elevated pressure (2-10 atm.), gives the diamine X. Reaction of diamine X with 2,2,2-trichloroethyl chloroformate, or equivalent N-blocking compound, at 20°-30° C. for 1-5 hours proceeds in the presence of an acid scavenger, e.g., triethylamine, to give the 2-(N-blocked amino) compound XI. Acylation of the N-blocked compound XI with the selected acid anhydride, ##STR19## by heating at 90°-120° C. for 12 to 30 hours gives the N-blocked anilide XII. Deprotection of the 2-amino function of the 2-N-blocked anilide XII is then accomplished by reaction with an N-deblocking agent such as metal dust in acid, e.g., zinc in acetic acid, in a polar organic solvent, e.g., methanol, at 20°-100° C. for 2 to 6 hours. Work-up, isolation and purification procedures are those standard in the art of organic chemistry.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1.Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][O:23][C:22]2=[O:31])[CH2:17][CH2:16]1>>[CH3:12][CH:11]([NH:10][C:8]([C:5]1[CH:6]=[N:7][C:2]([N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH2:24][O:23][C:22]3=[O:31])[CH2:19][CH2:20]2)=[CH:3][CH:4]=1)=[O:9])[CH3:13]
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Reactant: CC(C)NC(=O)c1ccc(Cl)nc1
Agent: Cl
Product: CC(C)NC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)nc1

Procedure:
The title compound was prepared from the product of step (i) (0.4 g) and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.5 g) using the method of example 115 step (ii). Yield 0.22 g.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH:8](CCN)[C:7]=2[CH:14]=1)#[N:2].CC[N:17](CC)CC.[C:22]1([C:28]2[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH:8]([C:35]3[CH:36]=[C:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:29]=[CH:30][C:31]=3[C:32]([NH2:17])=[O:33])[C:7]=2[CH:14]=1)#[N:2]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: N#Cc1ccc2c(c1)C(CCN)CO2
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)C(c1cc(-c3ccccc3)ccc1C(N)=O)CO2
Reaction time: 0.25 h
Yield: 69.9 %

Procedure:
To a cooled (0° C.) solution of 2-(5-cyano-2,3-dihydro-benzofuran-3-yl)-ethyl amine (reference example 6, 382 mg, 2 mmol) in CH2Cl2 (9 mL) is added Et3N (0.55 mL, 4 mmol) followed by 4-phenyl-benzoyl chloride (440 mg, 2.03 mmol). The resulting solution is stirred for 15 min. then diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (50% ethyl acetate/10% CH2Cl2 in hexanes) to give the title compound (476 mg) as a solid 1H NMR (CDCl3) d 1.96 (m, 1H), 2.10 (m, 1H), 3.50-3.70 (m, 3H), 4.50 (dd, J=9, 8 Hz, 1H), 4.83 (t, J=9 Hz, 1H), 6.31 (bt, 1H), 6.86 (d, J=8 Hz, 1H), 7.37-7.59 (m, 5H), 7.6-7.75 (m, 4H), 7.85 (d, J=8 Hz, 2H). MS (EI) m/z 368 (M)+.