Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:18][CH:5]([N:6]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:7]1)[CH2:4][CH2:3][NH:2]2.F[C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH2:27]([O:26][C:24]([C:23]1[CH:29]=[CH:30][C:20]([N:2]2[CH2:3][CH2:4][CH:5]3[CH2:18][CH:1]2[CH2:7][N:6]3[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:21][CH:22]=1)=[O:25])[CH3:28]
Reactant: O=C(OCc1ccccc1)N1CC2CC1CCN2
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCC3CC2CN3C(=O)OCc2ccccc2)cc1
Temperature: 130 °C

Procedure:
Benzyl 2,6-diazabicyclo[3.2.1]octane-6-carboxylate (300 mg) was dissolved in dimethylsulfoxide (3 mL), then ethyl 4-fluorobenzoate (172 mg) and potassium carbonate (206 mg) were added. The reaction was heated at 130° C. overnight. After cooling, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration and concentration of the filtrate, the resultant crude material was purified by column chromatography on silica gel using 7/3 hexanes/ethyl acetate to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][C:30]([CH3:34])=[N:31]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][C:30]([CH3:34])=[N:31]2)=[CH:26][CH:25]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Cc1ccc2ccc(O)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4ccc(C)nc4c3)ncnc2cc1OCCCN1CCCC1
Temperature: 90 °C
Yield: 68.9 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 9), and 7-hydroxy-2-methylquinoline (54 mg, 0.34 mmol), (J. Med. Chem. 1998, 41, 4062), in DMF (3 ml) containing potassium carbonate (86 mg, 0.62 mmol) was heated at 90° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried and the volatiles were removed by evaporation. The residue was triturated with minimal ether, collected by filtration and dried under vacuum to give 6-methoxy-4-(2-methylquinolin-7-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (95 mg, 69%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(C(C)=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[O:20][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1cccc(C#Cc2ccc3ccc(Br)cc3n2)c1
Reactant: CCOC(=O)CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCOc1cccc(C=Cc2ccc3ccc(Br)cc3n2)c1

Procedure:
A solution of the phenol from Step 3 (470 mg), methyl ethyl ketone (10 mL), milled potassium carbonate (600 mg) and ethyl 4-iodo-butyrate (421 mg) was refluxed overnight The solids were filtered, and the filtrate was evaporated. The residue was purified by flash chromatography using toluene-ethyl acetate (10:0.3) to afford the title product as yellow solid: m.p. 61°-63° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH2:15])[CH2:3]1.N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl.O>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH:15][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:3]1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1ccccc1N)N2
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)C(C)(C)CC(c1ccccc1NS(C)(=O)=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4,6-trimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (150 mg, 0.56 mmol) and pyridine (0.5 mL) in anhydrous dichloromethane (2 mL) was added methanesulfonyl chloride (44 μL) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Sodium sulfate, and then concentrated. The residue was purified by HPLC to give N-[2-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]methanesulfonamide LC/MS m/e obsd. (ESI+) [(M+H)+] 345.2.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[C:7]([O:10]C(=O)C)=[CH:8][O:9][C:5]=2[CH:4]=1.CO.Cl>O>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[CH:4]=1
Reactant: CC(=O)Oc1coc2cc(C(F)(F)F)ccc12
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1COc2cc(C(F)(F)F)ccc21
Temperature: 25 °C

Procedure:
A mixture of acetic acid 6-trifluoromethyl-benzofuran-3-yl ester (15 g), methanol (100 ml), water (53.8 ml) and 1 N HCl (18.8 ml) was heated at reflux for 6 hrs. Mixture was cooled to room temperature. Crude product was evaporated in vacuo and purified by chromatography to give product 6a (Hexane:EA=18:1).
Reaction SMILES: O[C:2]1([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:28][CH:27]=2)[C:7]2[CH:8]=[CH:9][C:10]([O:12]COC)=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22]COC)=[CH:18][CH:17]=1.[NH+]1C=CC=CC=1.O>CO>[OH:12][C:10]1[CH:9]=[CH:8][C:7]2[C:2]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]4)=[CH:28][CH:27]=3)=[C:3]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH2:4][O:5][C:6]=2[CH:11]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: Oc1ccc(C2=C(c3ccc(OCCN4CCCCC4)cc3)c3ccc(O)cc3OC2)cc1
Temperature: 25 °C
Yield: 37 %

Procedure:
4-Hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-4-[4-(piperidinoethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (83 mg, 0.14 mmol) and pyridinium p-toulenesulfonate (214 mg, 1.4 mmol) were dissolved in methanol (6 ml) and then refluxed for 12 hours. The reaction solution was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer thus separated was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The residue was separated by column chromatography (n-hexane:ethyl acetate=1:4) to obtain 23 mg (yield: 37%) of the title compound as a foam.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][C:8]1([NH:23][CH:24]1[N:29]([CH:30]([C:37]([F:40])([F:39])[F:38])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][C:27]([CH:53]([C:60]([F:63])([F:62])[F:61])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([O:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])[CH:26]=[N:25]1)[CH2:21][CH3:22])=[O:6])[CH3:3].O.C(OCC)(=O)C>C(O)(=O)C>[CH2:2]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([F:19])([F:20])[F:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][C:8]1([NH:23][CH:24]1[N:29]([CH:30]([C:37]([F:40])([F:38])[F:39])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][C:27]([CH:53]([C:60]([F:61])([F:62])[F:63])[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)([O:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47])[CH:26]=[N:25]1)[CH2:21][CH3:22])=[O:6])[CH3:3]
Reactant: CCOC(=O)N1c2ccc(C(F)(F)F)cc2CCC1(CC)NC1N=CC(OCCCCC(=O)OC(C)(C)C)(C(c2ccccc2)C(F)(F)F)CN1C(c1ccccc1)C(F)(F)F
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2CCC1(CC)NC1N=CC(OCCCCC(=O)O)(C(c2ccccc2)C(F)(F)F)CN1C(c1ccccc1)C(F)(F)F
Temperature: 50 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
5N HCl (0.5 ml) was added to a solution of the compound obtained in Example 6 (250 mg) in acetic acid (1.5 ml) and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was cooled to room temperature, water and ethyl acetate was added to the mixture and the organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution three times and then with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate=4:1→1:1) to give the titled compound (183 mg). MS (m/z): 737 [M+H]+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1.[I:17]I>C1COCC1.O>[F:9][C:10]1[C:15]([I:17])=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1
Reactant: II
Reactant: Cc1ccc(F)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(F)c(I)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 499.3 %

Procedure:
A solution of 2M LDA in THF (371 mL, 742 mmol) was added to THF (1400 mL) at −78° C. under an atmosphere of nitrogen. To this stirred, cooled solution was added 2-fluoro-5-methylpyridine (75.0 g, 67.6 mmol) in THF (280 mL) dropwise. The reaction mixture was allowed to stir at −78° C. for 2 h and then a solution of iodine (171.5 g, 67.6 mmol) in THF (560 mL) was added dropwise. The reaction mixture was allowed to stir at −78 for 2 h and then diluted with water (875 mL). The mixture was allowed to warm to rt and was then extracted with EtOAc. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 2-fluoro-3-iodo-5-methylpyridine (80 g, 50%).
Reaction SMILES: OO.[CH3:3][O:4][C:5]([CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH:13]1[C:17](=[CH:18][CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16](=[O:26])[CH:15]=[CH:14]1)=[O:6].[OH-].[Na+].[Cl-:29].[NH4+].Cl.C(=O)([O-])O.[Na+]>CO.CC(C)=O>[Cl:29][C:15]1[C:16](=[O:26])[C:17](=[CH:18][CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:13]([CH2:12]/[CH:11]=[CH:10]\[CH2:9][CH2:8][CH2:7][C:5]([O:4][CH3:3])=[O:6])[CH:14]=1
Reactant: CCCCCC=CC=C1C(=O)C=CC1C/C=C\CCCC(=O)OC
Reactant: [Cl-]
Agent: Cl
Agent: O=C([O-])O
Agent: OO
Solvent: CC(C)=O
Solvent: CO
Product: CCCCCC=CC=C1C(=O)C(Cl)=CC1C/C=C\CCCC(=O)OC
Yield: 49 %

Procedure:
0.5 ml of 30% aqueous hydrogen peroxide was added to a solution of 68 mg (206 micromol) of 4-[(2Z)-6-methoxycarbonyl-2-hexenyl]-5-(2-octenylidene)-2-cyclopentenone in 5 ml of methanol under ice cooling and stirring, and then 50 microliters of 1N sodium hydroxide was added. The mixture was stirred at 0° C. for 20 minutes. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with hexane. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The dried product was filtered and concentrated to give an oily product. The product was dissolved in 3 ml of acetone, and 0.5 ml of concentrated hydrochloric acid was added. The mixture was stirred for one hour. A saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with ethylacetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The dried product was filtered, concentrated and subjected to silica gel column chromatography (silica gel, 10 g; eluent, cyclohexane:ethylacetate=4:1) to give 37 mg (yield 49%) of 2-chloro-4-[(2Z)-6-methoxycarbonyl-2-hexenyl]-5-(2-octenylidene)-2-cyclopentenone.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[C:21]([O:29][CH3:30])=[N:22][C:23]([CH3:28])=[N:24][C:25]=1[O:26][CH3:27].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:3]2[N:17]=[C:18]([NH:19][C:20]3[C:21]([O:29][CH3:30])=[N:22][C:23]([CH3:28])=[N:24][C:25]=3[O:26][CH3:27])[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(OC)nc(C)nc2OC)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc(Nc3c(OC)nc(C)nc3OC)n(CCCO)c12
Temperature: 50 °C
Reaction time: 13 h
Yield: 52.1 %

Procedure:
A mixture of the resulting thiourea (435 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (195 mg, 1.02 mmol), and triethylamine (0.15 mL) in tetrahydrofuran (5.0 mL) was stirred at 50° C. for 13 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, 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 washed with diisopropyl ether to give the title compound as a colorless powder (210 mg, 0.482 mmol, 6% in 2 steps).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[N:13]1([CH2:18][CH2:19]O)[CH:17]=[CH:16][N:15]=[CH:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[N:13]1([CH2:18][CH2:19][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:12])[CH2:7][CH2:8][NH:9]3)=[CH:4][CH:3]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=C1CCNc2cc(O)ccc21
Reactant: OCCn1ccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCNc2cc(OCCn3ccnc3)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 11.7 %

Procedure:
Under N2, a solution of 0.8 g (5.0 mmol) of 7-hydroxy-1,2,3,4-tetrahydro-4-quinolinone in 20 mL of THF was treated with 0.62 g (5.5 mmol) of 2-(1H-1-imidazolyl)-1-ethanol and 1.13 (5.0 mmol) of tripenylphosphine. The mixture was warmed to effect solution, then allowed to cool to room temperature. This was then treated over 10 minutes with 0.8 mL (5.0 mmol) of diethyl azodicarboxylate. Some solid formed and the mixture was allowed to stir at room temperature for 3 days. The mixture was diluted with EtOAc and filtered. The filtrate was washed twice with H2O, saturated NaHCO3, then with saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with CHCl3/MeOH (90/10), gave 150 mg (11.8% yield) of the product as a golden oil. The structure was confirmed by mass spectroscopy. MS m/z 258 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1)[CH3:2].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CCCN2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCc1ccc(C2CCCN2S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound, white solid, m.p. 92° C. and MS: m/e=330.3 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-ethyl-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:15])[C:11]=2[C:12]([OH:14])=O)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:16][C:17]1[N:22]=[CH:21][N:20]2[CH:23]=[C:24]([C:26]3[CH:27]=[C:28]([O:32][C:33](=[O:35])[CH3:34])[CH:29]=[CH:30][CH:31]=3)[N:25]=[C:19]2[CH:18]=1>>[C:33]([O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([C:24]2[N:25]=[C:21]3[N:22]=[C:17]([NH:16][C:12]([C:11]4[N:10]([CH3:15])[N:9]=[CH:8][C:7]=4[C:5]([N:1]4[CH2:2][CH2:3][CH2:4]4)=[O:6])=[O:14])[CH:18]=[CH:19][N:20]3[CH:23]=2)[CH:27]=1)(=[O:35])[CH3:34]
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)O
Reactant: CC(=O)Oc1cccc(-c2cn3cnc(N)cc3n2)c1
Product: CC(=O)Oc1cccc(-c2cn3ccc(NC(=O)c4c(C(=O)N5CCC5)cnn4C)nc3n2)c1

Procedure:
The title compound was prepared in analogy to example 82, step 3, from 4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (156 mg, 746 μmol) and acetic acid 3-(7-amino-imidazo[1,2-c]pyrimidin-2-yl)-phenyl ester (200 mg, 746 μmol). Yield: 158 mg (42%). Yellow foam. MS (m/z)=459.2 [M+H+].
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30]C)=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+].C(O)=O.C(O)C>O1CCOCC1.O.C1(C)C=CC=CC=1>[CH2:33]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:15])=[O:16])[CH3:34]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Yield: 36.7 %

Procedure:
Methyl (1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 40, 0.185 g) and lithium hydroxide monohydrate (0.159 g) were suspended in dioxane (4 mL) and water (1 mL). The reaction mixture was irradiated in the microwave at 135° C. for 30 minutes. After cooling, the mixture was acidified to pH4 with formic acid, then ethanol and toluene were added and the mixture concentrated in vacuo. The residue was triturated with a mixture of methanol and DCM (10%) and the solid was filtered off and washed with a mixture of methanol and DCM. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-8%. The resultant product was triturated with ethyl acetate and dried in vacuo at 50° C. to give (1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.066 g) as a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[CH2:14])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[CH2:4]1.C([BH3-])#N.[Na+]>CO>[NH:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[CH2:14])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[CH2:4]1)[OH:1]
Reactant: C=C1c2ccccc2CC(=NO)c2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C=C1c2ccccc2CC(NO)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 15.3 of oxime from Step D, 500 ml of methanol, 12 g of sodium cyanoborohydride in 450 ml of methanol was treated dropwise with a solution of 12 ml of 12N hydrochloric in 50 ml of methanol over 5 hours, and then stirred overnight at room temperature. The solvent was evaporated, the residue was stirred with 200 ml of 1N aqueous hydrochloric acid, made alkaline with concentrated ammonium hydroxide and extracted with 3×175 ml of ether. The combined extracts were dried (Na2SO4), filtered and evaporated. The crystalline residue was washed with methanol to give 9.6 g of 10-hydroxamino-5-methylene-10,11-dihydro-5H-dibenzo[a,d]cyclohepten, m.p. 145°-147° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=3)[CH:14]2[CH3:27])=[O:12])=[CH:6][CH:5]=1)([O-])=O.C(OC(=O)C)C.Cl>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=3)[CH:14]2[CH3:27])=[O:12])=[CH:6][CH:5]=1
Reactant: COc1cc2c(cc1OC)C(C)N(C(=O)Cc1ccc([N+](=O)[O-])cc1)CC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)C(C)N(C(=O)Cc1ccc(N)cc1)CC2
Reaction time: 4 h
Yield: 86 %

Procedure:
A solution of N-(4-nitrophenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline (38.3 g, 0.1035 m) in a mixture of methanol (500 ml), ethylacetate (500 ml) and conc HCl (8 ml) in a pressure bottle was treated with 5.0 g 5% Pd/C catalyst under nitrogen and the mixture hydrogenated on a Parr apparatus at 50 psi for 4 hr. The catalyst was removed by filtration and the solvent evaporated to a solid residue. The solid was dissolved in water (2 liters), filtered, then basified to pH with 50% NaOH. Extraction with CHCl3 (3×250 ml) and evaporation of the extracts gave N-(4-aminophenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline as an off-white solid, 30.4 g (86% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:29]=[C:12]3[C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(O)[CH2:14][CH2:15][CH2:16][CH2:17][N:11]3[N:10]=2)[CH:6]=[CH:5][C:4]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:29]=[C:12]3[C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:27])([F:26])[F:28])=[CH:14][CH2:15][CH2:16][CH2:17][N:11]3[N:10]=2)[CH:6]=[CH:5][C:4]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1
Reactant: COc1nc(-c2nc3n(n2)CCCCC3(O)c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1nc(-c2nc3n(n2)CCCC=C3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Yield: 7.3 %

Procedure:
A mixture of 2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-9-(2-trifluoromethylphenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-9-ol obtained in Example 181 (49 mg), p-toluenesulfonic acid (76 mg) and toluene (7 mL) was heated under reflux for two hours. Ethyl acetate and saturated sodium bicarbonate were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The solid was removed by filtration. The mother liquor was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform-methanol system) to obtain 3.46 mg of the title compound as an oil. The property values of the compound are as follows.
Reaction SMILES: N1C2C=CC=CC=2N[CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[NH:18][C:19]1[N:27]=[C:26]2[C:22]([NH:23][C:24](=[O:34])[N:25]2[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:21]([Cl:35])[N:20]=1>>[Cl:35][C:21]1[N:20]=[C:19]([N:18]2[C:12]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=3[N:10]=[CH:2]2)[N:27]=[C:26]2[C:22]=1[NH:23][C:24](=[O:34])[N:25]2[CH:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Nc1ccc(Cl)cc1Nc1nc(Cl)c2[nH]c(=O)n(C3CCOCC3)c2n1
Product: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(Cl)cc43)nc2n1C1CCOCC1
Yield: 46 %

Procedure:
Pale yellow solid. 46% yield on 2 steps (reduction and benzimidazole closing), on 2.47 mmol scale. Synthesized from 2-(2-amino-5-chlorophenylamino)-6-chloro-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one. 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.08 (s, 1H), 8.61 (s, 1H), 7.74 (d, 1H), 7.40 (d, 1H), 4.65-4.58 (m, 1H), 4.23-4.19 (m, 2H), 3.62 (appt, 2H), 2.82-2.76 (m, 2H), 1.93 (br d, 2H); MS (EI) m/z 405.2 (MH)+.