Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[C:5]([F:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:21][C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>>[ClH:1].[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[C:5]([F:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccccc1N
Reactant: CN(c1ccccc1)c1nc(Cl)nc2c(F)cccc12
Product: Cc1ccccc1Nc1nc(N(C)c2ccccc2)c2cccc(F)c2n1
Product: Cl

Procedure:
In a procedure analogous to that of Example 41 2-chloro-4-(N-methylphenylamino)-8-fluoroquinazoline and o-toluidine are reacted together to give the title compound. The starting 2-chloro-4-(N-methylphenylamino)8-fluoroquinazoline is prepared via procedures analogous to those of Example 1.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8](Cl)=[O:9])(=[O:4])[CH:2]=[CH2:3].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(N(CC)CC)C.C1(C=CC(O)=CC=1)O>C1(C)C=CC=CC=1>[C:1]([O:5][CH2:6][CH2:7][C:8](=[O:9])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCC(=O)Cl
Reactant: Nc1ccccn1
Agent: Oc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCC(=O)Nc1ccccn1
Reaction time: 18 h

Procedure:
3-Chloro-3-oxopropyl acrylate, 1, (1 eq.), 2-aminopyridine (1 eq.) and triethylamine (3 eq.) are dissolved in toluene at 0° C. A few crystals of hydroquinone is added to inhibit any polymerization side reactions. The solution is allowed to stir approximately 18 hours at a temperature from about 0° C. to room temperature. The solvent is removed under reduced pressure and the crude material purified over silica. For a more detailed account of this procedure See M. A. Diab, A. Z. El-Sonbati, A. A. El-S anabori, F. I. Taha, Polymer Degrad. Stab. 1989, 24, 51, included herein by reference.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:21][CH3:22])=[C:16]([C:18](=[O:20])[CH3:19])[CH:17]=1.[OH-].[Na+]>O>[C:18]([C:16]1[CH:17]=[C:12]([F:11])[CH:13]=[CH:14][C:15]=1[N:21]([CH3:22])[CH:8]=[O:10])(=[O:20])[CH3:19]
Reactant: CNc1ccc(F)cc1C(C)=O
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)c1cc(F)ccc1N(C)C=O
Reaction time: 2 h

Procedure:
A mixture of acetic anhydride (4.6 ml) and formic acid (3.1 3 ml) was stirred at 60° for 2 hours and then cooled to 10°. 5'-Fluoro-2'-(methylamino)acetophenone (3.0 g) was then added and the mixture stirred overnight. The solution was cooled in an ice-bath and water (20 ml) added followed by aqueous sodium hydroxide (specific gravity 1.5) added dropwise to pH 10. The mixture was extracted with dichloromethane (3×30 ml) and the combined extracts dried over magnesium sulphate to give a solution of 2'-acetyl-4'-fluoro-N-methylformanilide.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH3:11]I.O>CN(C=O)C>[CH3:11][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: CI
Reactant: Cc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
Sodium hydride (3.6 g, 150 mmol) was added portionwise to 5-hydroxy-2-picoline (15.0 g, 137 mmol) in DMF (120 mL). After 30 min., CH3I (10.2 mL, 156 mmol) was added and the mixture stirred 2 hours at r.t. Water was added and the compound was extracted with Et2O (3×). The organic extracts were washed with brine (2×), dried over Na2SO4 and concentrated in vacuo to give 6.7 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][N:12]1[C:17]([CH3:18])=[C:16]([Cl:19])[N:15]=[C:14](Cl)[C:13]1=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][NH2:29])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:23]1([CH3:22])[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][NH:29][C:14]2[C:13](=[O:21])[N:12]([CH2:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[C:17]([CH3:18])=[C:16]([Cl:19])[N:15]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(CCN)cc1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)cc1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A solution of 1-benzyloxycarbonylmethyl-3,5-dichloro-6-methylpyrazinone (656 mg, 2.00 mmol), as prepared in the preceding step, 4-methylphenethylamine(380 mg, 2.81 mmol),triethylamine (405 mg, 4.01 mmol), and ethyl acetate (20 mL) was refluxed overnight. After cooling to room temperature, the solution was washed with 10% citric acid (×2). The aqueous solutions were back extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and contracted to give the title compound as a yellow solid (854 mg, 100%). 1H NMR (CDCl3) δ 7.38–7.32 (m, 5 H), 7.12 (s, 4 H), 6.09 (s, 1H), 5.21 (s, 2 H), 4.79 (s, 2 H), 3.65 (dd, 2 H, J=7.0, 13.0 Hz), 2.88 (t, 2 H, J=7.1 Hz), 2.32 (s, 3 H), 2.21 (s, 3 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:14](=[O:15])[CH2:13][C:12]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=3[CH:10]=[CH:9]2)[CH:2]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][CH2:35][Br:36])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].C(OCC)C>CO.C(Cl)Cl>[Br-:36].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][CH2:35][N+:1]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]3[C:14](=[O:15])[CH2:13][C:12]4[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=4[CH:10]=[CH:9]3)[CH:2]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: COc1ccc(CCBr)cc1OC
Reactant: COc1cc2c(cc1OC)CC(=O)N(Cc1cccnc1)C=C2
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CC[n+]2cccc(CN3C=Cc4cc(OC)c(OC)cc4CC3=O)c2)cc1OC
Product: [Br-]
Temperature: 110 °C

Procedure:
A mixture of 1.1 g (0.0035 mol) of 3-[(pyridin-3-yl)methyl]-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one and 2-(3,4-dimethoxyphenyl)-ethyl bromide is heated to 110° C. for 6 hours. After cooling, the reaction mixture is dissolved in a little methanol/ methylene chloride and added dropwize to 200 ml of diethylether, with vigorous stirring. The precipitate obtained is suction filtered and dried. Yield: 1.6 g (80% of theory), Melting point: 147°-150° C.
Reaction SMILES: BrC[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[CH2:27](O)C>>[N+:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:20]([CH2:27][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:7]=2[C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Reactant: CCO
Reactant: C1CCNCC1
Product: O=[N+]([O-])c1oc2cccc(CN3CCCCC3)c2c1-c1ccccc1

Procedure:
Using the method of Example 6, 5-bromomethyl-2-nitro-3-phenylbenzofuran is reacted with piperidine in ethanol to provide N-(2-nitro-3-phenylbenzofuranylmethyl)piperidine having the structure ##STR37##
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5](S(N2[CH2:16][C@H:15]3[CH2:17]C(C)(C)[C@@H:12]2[C:13](=O)[O:14]3)(=O)=O)=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH:15]([O:14][CH:13]([CH3:12])[CH3:22])([CH3:16])[CH3:17].[CH3:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC1(C)C[C@@H]2CN(S(=O)(=O)c3ccc(O)cc3)[C@H]1C(=O)O2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)OC(C)C
Product: CCCCCC

Procedure:
A mixture of (1R,4R)-5-(4-hydroxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (compound of formula XXXVIII, 0.15 g, 0.48 mmol), the appropriate alkyl halide (0.97 mmol), potassium carbonate (0.13 g, 0.97 mmol) and dimethylformamide (1 ml) was shaken at about 50° C. for about 24 hours. The mixture was diluted with ethyl acetate, washed 4 times with water, dried over sodium sulfate, filtered and concentrated. Trituration of the residue from isopropyl ether-hexane afforded the corresponding (1R,4R)-5-(4-arylmethoxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (compound of formula XXXIX) as a colorless solid.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]([F:14])([F:13])[F:12].[CH3:16][O:17][C:18](=[O:22])[CH2:19][C:20]#[N:21].C[O-].[Na+]>CO>[NH2:21][C:20]1[O:1][N:2]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][C:11]([F:14])([F:13])[F:12])[C:19]=1[C:18]([O:17][CH3:16])=[O:22]
Reactant: ON=C(Cl)c1ccccc1OC(F)(F)F
Reactant: COC(=O)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2OC(F)(F)F)noc1N
Yield: 89.9 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), N-hydroxy-2-(trifluoromethoxy)benzimidoylchloride (8.00 g, 33.39 mmol), methylcyanoacetate (4.31 g, 43.41 mmol) and sodium methoxide (3.61 g, 66.78 mmol), a white solid required compound (9.07 g, 30.02 mmol, 90%) was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:16][CH:15]=3)[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].Br[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]=1[Cl:37].C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[Cl:37][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:28]=1[N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:18]=[CH:19][C:14]([C:13](=[O:26])[NH:12][C:9]3[CH:10]=[C:11]4[C:6]([CH:5]=[CH:4][N:3]4[CH2:1][CH3:2])=[CH:7][CH:8]=3)=[CH:15][N:16]=2)[CH2:21][CH2:22]1)[C:32]([OH:34])=[O:33]
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(N4CCNCC4)nc3)cc21
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)O)cc5Cl)CC4)nc3)cc21

Procedure:
3-Chloro-4-{4-[5-(1-ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was synthesized from N-(1-ethyl-1H-indol-6-yl)-6-piperazin-1-yl-nicotinamide and 4-bromo-3-chloro-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C27H26ClN5O3 (m/e) 503, obsd 504 (M+H).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.Cl.[C:8]([C:11]1[CH:37]=[CH:36][C:14]([CH2:15][N:16]([C:18]([CH3:35])([CH3:34])[CH2:19][O:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:17])=[CH:13][CH:12]=1)(O)=[O:9].C[N:39](C)C=O>C(Cl)Cl>[ClH:4].[C:8]([C:11]1[CH:37]=[CH:36][C:14]([CH2:15][N:16]([C:18]([CH3:35])([CH3:34])[CH2:19][O:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:17])=[CH:13][CH:12]=1)(=[O:9])[NH2:39]
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(Cc1ccc(C(=O)O)cc1)C(C)(C)COC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CN(Cc1ccc(C(N)=O)cc1)C(C)(C)COC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (200 μl) was added to a solution of 2-[N-(4-carboxybenzyl)-N-methylamino]-1-diphenylmethoxy-2-methylpropane hydrochloride (300 mg -- see Example 43) in methylene chloride containing two drops of dimethylformamide and the mixture was stirred at room temperature for 30 minutes. Ammonia was then bubbled through the stirred solution for 30 minutes which was then diluted with methylene chloride, washed with 10% aqueous sodium hydroxide solution, dried over magnesium sulphate and evaporated. The residue was dissolved in ether and the solution was treated with excess saturated ethereal hydrogen chloride. The resulting precipitated oil was collected, washed with ether and dried to give the title compound as a colourless foam which was characterised as containing 0.75 molar equivalents of water (63 mg, 23%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:10]=[C:9]2[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])([CH3:27])[CH3:26])=[CH:4][CH:3]=1.[CH3:35][S:36]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1)(=[O:38])=[O:37].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:25]([C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:43]3[CH:42]=[CH:41][CH:40]=[C:39]([S:36]([CH3:35])(=[O:38])=[O:37])[CH:44]=3)=[CH:3][CH:4]=2)[CH:12]=[C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:10]=1)([CH3:26])[CH3:27]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cn(-c2ccc(Br)cc2)c(C(C)(C)c2ccccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(C(C)(C)c2ccccc2Cl)n1
Temperature: 82.5 °C
Reaction time: 0.08 h
Yield: 44.8 %

Procedure:
To a solution of tert-butyl 2-(1-(4-bromophenyl)-2-(2-(2-chlorophenyl)propan-2-yl)-1H-imidazol-4-yl)pyrrolidine-1-carboxylate (20 mg, 0.036 mmol) in THF (3 mL) was added 3-(methylsulfonyl)phenylboronic acid (14.7 mg, 0.073 mmol). The resulting solution was stirred at 80-85° C. for 5 min and then tetrakistriphenylphosphine palladium (0) (5-10 mg) was added followed by the addition of 60 μL of 1.0 M sodium carbonate. The reaction was maintained at 80-85° C. for 30 min. LC/MS analysis indicated the reaction was complete. The reaction mixture was cooled and filtered over celite, concentrated. The crude product was purified by prep HPLC to give 1,1-dimethylethyl 2-{2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-1H-imidazol-4-yl}pyrrolidine-1-carboxylate (10 mg, 50%). 1H NMR (CD3OD): δ 1.4 (m, 9H), 1.6 (m, 3H,), 1.8 (m, 1H), 1.9-2.3 (m, 5H), 3.2 (s, 3H), 3.4 (m, 1H), 3.6 (m, 1H) 4.6 (m, 1H), 6.9 (m, 1H), 7.0 (m, 1H), 7.2 (m, 6H), 7.7 (m, 3H), 7.95 (m, 2H), 8.2 (m, 1H); LC/MS M+H 620 (observed).
Reaction SMILES: [OH:1][CH:2]([CH3:20])[CH2:3][N:4]1[C:12]2[C:7](=[C:8]([C:15]([F:18])([F:17])[F:16])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[CH3:19].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1O>>[CH3:19][C:5]1[N:4]([CH2:3][CH:2]([O:1][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[CH3:20])[C:12]2[C:7]([CH:6]=1)=[C:8]([C:15]([F:18])([F:16])[F:17])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2
Reactant: Oc1ccccn1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)O
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)Oc1ccccn1

Procedure:
Synthesized as described in Example 139C using 1-(2-hydroxypropyl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 335) and 2-pyridinol: MS (ES) m/z 360 (M+1).
Reaction SMILES: CN([CH:4]=[O:5])C.[ClH:6].[N:7]12[CH2:15][CH:11]([CH2:12][CH2:13][CH2:14]1)[C:10](=O)[CH2:9][CH2:8]2.C(=O)([O-])[O-].[K+].[K+]>>[Cl:6][CH:10]1[CH:11]2[CH2:15][N:7]([CH2:14][CH2:13][CH2:12]2)[CH:8]=[C:9]1[CH:4]=[O:5]
Reactant: O=C1CCN2CCCC1C2
Reactant: CN(C)C=O
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=CC1=CN2CCCC(C2)C1Cl
Temperature: 100 °C
Yield: 91.6 %

Procedure:
To DMF (50 ml, 0.68 mol) was slowly added POCla (50 ml, 0.54 mol) at 0° C. over 1 h. 1-Azabicyclo[3.3.1]nonane-4-one hydrochloride (17.5 g, 0.1 mol) was added in one portion and the reaction mixture heated at 100° C. for 1 h. After cooling the reaction mixture was poured on ice (1000 g) and the reaction mixture neutralized with potassium carbonate. The water phase was extracted with ether (5×200 ml). The organic phase was dried over MgSO4 and evaporated. The residue was purified by column chromatography (eluent: CH2Cl2/CHaOH (9:1)), yielding 17 g of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:23][C:19]4[N:18]=[C:17]([CH3:16])[CH:22]=[CH:21][N:20]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccnc(N)n1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Solvent: c1ccncc1
Product: Cc1ccnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)n1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 4-methylpyrimidin-2-amine (22 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 297.3, found 298.3 (M+1)+. Retention time 2.14 minutes.
Reaction SMILES: C(O)C.[CH:4]1([C:7](=O)[CH2:8][C:9](=O)[CH3:10])[CH2:6][CH2:5]1.[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].N1CCCCC1>O>[CH:4]1([C:7]2[NH:18][C:16](=[O:17])[C:15]([C:13]#[N:14])=[C:9]([CH3:10])[CH:8]=2)[CH2:6][CH2:5]1
Reactant: N#CCC(N)=O
Reactant: CC(=O)CC(=O)C1CC1
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: Cc1cc(C2CC2)[nH]c(=O)c1C#N
Temperature: 75 °C

Procedure:
To a stirred solution of ethanol (5 mL) were added 1-cyclopropyl-1,3-butanedione (505 mg, 3.00 mmol) and cyanoacetamide (252 mg, 3.00 mmol), and the heterogenous contents heated until homogenous (ca. 75° C.). Piperidine was added (0.395 mL, 4.00 mmol) and the mixture was heated at reflux for 30 min. The reaction mixture was allowed to cool to room temperature, wherein precipitation ensued. The solid precipitate was filtered and set aside. The filtrate was concentrated in vacuo and the oily residue treated with minimal EtOAc and then 10 mL hexanes to afford a second crop of solid. The solid product crops were combined, suspended in water (7 mL), vigorously stirred, and vacuum filtered to afford 6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile as a nearly white solid (380 mg, 73%). LCMS E-S(M+H)=175.1. 1H NMR (400 MHz, CDCl3) δ ppm 1.01-1.09 (m, 2H), 1.28 (dd, J=8.59, 2.27 Hz, 2H), 1.95-2.01 (m, 1H), 2.43 (s, 3H), 5.82 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)([OH:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To an ice-cooled solution 3,3-Dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.6 g, 7.2 mmol) in THF (20 ml) was added 4-chlorophenylmagnesium bromide (1 M in ether, 15 ml, 15 mmol). The solution was allowed to warm to about room temperature, then stirred at room temperature for about 22 hours. The reaction was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were concentrated in vacuo, then purified by flash chromatography on silica gel (35 g SiO2, gradient elution from 100% hexane to 100% ethyl acetate) to yield the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:15]([CH3:19])([CH3:18])[C:16]#[CH:17])=[N:13][N:14]=1)=[O:8].[CH3:23][C:24](C)([O-:26])[CH3:25].[K+].CN(C)C=O.O1CC[CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[C:7](/[N:9]=[C:10]1\[S:11][C:12]([C:15]([CH3:18])([CH3:19])[C:16]#[CH:17])=[N:13][N:14]\1[CH2:23][C@H:24]1[CH2:25][CH2:36][CH2:35][O:26]1)=[O:8]
Reactant: CC(C)(C)[O-]
Reactant: C#CC(C)(C)c1nnc(NC(=O)c2cc(Cl)ccc2OC)s1
Reactant: C1CCOC1
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CC(C)(C)c1nn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(Cl)ccc2OC)s1
Temperature: 80 °C
Reaction time: 16 h
Yield: 29 %

Procedure:
To a solution of Example 6B (250 mg, 0.75 mmol) in N,N-dimethylformamide/tetrahydrofuran (1:4, 10 mL) was added a solution of potassium tert-butoxide (Aldrich, 125 mg, 1.1 mmol) and Example 1B (285 mg, 1.1 mmol). The reaction mixture was stirred at 80° C. for 16 h, cooled to room temperature, quenched with saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-1% methanol in dichloromethane) to afford 90 mg (29%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.65 (s, 6H), 1.69-1.81 (m, 1H), 1.80-1.92 (m, 2H), 1.92-2.05 (m, 1H), 3.57 (s, 1H), 3.59-3.72 (m, 1H), 3.72-3.79 (m, 1H), 3.81 (s, 3H), 4.21-4.31 (m, 1H), 4.31-4.43 (m, 1H), 4.44-4.58 (m, 1H), 7.15 (d, J=9.1 Hz, 1H), 7.52 (dd, J=8.9, 3.0 Hz, 1H), 7.77 (d, J=2.8 Hz, 1 H); MS (ESI+) m/z 420 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH2:17][CH2:18][CH3:19])[CH:11]=2)=[N:2]1.O[CH2:21][CH2:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([CH2:32][C:33]([O-:35])=[O:34])=[CH:27][CH:26]=2>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:21][CH2:22][C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[CH:29][C:28]([CH2:32][C:33]([OH:35])=[O:34])=[CH:27][CH:26]=4)=[C:12]([CH2:17][CH2:18][CH3:19])[CH:11]=2)=[N:2]1
Reactant: CCCc1cc(-c2noc3ccccc23)ccc1O
Reactant: O=C([O-])Cc1ccc2[nH]c(CCO)cc2c1
Product: CCCc1cc(-c2noc3ccccc23)ccc1OCCc1cc2cc(CC(=O)O)ccc2[nH]1

Procedure:
Using the procedures in Example 15, steps E and F, the title compound was prepared from 4-(1,2-benzisoxazol-3-yl)-2-propylphenol and 2-(2-hydroxyethyl)indole-5-acetate.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([NH2:14])=[N:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>C1COCC1>[CH2:17]([NH:19][C:20]([NH:14][C:12]1[NH:11][C:10]2[CH:15]=[CH:16][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][C:9]=2[N:13]=1)=[O:21])[CH3:18]
Reactant: Nc1nc2cc(-c3ccccc3)ccc2[nH]1
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3ccccc3)ccc2[nH]1

Procedure:
To a solution of 7 (40 mg, 0.19 mmol) in THF (1 mL) was added ethyl isocyanate (27 μL, 0.34 mmol) as a solution in THF (0.5 mL). The reaction was heated to reflux overnight then concentrated in vacuo. The crude product was purified by preparative HPLC to afford Ia-84.