Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](N)[C:5](=[CH:9][C:10]=1[F:11])[C:6]([OH:8])=[O:7].FC1C=C2C(=O)OC(=O)C2=CC=1F.FC1C=C(C(O)=O)C(=CC=1F)C(O)=O>FC1C=C2C(=O)OC(=O)C2=CC=1F.FC1C=C(C(O)=O)C(=CC=1F)C(O)=O.CN1CCCC1=O.N1C2C(=CC=CC=2)C=CC=1.CC(N(C)C)=O.[Cu].[Cu]=O.[Zn].[Ni]>[F:11][C:10]1[CH:9]=[C:5]([CH:4]=[CH:3][C:2]=1[F:1])[C:6]([OH:8])=[O:7]
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: O=[Cu]
Agent: [Cu]
Agent: [Ni]
Solvent: c1ccc2ncccc2c1
Solvent: CN1CCCC1=O
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(F)c(F)c1

Procedure:
According to the present invention, 4,5-difluoroanthranilic acid may be prepared from either 4,5 difluorophthalic anhydride or 4,5-difluorophthalic acid. The process of this invention comprises the decarboxylation of either 4,5-difluorophthalic anhydride and 4,5-difluorophthalic acid in N-methyl-2-pyrrolidone, quinoline, or dimethyl acetamide solution optionally using copper, copper oxide, copper salts, or halides and salts of Zn, Cd, Ag and Ni as a catalyst, to yield 3,4-difluorobenzoic acid; the nitration of the 3,4-difluorobenzoic acid in a mixture of nitric and sulfuric acids to form 2-nitro-4,5-difluorobenzoic acid; and the reduction of the 2-nitro-4,5-difluorobenzoic acid to form 4,5-difluoroanthranilic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:16]=[C:17]=S)[CH:14]=[CH2:15]>C(OCC)(=O)C>[CH2:13]([NH:16][C:17]1[NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[S:9](=[O:11])(=[O:10])[N:12]=1)[CH:14]=[CH2:15]
Reactant: C=CCN=C=S
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Solvent: CCOC(C)=O
Product: C=CCNC1=NS(=O)(=O)c2ccc(Cl)cc2N1

Procedure:
The title compound was prepared from 2-amino-4-chlorobenzenesulfonamide and allyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 284-286° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 3.88 (distorted t, 2H, NHCH2), 5.1-5.3 (m, 2H, ═CH2), 5.78-6.0 (m, 1H, ═CH), 7.22-7.35 (m, 2H, ArH), 7.50 (br.t, 1H, NH), 7.69 (d, 1H, ArH), 10.73 (br.s, 1H, NH); MS: m/e 271/273 (M+); (C10H10N3Cl1O2S1) calc. C, 44.20; H, 3.71 N, 15.46; found C, 44.10; H, 3.79; N, 15.32.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:34])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]([CH3:33])[CH3:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:52])[C@@H:15]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si](C(C)(C)C)(C)C)[CH2:38]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:34])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]([CH3:32])[CH3:33])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:52])[C@@H:15]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([OH:44])[CH2:38]2)=[CH:10]1
Reactant: CCC(Oc1ccccc1C(C)C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1ccccc1C(C)C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 96.3 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 700 mg of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2-isopropylphenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as describedin Example 7, above] and 14.0 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 470 mg of the title compound as a colorless foam.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][NH2:20]>C(O)C>[C:1]1([C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[NH:20][N:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1C(=O)CC(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Product: Cc1ccccc1-c1cc(-c2ccccc2)n[nH]1

Procedure:
1-Phenyl-3-(o-tolyl)-1,3-propanedione (b.p. 170° C./0.01 mm Hg) is condensed with hydrazine in ethanol to give 3-phenyl-5-(o-tolyl)pyrazole, m.p. 112.5°-113.5° C.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:16][O:17][C:18](=[O:40])[C@H:19]([CH2:36][CH2:37][S:38][CH3:39])[NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>ClCCl.CN(C=O)C>[CH3:16][O:17][C:18](=[O:40])[C@H:19]([CH2:36][CH2:37][S:38][CH3:39])[NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:9])=[CH:24][C:23]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)c1cccnc1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)c2cccnc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
Nicotinic acid (345 mg, 2.8 mmol) was suspended in 10 mL of dichloromethane and oxalyl chloride (2.8 mL of a 2.0 M soln in methylene chloride) was added by syringe followed by one drop of DMF. The reaction mixture was stirred at 25° C. for 2 hours and then was evaporated and azeotroped with toluene. The resulting acid chloride was then dissolved in dichloromethane and a solution of (4-amino-2-phenylbenzoyl)methionine methyl ester (669 mg, 1.87 mmol), prepared as in Example 192B, in 5 mL of dichloromethane was added followed by 4 mL of saturated aqeuous NaHCO3 and the reaction was stirred at 25° C. for 3 hours. The layers were separated and the organic layer was dried over Na2SO4, filtered and evaporated to give 830 mg (96%) of [4-(3-pyridylcarbonylamino)-2-phenylbenzoyl]methionine methyl ester as an oil. 1H NMR (300 mHz, CDCl3) δ 9.2 (d, 1H), 8.76 (d, 1H), 8.42 (bs, 1H), 8.2 (dt, 1H), 7.72-7.65 (m, 2H), 7.6 (dd, 1H), 7.45-7.35 (m, 5H), 6.02 (bd, 1H), 4.65 (dq, 1H), 3.68 (s, 3H), 2.20 (t, 2H), 2.01 (s, 3H), 1.98-1.88 (m, 1H), 1.80-1.78 (m, 1H). CIMS 464 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>C(OC(=O)C)(=O)C>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:13][C:14]([N+:1]([O-:4])=[O:2])=[CH:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cc([N+](=O)[O-])sc2-c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Nitric acid (d=1.42; 1.6 ml) was added dropwise to a stirred solution of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (6 g) in acetic anhydride (98 ml) at -5° to 0° C. The mixture was stirred for 1 hour at 0° C., treated with sodium bicarbonate (1 g), and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and an aqueous solution of sodium bicarbonate, and concentrated. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (20:1) to give yellow crystals of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-nitrothiophene (4.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)C)=[CH:9][N:10]=2)[N:7]=1.ClC1C=CC2N(C(C(C3C=C4C(=CC=3F)N(C)N=C4)O)=CN=2)N=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Agent: Cn1ncc2cc(C(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Product: Cn1ncc2cc(Cc3cnc4ccc(Cl)nn34)c(F)cc21

Procedure:
The title compound was prepared as a yellow solid in analogy to the synthesis of compound 39.2 from (6-chloroimidazo[1,2-b]pyridazin-3-yl)(6-fluoro-1-methyl-1H-indazol-5-yl)methanol. LCMS (method B): [MH]+=316, tR=2.56 min.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([SH:8])=[N:5][N:4]=1.[H-].[Na+].Cl[C:12]1[C:17]([Cl:18])=[N:16][CH:15]=[CH:14][N:13]=1>CN(C=O)C.C1C=CC=CC=1>[Cl:18][C:17]1[C:12]([S:8][C:6]2[S:7][C:3]([S:2][CH3:1])=[N:4][N:5]=2)=[N:13][CH:14]=[CH:15][N:16]=1
Reactant: CSc1nnc(S)s1
Reactant: Clc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nnc(Sc2nccnc2Cl)s1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
The title compound was prepared according the procedure described in Example 1 by using 5-(methylthio)-1,3,4-thiadiazole-2-thiol (1.64 g, 10.00 mmol), NaH (60% dispersion in mineral oil, 445 mg, 11.00 mmol), and 2,3-dichloropyrazine (1.04 ml, 10.00 mmol) in DMF and benzene (12 ml, 1/1) by stirring at 50° C. for 20 hr and then at 110° C. for 4 hr under nitrogen atmosphere.
Reaction SMILES: [OH:1][C:2]1([CH3:13])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(N(CC)CC)C>[C:14]([O:1][C:2]1([CH3:13])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:16])[CH3:15]
Reactant: CCCCCC1C(=O)C=CC1(C)O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCC1C(=O)C=CC1(C)OC(C)=O

Procedure:
Into the same flask as used in Example 1, dl-3-hydroxy-2-n-pentyl-3-methyl-4-cyclopentenone (18.2 g), triethylamine (0.1 g) and acetic anhydride (36 g) were charged, and the resultant mixture was stirred at 60°-80° C. for 3 hours. After completion of the reaction, the reaction mixture was subjected to the same work-up as in Example 1 to give 21.9 g of dl-3-acetoxy-2-n-pentyl-3-methyl-4-cyclopentenone. Yield, 98%. B.P., 100°-110° C./0.1-0.3 mmHg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 120 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
A pressure bottle was charged with 1-chloro-2-methoxy-4-nitrobenzene (10.0 g mg, 53.3 mmol, purchased from TCI America) and morpholine (15 mL, 172.0 mmol). The reaction mixture was stirred at 120° C. for 15 hours and it was allowed to cool to room temperature by itself. The resulting solid was suspended in 20 mL of ethyl acetate, filtered, and washed with 20 mL of tert-butyl methyl ether. 8.8 g of yellow solid as the desired product AA was collected (69% yield). 1H-NMR (400 MHz, d6-DMSO): 7.83 (dd, 1H), 7.67 (d, 1H), 6.98 (d, 1H), 3.88 (s, 3H), 3.71 (m, 4H), 3.16 (m, 4H). MS (EI) CH11H14N2O4: 239 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].Cl.Cl[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[N:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:15][C:16]1[CH:21]=[N:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: COc1ccc(CCl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOc1cc(C=O)ccc1OCc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To a stirred solution of 3-ethoxy-4-hydroxybenzaldehyde (2.75 g, 16.55 mmol) in acetonitrile (75 mL) was added 5-(chloromethyl)-2-methoxypyridine hydrochloride (3.37 g, 17.38 mmol) and potassium carbonate (9.15 g, 66.20 mmol). The mixture was heated to reflux. After 3 h, the yellow mixture was allowed to cool to room temperature and was diluted with water (400 mL), resulting in the formation of a precipitate. The solids were isolated by filtration and washed with water (50 mL). The filtrate was extracted with chloroform (2×100 mL). The organic phases were combined with the previously isolated solids. The resulting solution was dried over magnesium sulfate, filtered, and concentrated to provide 3.40 g (72%) of 3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzaldehyde as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][N:6]([CH3:20])[C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[CH:9][N:8]=1>CCO.[Ni]>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([CH3:20])[C:7]1[C:12]([NH2:13])=[CH:11][C:10]([C:16]([F:18])([F:19])[F:17])=[CH:9][N:8]=1
Reactant: CN(C)CCCN(C)c1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CN(C)CCCN(C)c1ncc(C(F)(F)F)cc1N
Reaction time: 2 h

Procedure:
To a solution of N-(3-(dimethylamino)propyl)-N-methyl-3-nitro-5-(trifluoromethyl)pyridin-2-amine (246 mg, 0.8 mmol) in EtOH was added Raney Nickel (700 mg, wet, washed). The reaction was allowed to stir for 2 h then filtered through a pad of Celite and concentrated under reduced pressure to afford N2-(3-(dimethylamino)propyl)-N2-methyl-5-(trifluoromethyl)pyridine-2,3-diamine. MS m/z=277 [M+H]+. Calc'd for C12H19F3N4: 276
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH:4]=O.[CH3:8][CH:9]([CH3:13])[C@H:10]([NH2:12])[CH3:11]>CO.[Pd].O>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:12][C@@H:10]([CH:9]([CH3:13])[CH3:8])[CH3:11]
Reactant: COC(C=O)OC
Reactant: CC(C)[C@@H](C)N
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(CN[C@H](C)C(C)C)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2-Dimethoxyacetaldehyde (60% in water, 8.7 mL) was added to (R)-3-methylbutan-2-amine (5.0 g) in methanol (25 mL) and the mixture stirred at ambient temperature overnight. A slurry of palladium on carbon (5%, 1.2 g) in water (10 mL) was added and the mixture was hydrogenated at 5 bar pressure with stirring for 3 hours. The mixture was filtered through Celite and the filter pad washed with methanol (3×100 mL). The combined filtrate and washings were concentrated to a volume of −10 mL and then toluene (200 mL) was added. The mixture was concentrated, more toluene (200 mL) was added and the mixture was concentrated once more to give the titled compound as a yellow oil. Yield 8.0 g.
Reaction SMILES: [CH2:1]([C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:23]([C@H:28]1[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH2:36]Br)[CH2:30][CH2:29]1)[CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:23]([C@H:28]1[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH2:36][O:22][C:19]2[CH:18]=[CH:17][C:16]([C:13]3[N:14]=[CH:15][C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:11][N:12]=3)=[CH:21][CH:20]=2)[CH2:30][CH2:29]1)[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCC[C@H]1CC[C@H](CCCBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCCCCCCc1cnc(-c2ccc(OCCC[C@H]3CC[C@H](CCCCC)CC3)cc2)nc1

Procedure:
A mixture of 0.5 g of 4-(5-nonyl-2-pyrimidinyl)phenol, 0.55 g of 3-(trans-4-pentylcyclohexyl)-1-propyl bromide, 0.91 g of potassium carbonate and 50 ml of absolute butanone was heated under reflux overnight. Subsequently, the cooled reaction mixture was poured into water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed with 500 ml of water, dried over magnesium sulfate, filtered and concentrated. Chromatography of the residue on silica gel with toluene and recrystallization from ethanol gave pure 2-(4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]phenyl-5-nonylpyrimidine with m.p. (C--SC) 83° C., transition SC --N 103° C., cl.p. (N-I) 133° C.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19]1([C:29](Cl)=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[NH2:17][C:11]1[N:10]=[C:9]([NH2:18])[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[N:1]2[CH2:6][CH2:5][N:4]([C:29]([C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)=[O:30])[CH2:3][CH2:2]2)[N:12]=1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: O=C(Cl)c1cccc2ccccc12
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4cccc5ccccc45)CC3)cccc2n1
Yield: 28 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 1-Naphthoyl chloride (78.2 mg; 0.41 mmol) to obtain 22.1 mg. (28% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.0 (d, J=7.6 Hz, 2H), 7.75 (br d, 1H), 7.59 (m, 3H), 7.45 (m, 2H), 7.30 (br s, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.89 (dd, J=17.6, 7.6 Hz, 1H), 6.11 (br s, 2H), 4.78 (br t, 1H), 3.42 (m, 2H), 3.24 (m, 3H), 2.89 (m, 2H). ESIMS+400.0 m/z
Reaction SMILES: CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+].[CH2:16]([N:23]([S:31]([CH2:34][CH2:35][CH2:36]Cl)(=[O:33])=[O:32])C(=O)OC(C)(C)C)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH:38]1([C:44]2[C:45]3[CH:46]=[CH:47][C:48]([C:68]([O:70][CH3:71])=[O:69])=[CH:49][C:50]=3[N:51]3[C:58]=2[C:57]2[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=2[O:55][CH2:54][C@@H:53]([O:63][CH2:64][CH2:65][NH:66][CH3:67])[CH2:52]3)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CC#N>[CH2:16]([NH:23][S:31]([CH2:34][CH2:35][CH2:36][N:66]([CH3:67])[CH2:65][CH2:64][O:63][C@H:53]1[CH2:52][N:51]2[C:50]3[CH:49]=[C:48]([C:68]([O:70][CH3:71])=[O:69])[CH:47]=[CH:46][C:45]=3[C:44]([CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)=[C:58]2[C:57]2[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=2[O:55][CH2:54]1)(=[O:32])=[O:33])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)S(=O)(=O)CCCCl
Reactant: CNCCO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCCN(C)CCCS(=O)(=O)NCc1ccccc1)COc1ccccc1-3
Temperature: 200 °C
Yield: 23 %

Procedure:
DIPEA (2 eq.), K2CO3(4 eq.) and tert-butyl benzyl[(3-chloropropyl)sulfonyl]carbamate (was added to a solution of methyl (7S)-14-cyclohexyl-7-[2-(methylamino)ethoxy]-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.08 M) in MeCN. The mixture was heated in the microwave at 200° C. for 30 min. The resulting mixture was filtered, concentrated in vacuo, and the residue purified by RP-HPLC (WATERS XTERRA column, C18, 5 um, 19×150 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound (23%) as a white powder. (ES+) m/z 674 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].F[C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[C:41]([C:40]1[CH:43]=[CH:44][C:37]([N:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:4]3[N:5]([CH3:26])[C:6]4[C:15]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[N:9]([CH2:16][C:17](=[O:24])[C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[C:8](=[O:25])[C:7]=4[C:3]=3[O:2][CH3:1])=[O:28])[CH2:35][CH2:34]2)=[CH:38][CH:39]=1)#[N:42]
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1c(C(=O)NC2CCN(c3ccc(C#N)cc3)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 19.9 %

Procedure:
A solution of the compound of Example 77 (300 mg, 0.64 mmol), 4-fluorobenzonitrile (115 mg, 0.95 mmol) and potassium carbonate (176 mg, 1.3 mmol) in N-methylpyrrolidone (3.0 mL) was stirred at 120° C. for 16.5 hr. The reaction mixture was diluted with water, and extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/hexane=30/70-100/0) and recrystallized from THF-diethyl ether to give the title compound (73 mg, 20%) as a pale-yellow solid.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C1(C)C=CC=CC=1>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:7]([CH2:6][CH2:5][CH2:4][NH2:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: NCCCNc1ccccn1
Reactant: Brc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NCCCN(c1ccccn1)c1ccccn1
Temperature: 90 °C
Yield: 38.8 %

Procedure:
A mixture of sodium hydride (0.92 g) and 2-(3aminopropylamino)pyridine (5 g) in toluene (100 ml) was heated under nitrogen to 90° C. until initial reaction ceased, and then under reflux for 2 hr. After cooling, 2-bromopyridine (5.53 g) was added and the mixture heated under reflux for 10 hr. The mixture was poured on to ice/water (100 ml), extracted at pH 14 with chloroform, and these extracts washed with 2N HCl. The acidic aqueous solution was adjusted to pH 9 and extracted with ether and the extracts were discarded. The aqueous phase was adjusted to pH 14 and extracted with ether and the latter ethereal extracts were washed with water, dried (K2CO3) and concentrated to give 3-(N,N-dipyrid-2-ylamino)propylamine (2.93 g, 39%) as an oil which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([CH3:38])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@H:19]([N:26]([C:34](=[O:36])[CH3:35])[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:18][CH:17]2[CH3:37])=[O:15])=[CH:10][CH:9]=1.[OH-].[Li+]>CO.C1COCC1>[C:34]([N:26]([C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C@H:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]([C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][C@H:4]([CH3:38])[C:3]([OH:39])=[O:2])=[CH:13][CH:12]=2)=[O:15])[CH:17]([CH3:37])[CH2:18]1)(=[O:36])[CH3:35]
Reactant: COC(=O)[C@@H](C)CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)CC2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1CC(C)N(C(=O)c2ccc(OCC[C@H](C)C(=O)O)cc2)c2ccccc21
Reaction time: 1 h

Procedure:
(2S,4R)-4-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-2-methyl-butyric acid methyl ester (100 mg) was dissolved in methanol/THF, and lithium hydroxide (1.0N, 2 mL) was added. After 1 hour, the reaction was acidified and extracted with methylene chloride. The organic layer was dried, filtered, and concentrated. The crude residue was purified by silica gel chromatography ethyl acetate—5% MeOH/ethyl acetate gradient) to afford the product.