Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO.[CH3:4][O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:12](=[O:30])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH3:29])[CH:14]=[CH:15][C:16]=2[C:17]=1[OH:18])=[O:7]>[Pd].CCOC(C)=O.C1COCC1>[CH3:4][O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:12](=[O:30])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH3:29])[CH2:14][CH2:15][C:16]=2[C:17]=1[OH:18])=[O:7]
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ncc2c(c1O)CCN(Cc1ccc(OC)cc1OC)C2=O
Reaction time: 16 h
Yield: 74.6 %

Procedure:
A round bottom flask was charged with 10% palladium on carbon (50 mg) and EtOH (5 mL). 7-(2,4-Dimethoxy-benzyl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (20 mg, 0.054 mmol) dissolved in EtOAc/THF (10 mL, 1:1) was added, and the mixture was stirred under H2 atmosphere (1 atm) for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (5-80% EtOAc/hexanes+2% AcOH) to give 15 mg of the title compound. MS: (+) m/z 373.33 (M+H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([CH:15]=O)=O.[OH-].[K+]>C(O)C>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:15]=[N:4][CH:1]=[CH:2][N:3]=1
Reactant: O=CC(=O)c1ccccc1Cl
Reactant: NCCN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Clc1ccccc1-c1cnccn1
Yield: 492.6 %

Procedure:
The procedure of Example 1 was repeated, using 1.96 g (3.16 mmol) of ethylenediamine, 4.9 g (2.13 mmol) of 2-chlorophenylglyoxal monohydrate, 1.6 g of potassium hydroxide and 50 ml of ethanol, with the result that 2.0 g of the titled compound was obtained (yield: 49%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[C:15]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>N1C=CC=CC=1>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[C:3]3[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=3[S:5][C:6]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:27])=[O:26])=[CH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1sc2ccccc2c1N
Solvent: c1ccncc1
Product: COC(=O)c1sc2ccccc2c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 29.7 %

Procedure:
To a solution methyl 3-aminobenzo[b]thiophene-2-carboxylate (0.207 g; 1 mmol) in pyridine (1 mL) was added 4-tert-butylbenzenesulfonyl chloride (0.256 g; 1.1 mmol). The resulting mixture was stirred at room temperature for 36 hours and then partitioned between dichloromethane and aqueous hydrochloric acid (2N). The organic layer was separated, dried over sodium sulfate, filtered through a pad of silica gel, and concentrated under reduced pressure to give the desired product as a yellow solid (120 mg).
Reaction SMILES: COC1C=C2C(CC(C3C=CC=CC=3N)C(C)(C)O2)=CC=1.Cl.[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=O)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.N1(CCOC2C=C[C:55]([CH2:56][NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=3[CH:64]3[CH2:73][C:72]4[C:67](=[CH:68][C:69]([O:74][CH3:75])=[CH:70][CH:71]=4)[O:66][C:65]3([CH3:77])[CH3:76])=CC=2)CCCCCC1>>[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([CH2:37][N:57]([CH2:56][CH3:55])[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=3[CH:64]3[CH2:73][C:72]4[C:67](=[CH:68][C:69]([O:74][CH3:75])=[CH:70][CH:71]=4)[O:66][C:65]3([CH3:76])[CH3:77])=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1ccc2c(c1)OC(C)(C)C(c1ccccc1NCc1ccc(OCCN3CCCCCC3)cc1)C2
Agent: COc1ccc2c(c1)OC(C)(C)C(c1ccccc1N)C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1ccccc1C1Cc2ccc(OC)cc2OC1(C)C

Procedure:
Synthesized from 2-(7-methoxy-2,2-dimethylchroman-3-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][2-(7-methoxy-2,2-dimethylchroman-3-yl)phenyl]amine (473 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[2-(7-methoxy-2,2-dimethylchroman-3-yl)phenyl]amine (472 mg). This compound (470 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (200 mg).
Reaction SMILES: Cl[O-].[Na+].O.[CH3:5][O:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8].[OH-].[Na+].[Cl-].[NH4+:21]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].[OH-].[NH4+].COC(C)(C)C>[CH3:5][O:6][C:7]([C:9]1[N:10]([NH2:21])[C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8]
Reactant: COC(=O)c1cc2ccccc2[nH]1
Reactant: [NH4+]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)c1cc2ccccc2n1N
Reaction time: 0.33 h
Yield: 14350.3 %

Procedure:
A 2 M solution of sodium hypochlorite in water (200 mL, 0.40 mol) was added dropwise to a biphasic mixture of commercially available 1H-indole-2-carboxylic acid methyl ester (20.00 g, 0.11 mol), capriquat (4.5 mL, 0.01 mol), 7 M of sodium hydroxide in water (326 mL, 2.28 mol), 8 M of ammonium hydroxide in water (100 mL, 0.80 mol), ammonium chloride (37 g, 0.68 mmol), and 2-methoxy-2-methylpropane (318 mL). The reaction was worked up about 20 min after the addition was completed. The organic layer was separated and was washed with saturated aqueous sodium thiosulfate. Organic extracts were dried over magnesium sulfate, then filtered, and the solvent was evaporated in vacuum to afford 1-amino-1H-indole-2-carboxylic acid methyl ester (18.56 g, 85%), which was used in the next step without further purification. 1H-NMR (CDCl3) δ 7.62 (m, 2H), 7.36 (m, 1H), 7.18 (s, 1H), 7.13 (s, 1H), 5.32 (br s, 2H), 3.93 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:20][CH:21]2[CH2:23][CH2:22]2)[CH2:11][N:10]([S:12]([C:15]2[N:16]=[N:17][NH:18][CH:19]=2)(=[O:14])=[O:13])[CH2:9]1)=[O:5].[C:29](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:20][CH:21]2[CH2:22][CH2:23]2)[CH2:9][N:10]([S:12]([C:15]2[N:16]=[N:17][N:18]([CH3:29])[CH:19]=2)(=[O:13])=[O:14])[CH2:11]1)=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=C(NCC1(CC2CC2)CN(S(=O)(=O)c2c[nH]nn2)C1)c1ccc(Cl)cc1Cl
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(S(=O)(=O)N2CC(CNC(=O)c3ccc(Cl)cc3Cl)(CC3CC3)C2)nn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2,4-dichloro-N-{[3-(cyclopropylmethyl)-1-(1H-1,2,3-triazol-4-ylsulfonyl)azetidin-3-yl]methyl}benzamide (0.1 g; 0.23 mmol) in DMF (5 ml) at 0° C. was added potassium carbonate (0.062 g; 0.45 mmol) followed by methyl iodide (0.048 g; 0.021 ml; 0.34 mmol) and the solution stirred for 18 hours at ambient temperature. LC/MS shows three new products of identical mass ion m/e=458:460 (3:2). Water (1 ml) was added, the solvent stripped at reduced pressure, and the residue azeotroped twice with toluene. The crude product was purified by preparative TLC on silica gel eluted with 4% Methanol DCM to give the title compound as the most polar isomer (24 mg).
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[O:26][CH2:27][C:28]([F:55])([F:54])[C@:29]([C:35]3[N:40]=[C:39]([NH:41][C:42]([C:44]4[C:49]([CH3:50])=[CH:48][C:47]([C:51]#[N:52])=[CH:46][N:45]=4)=[O:43])[CH:38]=[CH:37][C:36]=3[F:53])([CH2:31][CH2:32][O:33][CH3:34])[N:30]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl>[NH2:24][C:25]1[O:26][CH2:27][C:28]([F:54])([F:55])[C@:29]([C:35]2[N:40]=[C:39]([NH:41][C:42]([C:44]3[C:49]([CH3:50])=[CH:48][C:47]([C:51]#[N:52])=[CH:46][N:45]=3)=[O:43])[CH:38]=[CH:37][C:36]=2[F:53])([CH2:31][CH2:32][O:33][CH3:34])[N:30]=1
Reactant: COCC[C@]1(c2nc(NC(=O)c3ncc(C#N)cc3C)ccc2F)N=C(NC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)OCC1(F)F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC[C@]1(c2nc(NC(=O)c3ncc(C#N)cc3C)ccc2F)N=C(N)OCC1(F)F
Yield: 85 %

Procedure:
A solution of 5-cyano-3-methyl-pyridine-2-carboxylic acid {6-[(R)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]amino}-5,5-difluoro-4-(2-methoxy-ethyl)-5,6-dihydro-4H-[1,3]oxazin-4-yl]-5-fluoro-pyridin-2-yl}-amide (146 mg, 0.194 mmol), TFA (0.989 ml, 12.83 mmol) and triethylsilane (0.093 ml, 0.583 mmol) in dichloromethane (1.9 ml) was stirred at it for 18 hours. The reaction mixture was evaporated and the residue diluted with ethyl acetate, washed with sat. aqueous sodium bicarbonate solution, water and brine, dried over sodium sulfate, filtered and evaporated. 142 mg colourless resin. The product was chromatographed over a preparative silica gel plate (2 mm, 20×20 cm, Merck, dichloromethane/methanol 95:5) to give the title compound as a colourless foam. 74 mg (85% yield).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[C:6]([N+:19]([O-])=O)=[C:7]([C:13]([N+:16]([O-])=O)=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>[Ni].CCO>[NH2:16][C:13]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]2[C:5]([CH:4]=[CH:3][NH:19]2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1c([N+](=O)[O-])ccc(/C=C/N(C)C)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1c(N)ccc2cc[nH]c12
Reaction time: 2 h
Yield: 16.2 %

Procedure:
A mixture of (E)-ethyl 3-(2-(dimethylamino)vinyl)-2,6-dinitrobenzoate (30 g, 0.097 mol) and Raney Nickel (10 g) in EtOH (1000 mL) was hydrogenated at room temperature under 50 psi for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel to give ethyl 6-amino-1H-indole-7-carboxylate as an off-white solid (3.2 g, 16%). 1H NMR (DMSO-d6) δ 10.38 (s, 1H), 7.42 (d, J=8.7 Hz, 1H), 6.98 (t, J=3.0 Hz, 1H), 6.65 (s, 2H), 6.48 (d, J=8.7 Hz, 1H), 6.27-6.26 (m, 1H), 4.38 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.C([O:20][CH2:21][C:22](Cl)=[O:23])(=O)C.C1CCN2C(=NCCC2)CC1.Cl>CC#N.N1C=CC=CC=1>[CH3:15][C:2]1([CH3:16])[O:1][C:21](=[O:20])[C:22]([OH:23])=[C:3]1[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(O)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 61.6 %

Procedure:
To a 0° C. solution of the alcohol of Example 1, Step 3 (29.5 g, 122 mmol) in CH3CN (350 mL) were added pyridine (25 mL) and acetoxyacetyl chloride (25 g, 183 mmol). After a period of 7 h at r.t., DBU (31 mL) was added to the reaction mixture. After a period of 1 h at 80° C., a second portion of DBU (35 mL) was added. The reaction mixture was kept at 80° C. for 18 h. The reaction mixture was allowed to cool to r.t. The mixture was poured onto ice-water (2.5 L) containing 100 mL of concentrated HCl. The brown solid was collected and dissolved in hot acetonitrile and was filtered through a plug of silica. The solvent was evaporated and the resultant solid was swished in EtOAc to give the title compound (21.2 g, 62%).
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[C:7](=O)(OC)OC.CN(C)CC>>[CH3:7][CH:2]1[CH2:3][CH2:4][O:5][C:1]1=[O:6].[C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)OC
Agent: CCN(C)C
Solvent: O=C1CCCO1
Product: CC1CCOC1=O
Temperature: 200 °C
Reaction time: 5 h

Procedure:
A mixture of 21.5 g (250 mmol) of gamma-butyrolactone, 45 g (500 mmol) of dimethyl carbonate and 0.93 g (12.5 mmol) of dimethylethylamine was heated to 200° C. in an autoclave and stirred at this temperature for 5 hours. After cooling, 13.3 g (53%) of 2-methylbutyrolactone (selectivity 74%) and 6 g of unreacted gamma-butyrolactone were obtained by quantitative gas-chromatographic analysis of the discharged reaction mixture.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>C(O)CCC>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)=[CH:26][CH:25]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Br)n2)cc1
Reactant: COc1ccc(CN)cc1
Solvent: CCCCO
Product: COc1ccc(CNc2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cc1

Procedure:
A mixture of 2-bromo-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (5.55 g, 15 mmol) and 4-methoxybenzylamine (5.9 mL, 45 mmol) in n-butanol (15 mL) was refluxed for 2 days. Evaporated to dryness, diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left the title compound as an orange oil (6.409 g, 100%). MS (ISP) 427.3 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:23]2[CH2:26][CH:25]([C:27](=O)[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[CH2:24]2)=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].Cl.[CH3:37][O:38][NH2:39]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:23]2[CH2:26][CH:25]([C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[N:39][O:38][CH3:37])[CH2:24]2)=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:20][CH:21]=2)[CH2:11][CH2:12]1)=[O:8]
Reactant: CON
Reactant: O=C(O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(C(=O)c4cccc(F)c4)C3)CC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(c1cccc(F)c1)C1CN(c2ncc(Cl)cc2C(=O)NC2(c3ccc(C(=O)O)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 22.9 %

Procedure:
4-(1-(5-chloro-2-(3-(3-fluorobenzoyl)azetidin-1-yl)nicotinamido)cyclopropyl)benzoic acid (E25) (12.6 mg, 0.025 mmol) was dissolved in dry pyridine (1.2 ml) then O-methylhydroxylamine hydrochloride (4.3 mg, 0.051 mmol) was added and the resulting mixture was stirred at room temperature for 60 h. Solvents were evaporated in vacuo, and the residue was diluted with water (5 ml) and extracted with ethylacetate (3×20 ml). Collected organics, after solvent evaporation, afforded a residue that was washed with methanol and dried in vacuo to afford the title compound (E26) (D021/092/2) (3 mg).
Reaction SMILES: [C:1]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[C:21]([O:32][CH2:33][C:34]([O:36]CC)=[O:35])[CH:20]=[CH:19]2)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+]>C1COCC1.O>[C:1]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[C:21]([O:32][CH2:33][C:34]([OH:36])=[O:35])[CH:20]=[CH:19]2)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)c1c(-c2ccc3c(-c4ccccc4)c(OCC(=O)OCC)ccc3c2)oc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(=O)c1c(-c2ccc3c(-c4ccccc4)c(OCC(=O)O)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 4 of Example 6, ethyl 2-{[6-(3-pentanoyl-1-benzofuran-2-yl)-1-phenyl-2-naphthyl]oxy}acetate (0.161 g, 0.318 mmol) was hydrolyzed with potassium hydroxide (0.0693 g, 1.24 mmol) in THF (6 mL) and water (6 mL). 2-{[6-(3-pentanoyl-1-benzofuran-2-yl)-1-phenyl-2-naphthyl]oxy}acetic acid was obtained and was converted to the sodium salt by dissolving (0.103 g, 0.215 mmol) of the acid in methanol (5 mL) and adding 1N sodium hydroxide (0.22 mL, 22 mmol). After standing for 25 minutes, the mixture was solvent evaporated and the residue was rinsed with hexane and dried for 24 hours at 100° C. to give a yellow solid (0.0913 g), mp 272-273° C. (dec.). Mass spectrum (−ESI, [M−H]−) m/z 477. 1HNMR (500 MHz, DMSO-d6): δ8.35 (d, 1H, J=1.7 Hz), 8.05 (t, 2H, J=7.6 Hz), 7.65-7.7 (m, 2H), 7.5-7.55 (m, 3H), 7.35-7.45 (m, 6H), 4.25 (s, 2H), 2.75 (t, 2H, J=7.3 Hz), 1.5-1.55 (m, 2H), 1.1-1.2 (m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz). Elemental Analysis for C31H26O5Na.0.6H2O: Calculated: C, 72.82; H, 5.16; N, 0.00. Found: C, 72.57; H, 4.92; N, 0.05.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:20](=[O:41])[N:21]([CH3:40])[C@@H:22]([C:34]1[O:38][N:37]=[C:36]([CH3:39])[N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([N:21]([CH3:40])[C@@H:22]([C:34]1[O:38][N:37]=[C:36]([CH3:39])[N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[O:41]
Reactant: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@H](N)Cc2ccc3ccccc3c2)n1
Yield: 61 %

Procedure:
{(1R)-1-{N-Methyl-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-carbamoyl}-2-(2-naphthyl)ethyl}carbamic acid tertbutyl ester (2.4 g, 4.2 mmol) was dissolved in a mixture of trifluoroacetic acid (40 mL) and dichloromethane (40 mL) at 20° C. After 10 min the reaction mixture was concentrated in vacuo and coevaporated from dichloromethane (80 mL). The residue was crystallised from ethyl acetate to give 1.19 g of (2R)-2-amino-N-methyl-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)-ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][C:4](=O)[NH:3][C:2]1=O.CO.[ClH:16]>C(OCC)C>[ClH:16].[CH2:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:1][CH2:2][NH:3][CH2:4]1
Reactant: O=C1Cc2ccccc2CC(=O)N1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: c1ccc2c(c1)CCNCC2
Temperature: 25 °C
Yield: 78 %

Procedure:
To a suspension of 1,5-dihydro-benzo[d]azepine-2,4-dione (9.3 g) in toluene (250 ml) borane-methylsulfide complex (20 ml) was added dropwise under nitrogen atmosphere, then the mixture was heated at reflux for 4 h. MeOH (20 ml) was added dropwise and the mixture refluxed for additional 1 h, then cooled to room temperature. A 10% solution of anidrous HCl in ethyl ether (50 ml) was added and the solid precipitate was filtered off, washed with ethyl ether and desiccated under reduced pressure to afford the title compound as a white solid (7.6 g, 78% yield).
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.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[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:22]([C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[F:19])=[O:23])[CH2:3][CH2:2]2)[N:12]=1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: O=C(Cl)c1ccccc1F
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4ccccc4F)CC3)cccc2n1
Yield: 55 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-fluorobenzoyl chloride (65 mg; 0.41 mmol) to obtain 40.2 mg. (55% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.50 (m, 2H), 7.34 (m, 3H), 7.09 (br s, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 5.93 (br s, 2H), 4.60 (br d, J=13.5 Hz, 1H), 3.46 (br s, 2H), 3.17 (m, 2H), 3.02 (m, 1H), 2.72 (m, 2H). ESIMS+368.0 m/z
Reaction SMILES: C(Cl)Cl.[C:4]([Cl:7])(Cl)=[O:5].C(N(CC)CC)C.[CH2:15]([NH:22][C:23](=[N:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[S:24][CH2:25][CH3:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1C=CC=CC=1>[CH2:28]([N:27]([C:4]([Cl:7])=[O:5])[C:23](=[N:22][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[S:24][CH2:25][CH3:26])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCN=C(NCCCCCCC)SCC
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCCCCCCN=C(SCC)N(CCCCCCC)C(=O)Cl
Temperature: 5 °C
Reaction time: 8 h

Procedure:
100 ml of dry CH2Cl2 was placed in a 500 ml flask equipped with a thermometer and dropping funnel and cooled to 5° C. in an ice bath. A solution of phosgene in benzene (170 g of 17.5 percent weight concentration) was then added. Next, a solution of 100 ml of dry CH2Cl2, 10.1 g triethylamine and 30 g of 1,3-diheptyl-2-ethyl isothiourea was added dropwise over a one hour period at 5° C. The mixture was then stirred overnight at ambient temperature.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[CH:19]=[CH2:18]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
Isatin (10.102 g, 68.7 mmol) was dissolved in 100 mL dry DMF, and Cs2CO3 (24.609 g, 75.5 mmol) was added. To the resulting purple-brown suspension was added allyl bromide (7.2 mL, 83 mmol) and the reaction was stirred at room temperature for 16 h. The resulting cloudy orange-brown mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (160 mL) and water (80 mL). The layers were separated, and the aqueous layer was extracted with additional EtOAc (2×80 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. To the residue was added 300 mL hexanes. The mixture was heated to 70° C. with a water bath, and EtOAc was added until the compound went into solution (approx. 80 mL EtOAc). A small amount of insoluble red material was removed, and then the solution was allowed to cool. The resulting red crystals were filtered, washed with 3×30 mL hexanes, and then dried under vacuum to provide the title compound (11.740 g, 91%). 1H NMR (600 MHz, CHLOROFORM-D) δ ppm 4.36 (d, J=5.6 Hz, 2H), 5.26-5.34 (m, 2H), 5.78-5.88 (m, 1H), 6.88 (d, J=7.9 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 7.56 (td, J=7.8, 1.3 Hz, 1H), 7.61 (d, J=7.4 Hz, 1H). MS (ESI) (M+H)+=188.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][O:13][C:14]1[CH:29]=[CH:28][C:17]3[O:18][CH2:19][C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH:22](O)[C:16]=3[CH:15]=1)[CH:6]=[CH:5]2.[SH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[C:33]([CH2:32][CH2:31][S:30][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][CH2:12][C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[N:8]=3)=[CH:15][C:16]1=2)([OH:35])=[O:34]
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4cc(Cl)ccc4n3)cc21
Reactant: O=C(O)CCS
Product: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4cc(Cl)ccc4n3)cc21

Procedure:
2-(6-Chloroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.