Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[C:25](O)(=O)[CH3:26].C[C:30]1[N:31]=[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]2[CH:38]=1.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:30][C:38]3[N:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]4=[N:31][C:25]=3[CH3:26])[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: Cc1cn2ccccc2n1
Reactant: CC(=O)O
Agent: *CO*
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2ccccn2c1CN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a stirred and cooled (0° C.) mixture of 3.8 parts of poly(oxymethylene) 37%, 15.5 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine and 7 parts of glacial acetic acid were added 6.5 parts of 2-methylimidazo[1,2-a]pyridine under nitrogen atmosphere. The whole was heated slowly to 50° C. and stirring was continued at 50° C. for 2 hours. After stirring was continued overnight at room temperature, the reaction mixture was poured into water and the whole was made alkaline with sodium hydroxide. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 6.7 parts (30%) of 1-[(4-fluorophenyl)methyl]-N-[1-[(2-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 198.1° C. (compound 106).
Reaction SMILES: S([C:5]1[CH:11]=CC(C)=[CH:7][CH:6]=1)([O-])(=O)=O.[Na+].[CH3:13][C:14]([NH2:20])([CH2:18][CH3:19])[C:15](=[S:17])[NH2:16]>CCC(C)=O>[CH2:5]([C:6]1([CH3:7])[NH:16][C:15](=[S:17])[C:14]([CH2:18][CH3:19])([CH3:13])[NH:20]1)[CH3:11]
Reactant: CCC(C)(N)C(N)=S
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCC1(C)NC(=S)C(C)(CC)N1
Reaction time: 16 h

Procedure:
The thione can be purified by column chromatography on silica gel using hexane to elute an odorous fraction before the thione. The effect of variation of temperature and concentration of the reactants on yield and reaction rate was examined in a sealed NMR tube using D20 as a solvent and sodium tosylate as an internal standard. What was observed was a smooth decrease in concentration of starting materials and smooth increase in concentration of product. The reaction time can be reduced from 16 hours at 50° C. to 6 hours at 80° C. The compound, 2-methyl-2-aminobutyrothioamide, was not observed indicating that this alicyclic intermediate reacts with MEK in a fast step to yield the cyclic product
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:11][CH2:12][CH2:13][CH3:14].O1[CH2:19][CH2:18][CH2:17][CH2:16]1>[Pd].BrCC1C=CC(C#N)=CC=1.[Zn].O>[CH2:11]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:2]=1[CH2:16][C:17]1[CH:13]=[CH:12][C:11]([C:3]#[N:4])=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1nc2ccccn2c1Br
Reactant: C1CCOC1
Agent: [Pd]
Agent: N#Cc1ccc(CBr)cc1
Agent: [Zn]
Solvent: O
Product: CCCCc1nc2ccccn2c1Cc1ccc(C#N)cc1

Procedure:
A mixture of 2 g of the product of Stage D, 100 ml of tetrahydrofuran and 1 -g of [tetra-bis(triphenylphosphine)] palladium was added to 35.9 ml of zinc 4-bromomethyl benzonitrile at ambient temperature and the mixture was refluxed for one hour. The mixture was allowed to return to ambient temperature, poured into water and extracted with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium chloride, dried, filtered and brought to dryness to obtain after chromatography on silica (ethyl acetate), 1.1 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[CH3:30][O:31][C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][CH2:37][NH:38]2)=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]4[CH:21]=[C:22]([C:26]([N:38]5[C:39]6[C:35](=[CH:34][CH:33]=[C:32]([O:31][CH3:30])[CH:40]=6)[CH2:36][CH2:37]5)=[O:28])[N:23]=[CH:24][N:25]=4)[CH2:18][CH2:19]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1
Reactant: COc1ccc2c(c1)NCC2
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5ccc(OC)cc54)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
80 mg (0.20 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]pyrimidine-4-carboxylic acid and 30 mg (0.20 mmol) 6-methoxy-2,3-dihydro-1H-indole in 50 μL (0.36 mmol) TEA and 1.5 mL DMF were combined with 70 mg (0.22 mmol) TBTU and the mixture was stirred for 1 h at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1Br.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CN1C(=O)CCC1.CCOC(C)=O>O>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: C1COCCN1
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)n1cc(-c2nc(N3CCOCC3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 150 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
A mixture of 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg), morpholine (113 mg), and NMP (1.0 ml) was heated at 150° C. with stirring for 1 day. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was recrystallized from MeOH-IPE and dried in vacuo to give 5-[5-amino-6-(4-morpholinyl)-3-phenyl-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (84 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:30](=[CH:31][CH:32]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[C@H:17]4[CH2:18][C@H:14]([CH2:15][CH2:16]4)[N:13]3[C:19](=[O:29])[C@@H:20]([NH:24][C:25](=[O:28])[O:26][CH3:27])[CH:21]([CH3:23])[CH3:22])=[N:11][C:7]=1[CH:6]=[CH:5]2.CC1(C)C(C)(C)OB([C:41]2[CH:42]=[C:43]3[C:63](=[CH:64][CH:65]=2)[C:47]2[NH:48][C:49]([C@@H:51]4[CH2:55][CH2:54][CH2:53][N:52]4[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[N:50][C:46]=2[CH:45]=[CH:44]3)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(OCC)(=O)C>[CH3:27][O:26][C:25]([NH:24][C@@H:20]([CH:21]([CH3:23])[CH3:22])[C:19]([N:13]1[C@H:12]([C:10]2[NH:9][C:8]3[C:30]4[C:4]([CH:5]=[CH:6][C:7]=3[N:11]=2)=[CH:3][C:2]([C:41]2[CH:42]=[C:43]3[C:63](=[CH:64][CH:65]=2)[C:47]2[NH:48][C:49]([C@@H:51]5[CH2:55][CH2:54][CH2:53][N:52]5[C:56]([O:58][C:59]([CH3:61])([CH3:62])[CH3:60])=[O:57])=[N:50][C:46]=2[CH:45]=[CH:44]3)=[CH:32][CH:31]=4)[C@H:17]2[CH2:18][C@@H:14]1[CH2:15][CH2:16]2)=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1[C@H]2CC[C@H](C2)[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1)C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1[C@H]2CC[C@H](C2)[C@H]1c1nc2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]c65)c4)ccc3c2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.1 %

Procedure:
Methyl (S)-1-((1S,3S,4R)-3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (0.300 g, 0.601 mmol), (S)-tert-butyl 2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (0.334 g, 0.721 mmol), and aqueous potassium phosphate (2M, 0.901 mL, 1.802 mmol) were suspended in 1,2-dimethoxyethane (3.00 mL) and sparged with argon gas for 30 minutes. Palladium tetrakis triphenylphosphine (0.069 g, 0.060 mmol) was added and the reaction mixture was capped and placed in a preheated 80° C. oil bath. The solution was heated for 18 hours and subsequently stirred at room temperature for two days. Upon completion, the reaction was diluted with ethyl acetate and washed with brine. The concentrated organic layer was purified by normal phase chromatography (40-100% ethyl acetate (10% MeOH) in hexanes) to give (S)-tert-butyl 2-(2′-((1S,3S,4R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (0.305 g, 67%). LCMS-ESI+: calc'd for C44H49N7O5: 755.38 (M+); Found: 756.8 (M+H+).
Reaction SMILES: C[O:2][C:3]1C=CC2C[C@H]3NCC[C@]45[C@H](C(CC[C@@]34O)=O)O[C:4]=1C=25.[CH3:23][N:24]1[C@@H:41]2[CH2:42][C:29]3[CH:30]=[CH:31][C:32]([O:44][CH3:45])=[C:33]4[O:34][C@H:35]5[C:36]([CH2:38][CH2:39][C@:40]2([OH:43])[C@:27]5([C:28]=34)[CH2:26][CH2:25]1)=[O:37].C(OC(=O)C)(=O)C>>[CH3:4][C:3]([O:43][C@@:40]12[C@H:41]3[CH2:42][C:29]4[CH:30]=[CH:31][C:32]([O:44][CH3:45])=[C:33]5[O:34][C@H:35]([C@@:27]1([C:28]=45)[CH2:26][CH2:25][N:24]3[CH3:23])[C:36](=[O:37])[CH2:38][CH2:39]2)=[O:2]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)NCC[C@]314
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@]4(OC(C)=O)[C@@H](C2)N(C)CC[C@]314

Procedure:
The noroxycodone used as starting material for Method II is prepared from oxycodone by the following steps: ##STR13## Oxycodone is refluxed with acetic anhydride to yield 14-acetyloxycodone. This product is reacted with cyanogen bromide to yield 14-acetyloxy-17-cyano-7,8-dihydronorcodone which is in turn converted to noroxycodone by reaction with hydrogen chloride. The oxycodone starting material is prepared according to M. Freund and E. Speyer, J. fur Praktische Chemie, 94, 135-137 (1916), the disclosure of which is hereby incorporated by reference.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:18])[CH2:13][C:14](OC)=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].BrC[C:23]([O:25]CC)=[O:24]>O1CCCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12](=[O:18])[CH2:13][CH2:14][C:23]([OH:25])=[O:24])=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CBr
Reactant: COC(=O)CC(=O)c1ccc(-n2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)c1ccc(-n2ccnc2)cc1
Yield: 54 %

Procedure:
A solution of methyl 4-(1H-imidazol-1-yl)-β-oxobenzenepropanoate (6.1 g, 0.025 mol) in tetrahydrofuran (65 ml) is added slowly to a stirred suspension of 50% NaH (1.2 g, 0.025 mol) in tetrahydrofuran (20 ml) and the solution is stirred for one additional hour. Ethyl bromoacetate (4.5 g) is added followed by refluxing the mixture for 7 to 8 hours. The tetrahydrofuran is removed, the residue is treated with water, and the organic material is extracted with ether. The residue obtained after removal of ether is hydrolysed by heating with 6 N HCl for 7 to 8 hours. The crude acid is finally crystallized from dimethylformamide to yield 3.3 g of the product 4-(1H-imidazol-1-yl)-γ-oxobenzenebutanoic acid.
Reaction SMILES: [O:1]1[CH2:27][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[CH:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH3:28][NH:29][CH3:30]>C(O)C>[C:17]1([C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:27][N:29]([CH3:30])[CH3:28])=[CH:6][CH:7]=3)[O:12][C:11]([CH3:16])([CH3:15])[CH:10]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CNC
Reactant: CC1(C)C=C(c2cccc3ccccc23)c2ccc(OCC3CO3)cc2O1
Solvent: CCO
Product: CN(C)CC(O)COc1ccc2c(c1)OC(C)(C)C=C2c1cccc2ccccc12
Reaction time: 48 h

Procedure:
7-(2,3-Epoxypropoxy)-2,2-dimethyl-4-(1-naphthyl)-2H-chromene (4.4g., 0.012 moles) was dissolved in a solution of dimethylamine in ethanol (28 ml., ~40% solution) and left to stand at room temperature for 48 hours. Removal of solvent gave the title product as an orange oil which was converted to the hydrochloride salt. Recrystallization from acetone gave a white solid (3.13g., 64%) m.p. 185°-187° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>CN(C=O)C>[CH2:17]([O:16][CH:15]([O:19][CH2:20][CH3:21])[CH2:14][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[CH3:18]
Reactant: CCOC(CBr)OCC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(CN1C(=O)c2ccccc2C1=O)OCC
Temperature: 150 °C
Yield: 86.7 %

Procedure:
A three-necked round-bottomed flask fitted with an efficient stirrer and a reflux condenser was charged with potassium phthalimide (150 g, 0.81 mol) and 2-bromo-1,1-diethoxy-ethane (196 g, 1.0 mol) and DMF (500 mL). The stirrer was started and the mixture was heated for about 3-4 h in an oil bath maintained at 150° C. The solvent DMF was removed under reduced pressure. The residue was purified by column chromatography to afford pure 2-(2,2-diethoxyethyl)isoindoline-1,3-dione (185 g, yield 87%). 1H NMR (400 MHz, MeOD): 1.16 (t, 6H), 3.48-3.60 (m, 2H), 3.68-3.75 (m, 2H), 3.76-3.89 (d, 2H), 4.89 (t, 1H), 7.68-7.75 (m, 2H), 7.85-7.96 (m, 2H). MS (E/Z): 264 (M+H+).
Reaction SMILES: CS([C:5]1[N:6]=[C:7]([O:34][CH3:35])[C:8]2[N:13]=[C:12]([NH:14][C:15]([N:17]3[CH2:22][CH2:21][C:20]([OH:33])([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH2:19][CH2:18]3)=[O:16])[S:11][C:9]=2[N:10]=1)(=O)=O.[OH-:36].[K+]>C1COCC1.O>[OH:36][C:5]1[N:6]=[C:7]([O:34][CH3:35])[C:8]2[N:13]=[C:12]([NH:14][C:15]([N:17]3[CH2:22][CH2:21][C:20]([OH:33])([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH2:19][CH2:18]3)=[O:16])[S:11][C:9]=2[N:10]=1
Reactant: [OH-]
Reactant: COc1nc(S(C)(=O)=O)nc2sc(NC(=O)N3CCC(O)(c4cccc(C(F)(F)F)c4)CC3)nc12
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(O)nc2sc(NC(=O)N3CCC(O)(c4cccc(C(F)(F)F)c4)CC3)nc12
Temperature: 75 °C
Reaction time: 4 h
Yield: 14.5 %

Procedure:
A magnetically stirred mixture of 4-hydroxy-4-[3-(trifluoromethy)phenyl]piperidine-1-carboxylic acid (5-methanesulfonyl-7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (250 mg, 0.47 mmol) in THF (10 mL) and water (5 mL) was treated with a 2N aqueous KOH solution (0.5 mL, 0.94 mmol). The reaction mixture was stirred at 75° C. for 4 h. The reaction was then cooled to room temperature and poured into water and extracted with methylene chloride. The organics were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 4-hydroxy-4-[3-(trifluoromethy)phenyl]piperidine-1-carboxylic acid (5-hydroxy-7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (32 mg, 15%) as a white solid. LRMS for C19H18F3N5O4S2 (M+H)+ at m/z=469. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: C([O:3][C:4]([C@@H:6]([NH:17][CH:18]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]([CH2:29][C:30]([O:32]CC)=[O:31])[C:19]1=[O:35])[CH2:7][S:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:5])C.[OH-].[Na+].CO.C(O)(=O)C>O>[OH2:3].[C:4]([C@@H:6]([NH:17][CH:18]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]([CH2:29][C:30]([OH:32])=[O:31])[C:19]1=[O:35])[CH2:7][S:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CN1C(=O)C(N[C@@H](CSCCC2CCNCC2)C(=O)OCC)CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)C(N[C@@H](CSCCC2CCNCC2)C(=O)O)CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.5 g of dihydrobromide of the A-isomer of ethyl 3-[1(R)-ethoxycarbonyl-2-{2-(4-piperidyl)ethylthio}ethyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate obtained in Example 4 is dissolved in 10 ml of water. The resulting aqueous solution is added dropwise to 18 ml of an aqueous solution of 2N sodium hydroxide. After stirring for 1 hour at room temperature, 6 ml of methanol is added, and the system further stirred for 1 hour. After neutralizing the reaction liquid with 7.2 ml of acetic acid, the solvent is distilled off under reduced pressure. After concentration, the residue is purified by HP-20 column chromatography (water:methanol=3:1). The effluent is concentrated under reduced pressure, and the resulting residue is recrystallized from 5 ml of water to give 324 mg of the A isomer of 3-[1(R)-carboxy-2-{2-(4-piperidyl)ethylthio}ethyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid monohydrate as a colorless powder.
Reaction SMILES: C1(=O)[N:5]([C:6]2[C:11]([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:10][CH:9]=[CH:8][N:7]=2)C(=O)C2=CC=CC=C12.O.NN>CCO>[NH2:5][C:6]1[C:11]([CH2:12][N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ncccc1CN1CCCCC1
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ncccc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(Phthalimidyl)-3-(1-piperidinylmethyl)-pyridine (196 mg, 0.609 mmol) was dissolved in EtOH (95%, 2 mL) at 23° C., and treated with hydrazine monohydrate (0.0320 mL, 0.670 mmol) in a dropwise fashion. The resulting mixture was warmed to reflux and stirred for 3 h at reflux. The solution was treated with additional hydrazine monohydrate (0.150 mL, 3.050 mmol), and reflux continued. After 14 h at reflux, the mixture was cooled to RT, and concentrated using a rotary evaporator to a white paste. The resulting white paste was dissolved in CHCl3: IpOH (3:1, 75 mL), and washed with saturated NaHCO3 (3×50 mL), and H2O (1×50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to provide the title compound as a white solid. MS m/z: 192 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[S:6][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19](=[O:21])[O:18][N:17]=2)=[C:12]([O:22][CH3:23])[CH:11]=1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>CN(C)C=O>[CH3:23][O:22][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[C:16]1[NH:20][C:19](=[O:21])[O:18][N:17]=1)[O:9][CH2:8][C:7]1[S:6][C:5]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)=[N:4][C:3]=1[CH2:2][O:1][S:42]([CH3:41])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CO)ccc1-c1noc(=O)[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COS(C)(=O)=O)ccc1-c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 400 mg of 3-{4-[4-hydroxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one in 8 mL of dimethylformamide was added 0.42 mL of triethylamine followed by dropwise addition of 0.1 mL of methanesulfonyl chloride. The resulting mixture was stirred at room temperature for 45 minutes then concentrated under reduced pressure to give 830 mg of crude methanesulfonic acid 5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester which was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C:12]1=[O:20].N1CCCCC1.O>CN(C)C=O>[C:1]1(=[C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:12]2=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1Cc2ccccc2C1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C1=C1CCc2ccccc21
Temperature: 130 °C
Yield: 21.4 %

Procedure:
A mixture of 0.4 g indan-2-one, 1.33 g oxindole and 0.5 ml piperidine in 3 ml dimethylforamide was heated in a sealed tube at 130° C. for 60 hours. Enough water was added to cause recipitation of an oily solid. The mixture was decanted and the remaining oily solid heated with 5 ml of ethanol using a heat gun. Upon cooling, the solid was filtered off. The solid was slurried with 3 ml of ethanol and filtered to give 160 mg of 3-indan-1-ylidene-1,3-dihydroindol-2-one as an orange solid.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]2[O:9][C:8]1=[O:17].C1(C)C=CC=CC=1.O>CCCCCC>[Cl:3][CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]2[O:9][C:8]1=[O:17]
Reactant: O=c1oc2cc(Cl)cnc2n1CO
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1oc2cc(Cl)cnc2n1CCl
Reaction time: 4 h
Yield: 83 %

Procedure:
39 Parts of thionyl chloride are added dropwise, in a manner ensuring that the internal temperature does not exceed 50° C., to a solution of 45 parts of 3-hydroxymethyl-6-chloro-oxazolo[4,5-b]pyridin-2-(3H)-one in 200 parts of toluene; and the whole is stirred for a further 4 hours at 40°-50° C. The resulting solution is subsequently freed from gases in a water-jet vacuum, and sufficient toluene is evaporated off to leave a crystal sludge that can still just be stirred. After the addition of 100 parts of hexane, filtration is carried out and the filter cake is washed twice with cold hexane. There are obtained 40 parts of 3-chloromethyl-6-chloro-oxazolo[4,5-b]pyridin-2-(3H)-one (83% of theory), m.p. 105°-107° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]1=[O:23].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](Cl)=[O:35]>O1CCOCC1>[Cl:9][C:6]1[CH:5]=[C:4]([F:10])[C:3]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:2]([NH:1][C:34]([C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:24]=2)=[O:35])[C:7]=1[OH:8]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Solvent: C1COCCO1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2NC(=O)c2ccc3ccccc3c2)c1=O
Yield: 84.4 %

Procedure:
3-(2-Amino-4-chloro-6-fluoro-3-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.50 g, 1.4 mmol) and 2-naphthoyl chloride (0.27 g, 1.4 mmol) were dissolved in 1,4-dioxane (10 ml) and the solution heated under reflux for 4 hr. Solvent was evaporated under reduced pressure and the product purified by column chromatography on silica gel (eluent, hexane-ethyl acetate, 8:2) to furnish the title compound (0.60 g).