Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.CN(P(N(C)C)(N(C)C)=O)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH:36](Br)[CH2:37][CH3:38])[CH:30]=1>C1COCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH2:35][CH:36]([CH2:37][CH3:38])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([OH:10])=[O:9])[CH:32]=[CH:33][CH:34]=1
Reactant: CCC(Br)Cc1cccc(OC)c1
Reactant: O=C(O)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(Cc1cccc(OC)c1)C(C(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
Phenylacetic acid (0.84 g, 6.07 mmol) was dissolved in THF (50 mL) and cooled in an ice bath. nBuLi (2.5 M in hexanes, 5.4 mL, 13.4 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 h, then at room temperature for 5 h. HMPA (0.25 mL) was added, and the stirring was continued for another 30 min. Cooled in an ice bath, a solution of 3-(2-bromobutyl)phenyl methyl ether (53) (1.77 g, 7.28 mmol) in THF (10 mL) was added dropwise. The resulting mixture was allowed to warm up to room temperature and stir at room temperature overnight, then heated at 50° C. for 1 h. Cooled and quenched with 0.5 N NaOH (25 mL), the mixture was again heated at 50° C. for 1 h. After cooled to room temperature and extracted with ether, the aqueous layer was acidified with 5 N HCl and extracted with CHCl3. The extracts were combined and washed with brine, dried (Na2SO4), filtered, and the filtrate was concentrated to give the crude product as a yellow oil. The crude product was purified by flash chromatography over SiO2 with CH2Cl2:Acetone (8:1) to give 0.81 g (45%) of the title compound (54) as a colorless viscous oil. 1HNMR indicated it was a mixture of two diastereomers with a ratio of 2:1.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[CH:46]([N:48]=[C:49]=[O:50])=[CH2:47]>C(OCC)(=O)C>[CH:46]([NH:48][C:49]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])=[O:50])=[CH2:47]
Reactant: O=C1CCCCCN1
Reactant: C=CN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOC(C)=O
Product: C=CNC(=O)N1CCCCCC1=O
Temperature: 50 °C
Reaction time: 5 h

Procedure:
113 parts of ε-caprolactam, 91 parts of ethyl acetate and 0.015% of dibutyl-tin dilaurate are initially taken in a reaction vessel and are heated at about 50° C. A mixture of 69 parts of vinyl isocyanate and 91 parts of ethyl acetate is added dropwise in the course of 1 hour, after which the mixture is allowed to continue reacting for a further 5 hours. A pale yellow clear solution is obtained. Content of blocked isocyanate groups: 11.5%. Preparation of component (C)
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].C1C=CC=CC=1.C[C:15]1(C)[C:19]2(CS(O)(=O)=O)[C:20]([CH2:22][CH:16]1[CH2:17][CH2:18]2)=O.C(N(CC)CC)C>CN(C=O)C.O>[C:16]1([CH:15]2[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]2)[CH:22]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: OCC(CO)CO
Solvent: O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: OCC1COC(c2ccccc2)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 411.8 %

Procedure:
To a solution of 2-(hydroxymethyl)-1,3-propanediol (3.0 g) and dimethoxymethyl)benzene (6.36 ml) in DMF (50 ml) was added D-10-camphorsulfonic acid (1.31 g), and the mixture was stirred at ambient temperature overnight. To a reaction mixture were added triethylamine (1.18 ml) and water (150 ml) and the solution was extracted twice with ethyl acetate (150 ml). The extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (200 ml) eluting with a mixture of hexane and ethyl acetate (1:1 v/v). The fractions containing the object compound were collected and evaporated under reduced pressure to give (2-phenyl-1,3-dioxan-5-yl)methanol (4.51 g).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[H-].[Na+].Br[C:28]1[S:32][C:31]([C:33]2[CH:34]=[C:35]3[C:40](=[CH:41][CH:42]=2)[CH:39]=[N:38][CH:37]=[CH:36]3)=[N:30][N:29]=1>CN1CCCC1=O>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][C@H:3]([N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])[CH2:2][O:1][C:28]2[S:32][C:31]([C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][CH:42]=3)[CH:39]=[N:38][CH:37]=[CH:36]4)=[N:30][N:29]=2)=[CH:6]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H](CO)Cc1c[nH]c2ccccc12
Reactant: Brc1nnc(-c2ccc3cnccc3c2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1[C@H](COc1nnc(-c2ccc3cnccc3c2)s1)Cc1c[nH]c2ccccc12

Procedure:
(S)-2-(1-Hydroxy-3-(1H-indol-3-yl)propan-2-yl)isoindoline-1,3-dione (150 mg, 0.47 mmol) and 60% sodium hydride in mineral oil (37.6 mg, 0.94 mmol) was mixed in 2 ml N-methylpyrrolidinone. After stirring for ten minutes, compound 1b suspended in 2 ml N-methylpyrrolidinone was added and the reaction mixture was stirred at 20° C. for an hour. The reaction mixture was partitioned between ethylacetate and saturated aqueous ammonium chloride. The ethylacetate phase was washed with more saturated aqueous ammonium chloride and dried over anhydrous sodium sulfate. After removing the ethylacetate, the remaining residue was subjected to a silica gel column chromatography separation to yield the intermediate 2-((S)-3-(1H-indol-3-yl)-1-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yloxy)propan-2-yl)isoindoline-1,3-dione (3a). Compound 3a was dissolved in 4 ml ethyl alcohol, 0.5 ml water and 0.5 ml hydrazine monohydrate in a microwave heating tube. The tube was heated at 100° C. under microwave for five minutes. After removing all the solvent, the residue was subjected to a C18 reverse phase HPLC separation to yield (2S)-1-(1H-indol-3-yl)-3-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yloxy)propan-2-amine (3) (2.4 mg) as a TFA salt. 1H NMR (400 MHz, Methanol-d4): δ 3.08 (m, 1H), 3.12 (m, 1H), 3.58 (m, 2H), 3.74 (m, 1H), 7.33 (t, J=7.2 Hz, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 8.32 (m, 2H), 8.46 (d, J=8.8 Hz, 1H), 8.53 (m, 2H), 8.72 (s, 1H), 9.60 (s, 1H); MS (API-ES) m/z (%): 402 (95%, M++1), 424 (100%, M+Na+); HRMS (ESI): calculated for C22H19N5OS [M+1]: 402.1388; found: 402.1394.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[C:6]([O:10][C:11]([NH:13][OH:14])=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:1]([O:14][NH:13][C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NO
Product: CCC(=O)ONC(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino propanoate is prepared from propionyl chloride and N-tert-butoxycarbonyl hydroxylamine according to Scheme 1 described by Carpino et al. J. Am. Chem. Soc. 1959, 955-957. (3.4 g, 48%), 1H NMR (250 MHz, DMSO-d6) δ ppm 10.57 (1H, br. s.), 2.40 (2H, q, 7.5 Hz), 1.40 (9H, s), 1.07 (3H, t, 7.4 Hz).
Reaction SMILES: [B:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H](C(O)=O)N)=[CH:6][CH:5]=1)([OH:3])[OH:2].BrC1C=CC(C)=CC=1.C(OB(OCC)OCC)C>>[B:1]([C:4]1[CH:15]=[CH:14][C:7]([CH3:8])=[CH:6][CH:5]=1)([OH:3])[OH:2]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: CCOB(OCC)OCC
Agent: Cc1ccc(Br)cc1
Product: Cc1ccc(B(O)O)cc1

Procedure:
p-Boronophenylalanine can be synthesized by the scheme illustrated in FIG. 5D. Accordingly, from p-bromotoluene 81 by Grignard reaction and treatment with triethylborate at -78° C. followed by hydrolysis gave p-boronotoluene 82. This on bromination and oxidation gave 84 according to Snyder et al. (1958) J Am Chem Soc 80:835-838. Further treatment with N-methyldiethanolamine in THF afforded the cyclic boronate, which on reaction with ethylisocyanate and sodium hydride at -70°-20° C. gave (Z)-ethyl α-formyl cinnamate derivative 86. Catalytic hydrogenation of 86 gave boronophenylalanine ethyl ester derivative 87. Finally, 87 was treated with sodium hydroxide and HCl in one pot to afford boronophenylalanine.
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)(O)[O-].[Na+].[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][S:16][C@@H:17]2[CH2:21][NH:20][C@H:19]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18]2)=[CH:13][CH:12]=1.[Cl-].[Na+]>CN(C)C=O>[CH2:1]([N:20]1[CH2:21][C@@H:17]([S:16][CH2:15][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:27][CH:26]=2)[CH2:18][C@H:19]1[C:22](=[O:25])[NH:23][CH3:24])[CH3:2]
Reactant: CCI
Reactant: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C[C@@H](SCc2ccc(OC)cc2)C[C@H]1C(=O)NC
Reaction time: 1 h

Procedure:
0.71 ml of ethyl iodide and 742 mg of sodium bicarbonate were added to a solution of 2.25 g of (2S, 4S)-4-(4-methoxybenzylthio)-2-methylcarbamoylpyrrolidine dissolved in 20 ml of dry dimethylformamide, and the mixture was stirred at 0° to 5° C. for 1 hour and then at room temperature for 5 hours. At the end of this time, the reaction mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluted with ethyl acetate), to afford 1.87 g of the title compound as colorless crystals, melting at 68°-70° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16].CO.[BH4-].[Na+]>C1(C)C=CC=CC=1.[Na+].[Cl-].O>[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:25]2[CH:32]=[CH:31][C:28]([CH2:29][NH:1][C:2]3[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=3)[C:7]([O:9][CH3:10])=[O:8])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: COC(=O)c1cc(N)ccc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
A solution of methyl 5-amino-2-fluorobenzoate (1.20 g, 7.1 mmol, described in J. Chem. Soc. Perkin Trans. I, 1975, 1283-1284 and J. Org. Chem., 1990, 2034-2044) and 4-[(4-butylphenyl)ethynyl]benzaldehyde (1.95 g, 7.4 mmol, intermediate which may be obtained according to methods disclosed in EP03103780.7) in toluene (30 ml) was heated under reflux for 2.5 hrs with azeotropic removal of water. The reaction mixture was cooled down to 0° C., then MeOH (30 mL) and sodium borohydride (540 mg, 14.2 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min, then at rt for 1 hr. The reaction mixture was diluted with a saturated aqueous solution of NaCl (100 mL) and water (30 mL) and then extracted with Et2O (300 mL+50 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure. The residual brown gummy oil was taken up in MeOH (10 mL) and a white solid precipitated out. Filtration and washing with MeOH (2×) gave 2.23 g (76%) of the title compound as a white powder. HPLC, Rt: 5.8 min (purity: 98.2%). LC/MS, M−(ESI): 414.0. 1H NMR (CDCl3) δ: 7.51 (d, J=7.9 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.17 (m, 3H), 6.97 (m, 1H), 6.76 (m, 1H), 4.35 (s, 2H), 3.92 (s, 3H), 2.63 (t, J=7.8 Hz, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Br:8])[N:3]=1.[N:9]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CC(O)C>[Br:8][C:4]1[N:3]=[C:2]([N:12]2[CH2:13][CH2:14][CH2:15][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]2)[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCCN(c2cncc(Br)n2)CC1
Temperature: 120 °C
Yield: 94.6 %

Procedure:
A mixture of 2,6-dibromopyrazine (5.0198 mmol; 1194.1 mg), tert-butyl 1,4-diazepane-1-carboxylate (5.271 mmol; 1055.6 mg), and triethylamine (15.06 mmol; 1539 mg; 2.12 mL) in IPA (10 mL) in a sealed pressure vial was heated at 120° C. overnight. The mixture was cooled to room temperature, and then concentrated. The residue was purified on silica elute with 0 to 100% EtOAc in Heptane to afford tert-butyl 4-(6-bromopyrazin-2-yl)-1,4-diazepane-1-carboxylate (1.6965 g, 95%). MS (ESI) m/z: 357 [M+H]+
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([OH:11])=[O:10].Cl[C:16]1[C:25]2[C:20](=[C:21]([C:26]3[N:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH:38]([CH3:40])[CH3:39])=[C:33]([Cl:41])[CH:32]=4)[O:28][N:27]=3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1>C(Cl)Cl>[Cl:41][C:33]1[CH:32]=[C:31]([C:29]2[O:28][N:27]=[C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:20]=3[CH:19]=[CH:18][N:17]=[C:16]4[N:7]3[CH2:14][CH2:13][CH2:12][C@H:8]3[C:9]([OH:11])=[O:10])[N:30]=2)[CH:36]=[CH:35][C:34]=1[O:37][CH:38]([CH3:40])[CH3:39]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Cl)nccc34)no2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N5CCC[C@H]5C(=O)O)nccc34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
A mixture of sodium hydride (60%; 9.99 mg, 0.250 mmol), dimethyl sulfoxide (DMSO) (2 ml) and proline (36.0 mg, 0.312 mmol) were stirred at room temp under nitrogen for 1 hour. 1-Chloro-5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D7; 50 mg, 0.125 mmol) was added and the reaction mixture was heated at 120° C. under nitrogen for 3 hr. The cooled reaction mixture was loaded onto an SCX column. The column was washed with methanol and then eluted using 2M methanolic ammonia. The appropriate fractions were combined and the solvent was removed in vacuo to give an orange oil which was dissolved in DCM and washed with water. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give the title compound as an orange solid (40 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:23]([O:24][CH2:25][CH2:26][CH3:27])=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[CH2:25]([O:24][C:23]1[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:26][CH3:27]
Reactant: CCCOc1cccnc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CCCOc1cccnc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 22 h
Yield: 101.4 %

Procedure:
A 100 mL round bottom flask which contains 2-[(3-propoxy-pyridine-2-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (332, 620 mg, 1.68 mmol) is charged with 1,4-dioxane (6 mL) and MeOH (6 mL). A stirring bar is added and stirring is initiated. After dissolution, water (3 mL) is added followed by the LiOH monohydrate (178 mg, 4.25 mmol). After 22 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction flask. The reaction is capped and allowed to stir at ambient temperature. After 125 h, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+10 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides 0.58 g of white solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:22])[C:4]([C:6]1(O)[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:7]1)=O.Cl.[N-:24]=[C:25]=[O:26].[K+]>C(O)C>[C:17]([C:8]1[CH:7]=[C:6]([C:4]2[NH:24][C:25](=[O:26])[NH:2][C:3]=2[CH3:22])[CH:11]=[C:10]([C:12]([CH3:14])([CH3:15])[CH3:13])[C:9]=1[OH:16])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(N)C(=O)C1(O)C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C1
Reactant: [N-]=C=O
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1[nH]c(=O)[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 48 %

Procedure:
By following the same procedure as in Example 6 using 1.6 g of 4-(2-aminopropionyl)-2,6-di-tert-butyl-4-hydroxyphenol hydrochloride, 20 ml of ethanol, 0.5 ml of concentrated hydrochloric acid, 0.8 g of potassium isocyanate, a reaction product thus obtained was recrystallized from aqueous isopropanol to provide 0.7 g of 4-(3.5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-oxo-4-imidazoline.
Reaction SMILES: Cl.[CH2:2]([NH:10][NH2:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([O:17][CH3:18])(=[O:16])[C:13]([CH3:15])=O.CO>O>[CH2:2]([NH:10][N:11]=[C:13]([CH3:15])[C:12]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C(C)=O
Reactant: NNCCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)C(C)=NNCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3.6 g. Phenethylhydrazine hydrochloride and 2.0 g. methyl pyruvate are dissolved in 20 ml. methanol and left to stand at ambient temperature for 30 minutes, followed by cooling to 0° C., whereafter 30 ml. water are added thereto. 2.8 g. (61% of theory) methyl 2-(phenethylhydrazono)-propionate crystallizes out; m.p. 59°-60° C. (decomp.).
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[Cl:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41](O)=[O:42])=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:44])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41]([NH2:7])=[O:42])=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:44])=[CH:27][CH:26]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(Cl)cc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(Cl)cc3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with 2-(3-(4-chlorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp >200° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.46-7.37 (m, 6H), 4.47 (s, 2H), 4.03 (br s, 2H), 3.49-3.37 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 350.8 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:9]=2[CH3:18])=[C:5]([NH2:19])[NH:4][N:3]=1.O=[C:21]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[CH2:22][C:23]#[N:24]>C(O)(=O)C>[CH3:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[C:9]=2[CH3:18])=[C:5]2[N:19]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:22]=[C:23]([NH2:24])[N:4]2[N:3]=1
Reactant: N#CCC(=O)c1ccncc1
Reactant: Cc1n[nH]c(N)c1Cc1cccc(C(F)(F)F)c1C
Solvent: CC(=O)O
Product: Cc1nn2c(N)cc(-c3ccncc3)nc2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 140 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 3-methyl-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-5-amine (100 mg, 0.37 mmol) in acetic acid (2 mL) was added 3-oxo-3-(4-pyridinyl)propanenitrile (54.3 mg, 0.37 mmol). The reaction mixture was irradiated (microwave) and stirred at 140° C. for 40 minutes. Reaction mixture was cooled down, diluted with acetic acid (2 mL) and stood still overnight. Precipitate was collected by filtration. The crude product was purified with column chromatography to provide titled product. (23 mg, 16%); LC/MS: MS (ES+) m/e 398 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3H) 1.72 (s, 3H) 3.44 (s, 2H) 6.01 (s, 1H) 6.45 (d, J=7.58 Hz, 1H) 6.50-6.55 (m, 1H) 6.73 (d, J=7.58 Hz, 1H) 7.72-7.80 (m, 2H) 8.03-8.10 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:7][C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:27])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:12](=[O:21])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]2=[O:20])=[CH:7][C:6]=1[O:22][CH3:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)c1ccc(N2C(=O)c3ccccc3C2=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(N2C(=O)c3ccccc3C2=O)ccc1C(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
A mixture of 2-(4-tert-butyl-3-hydroxy-phenyl)isoindoline-1,3-dione (450 mg, 1.52 mmol), dimethyl sulfate (385 mg, 288 μL, 3.05 mmol), K2CO3 (632 mg, 4.57 mmol) in acetone (10 mL) was stirred at 50° C. for 3 h. The reaction was cooled to room temperature, filtered and washed with acetone (10 mL). The filtrate was concentrated in vacuo and the residue purified by silica gel chromatography (20% ethyl acetate/hexane) to provide 2-(4-tert-butyl-3-methoxyphenyl)isoindoline-1,3-dione (420 mg, 89% yield). 1H NMR (400.0 MHz, CDCl3) δ 7.72 (m, 2H), 7.55 (m, 2H), 7.15 (d, J=8.3 Hz, 1H), 6.72 (dd, J=2.1, 8.2 Hz, 1H), 6.68 (d, J=2.0 Hz, 1H), 3.61 (s, 3H), 1.15 (d, J=3.4 Hz, 9H).
Reaction SMILES: [CH3:1][C:2]([C:5]([CH2:7]Cl)=O)([CH3:4])[CH3:3].[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]([NH2:18])=[S:17])[CH2:12][CH2:11]1.C(OCC)C>C(O)C>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[S:17][CH:7]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[N:18]=2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)C(=O)CCl
Reactant: CN1CCN(C(N)=S)CC1
Solvent: CCO
Solvent: CCOCC
Product: CN1CCN(c2nc(C(C)(C)C)cs2)CC1

Procedure:
1.34 g of chloropinacoline are dissolved in 15 cc of absolute ethanol. After the addition of 1.6 g of 4-methyl-1-piperazinyl-thiocarboxamide, the mixture is heated to the boil on a water bath for 1 hour. Cooling is then effected and diethyl ether is added until the mixture remains turbid. The precipitated crystals are filtered off and recrystallized from ethanol. The resulting 2-(4-methyl-1-piperazinyl)-4-tert.butyl-thiazole hydrochloride has an M.P. of 206°. The base liberated from its hydrochloride in known manner by treatment with an aqueous sodium hydroxide solution has a B.P. of 97°-99°/0.2 mm Hg.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[I-].[Na+].[CH2:18](Cl)[C:19](=[CH2:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)[C:19](=[CH2:18])[CH3:21]
Reactant: C=C(C)CCl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)COc1ccc(C(=O)c2ccccc2)cc1

Procedure:
A mixture of 34 g of 4-hydroxybenzophenone, 1.0 g of sodium iodide, 18.7 ml of methallyl chloride, and 25 g of potassium carbonate in 350 ml of acetone was refluxed for 96 h. After cooling the reaction mixture was filtered, concentrated, dissolved in methylene chloride, washed with sodium hydroxide solution, washed with water, dried over magnesium sulfate, and concentrated to obtain crystalline product; 41.6 g; M.P.~85°-86.5° C.
Reaction SMILES: Cl.O1CCOCC1.[S:8]1[C:12]2[CH:13]=[C:14]([N:17]3[CH2:21][CH2:20][N:19]([C:22]4[CH:23]=[C:24]5[N:30]=[CH:29][N:28](OCC[Si](C)(C)C)[C:25]5=[N:26][CH:27]=4)[C:18]3=[O:38])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1.CO>C(Cl)Cl>[S:8]1[C:12]2[CH:13]=[C:14]([N:17]3[CH2:21][CH2:20][N:19]([C:22]4[CH:23]=[C:24]5[N:30]=[CH:29][NH:28][C:25]5=[N:26][CH:27]=4)[C:18]3=[O:38])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1
Reactant: C[Si](C)(C)CCOn1cnc2cc(N3CCN(c4ccc5ncsc5c4)C3=O)cnc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: O=C1N(c2cnc3[nH]cnc3c2)CCN1c1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 27.7 %

Procedure:
1,4-Dioxane HCl (5 ml) was added to 1-benzothiazol-6-yl-3-[3-(2-trimethylsilanyl-ethoxy)-3H-imidazo[4,5-b]pyridin-6-yl]-imidazolidin-2-one (I-183b: 100 mg, 0.2145 mmol) and the resulting mixture was stirred room temperature for 6 hours. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was concentrated and washed with diethyl ether. Purification by preparative HPLC afforded 20 mg of the product (25.4% yield).