Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1)(=O)C.[OH-].[Na+].CCOC(C)=O>CO>[O:9]1[C:8]2[CH:13]=[CH:14][C:5]([OH:4])=[CH:6][C:7]=2[O:12][CH2:11][CH2:10]1
Reactant: CC(=O)Oc1ccc2c(c1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1 g of 2,3-dihydro-1,4-benzodioxin-6-yl acetate (5.149 mmol) is dissolved in a solution of methanol (7.5 ml) and, under an argon atmosphere, the mixture is made basic, dropwise, with a 10% sodium hydroxide solution. The mixture is stirred at ambient temperature for 4 hours. At the end of the reaction, the methanol is evaporated and the reaction medium is acidified (to pH=1) with a 2N HCl solution and then washed with ethyl acetate. After extraction, drying over MgSO4 is carried out and the product is concentrated in vacuo. Purification on a silica column allows an oil to be obtained (eluant: PE/AcOEt 8/2 then 7/3).
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(OC(Cl)=O)C(C)C.[NH2:22][CH:23]1[C:30](=[O:31])[N:29]2[CH:24]1[S:25][CH2:26][C:27]([Cl:35])=[C:28]2[C:32]([OH:34])=[O:33].O1CCCC1.O>O1CCCC1.C(N(CC)CC)C>[N:1]1([CH2:10][C:11]([NH:22][CH:23]2[C:30](=[O:31])[N:29]3[CH:24]2[S:25][CH2:26][C:27]([Cl:35])=[C:28]3[C:32]([OH:34])=[O:33])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)Cn1ccc2ccccc21
Reactant: NC1C(=O)N2C(C(=O)O)=C(Cl)CSC12
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cn1ccc2ccccc21)NC1C(=O)N2C(C(=O)O)=C(Cl)CSC12
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
(1H-Indol-1-yl)acetic acid (0.05 m) is added to tetrahydrofuran. The temperature is lowered to about -10° C. and 1 equivalent of isobutylchloroformate in tetrahydrofuran is added. This mixture is stirred for about 30 minutes. A solution of 7-amino-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 1:1 tetrahydrofuran/water containing 1 equivalent of triethylamine is added to the previously formed solution maintained at -10° C. The resulting solution is stirred for about 60 minutes at -10° C. to 0° C. and then stirred for 60 minutes at 30° C. to 30° C. The solvents are removed at reduced pressure to give a residue which is extracted with ethyl acetate. The ethyl acetate is dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].[CH2:11]=[O:12].[OH-:13].[K+].[CH3:15]N(C)C=O>O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:11]([OH:12])[CH3:15])([O-:2])=[O:13].[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2]
Reactant: C=O
Reactant: CN(C)C=O
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1[N+](=O)[O-]
Product: CC(O)c1ccccc1[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 1.5 h

Procedure:
A mixture of 137 g (1 mole) of o-nitrotoluene, 120 g of paraformaldehyde, 34 g of potassium hydroxide and 500 ml of dimethyl formamide containing 0.7% by weight of water is stirred at 30° C. for 1.5 hours and then at 55° C. for 1 hour. The reaction mixture is processed as described in Example 1 to obtain 35 g of o-nitrophenylethanol, 20 g of o-nitrotoluene and 35 g of bis-methylol compounds. The bis-methylol compounds were identified by gas chromatographical mass spectrum (GCMS) analysis.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>CO.C(OCC)C>[Cl:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ncc(Cl)nc1Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1ncc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of 3,5-dichloropyrazine-2-carboxylic acid (0.304 g, 1.58 mmol) in MeOH (5 mL) and diethyl ether (5 mL) at room temperature was added (trimethylsilyl)diazomethane (2.0 M solution in hexanes, 4.00 mL, 8.00 mmol). The reaction mixture was stirred at RT for 30 min and concentrated. Purification by flash column chromatography on silica gel (5% to 20% EtOAc in hexanes) gave methyl 3,5-dichloropyrazine-2-carboxylate (0.312 g, 1.51 mmol, 96% yield) as a white solid. LC/MS
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30]Br>>[CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[N:9]1[CH2:28][O:29][CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCBr
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(Cc3ccccc3)c2=O)cn1
Product: COCn1c(=O)n(-c2cnn(Cc3c(C)noc3C)c2)c(=O)n1Cc1ccccc1
Yield: 18 %

Procedure:
Prepared as in example 10-91 from 1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,2,4-triazolidine-3,5-dione (example 10-91a) and bromomethyl methyl ether. Yield: 18%. MS M+H calculated 411.17. Found 411.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.02 μM.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[O:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.O.[C:15]([O:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](CCC=C)[N:24]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>[Os](=O)(=O)(=O)=O>[OH:5][CH:12]([CH2:13][OH:9])[CH2:11][CH2:10][C:25]1[N:24]=[C:23]([NH:22][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH:28]=[CH:27][CH:26]=1
Reactant: C1CCOC1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCCc1cccc(NC(=O)OC(C)(C)C)n1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(CCC(O)CO)n1
Reaction time: 18 h

Procedure:
To a stirring solution of 4-methylmorpholine N-oxide(2.1 eq) and osmium tetraoxide (2.5 eq) in tetrahydrofuran/water (5 eq/1 eq) was added (tert-butoxy)-N-(6-but-3-enyl(2-pyridyl))carboxamide (1.0 eq) at 25° C. and stirred for 18 hr. The reaction was quenched with solution of sodium bisulfate (0.5M) and sodium sulfite (1M) and stirred for 30 mins. The reaction was poured into a brine and extracted with ethyl acetate. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (50% EtOAc/Hexane). EI-MS m/z 283(M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Br)[C:5](Br)([CH3:7])[CH3:6].[CH3:11][O:12][C:13](=[O:17])[CH2:14][C:15]#[N:16].C[O-].[Na+].O>CO.CCOCC>[CH3:11][O:12][C:13]([C:14]1([C:15]#[N:16])[C:5]([CH3:7])([CH3:6])[CH:4]1[C:3]([O:2][CH3:1])=[O:10])=[O:17]
Reactant: COC(=O)CC#N
Reactant: COC(=O)C(Br)C(C)(C)Br
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1C(C)(C)C1(C#N)C(=O)OC
Temperature: 64 °C
Yield: 56.8 %

Procedure:
27.2 g (0.1 mol) of α,β-dibromo-isovaleric acid methyl ester were added dropwise to a solution of 19.9 g (0.2 mol) of cyanoacetic acid methyl ester and 10.8 g (0.2 mol) of sodium methylate in 50 ml of methanol at 20° C. The mixture was then heated to 64° C. for 5 hours. The solvent was then stripped off in vacuo. 100 ml of water and 100 ml of ether were added to the residue. The ether phase was separated off, dried over sodium sulphate and evaporated. The residue was fractionated twice. 12 g (57% of theory) of 3,3-dimethyl-1-cyano-cyclopropane-1,2-dicarboxylic acid dimethyl ester were obtained in the form of a colorless oil of boiling point 152° C./10 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12][C:13]1[C:14]([F:23])=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>CN(C1C=CN=CC=1)C>[Cl:12][C:13]1[C:14]([F:23])=[C:15]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1F
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1cccc(Cl)c1F
Yield: 33.9 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.70 mmol), 3-chloro-2-fluorobenzenesulfonyl chloride (180 mg, 0.83 mmol) and DMAP (cat.) gave the title compound (80 mg, 35%) after purification by column chromatography with DCM as the eluent followed by trituration from EtOAc/n-hexane.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[S:14]1[C:18]2[CH:19]=[C:20]([C:23]([N:25]3[CH2:32][CH2:31][C:30]4([C:34]([NH2:36])=O)[CH2:33][CH:26]3[CH2:27][C:28]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][C:29]=34)=[O:24])[CH:21]=[CH:22][C:17]=2[N:16]=[CH:15]1.C(N(C(C)C)C(C)C)C>ClCCl>[S:14]1[C:18]2[CH:19]=[C:20]([C:23]([N:25]3[CH2:32][CH2:31][C:30]4([C:34]#[N:36])[CH2:33][CH:26]3[CH2:27][C:28]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][C:29]=34)=[O:24])[CH:21]=[CH:22][C:17]=2[N:16]=[CH:15]1
Reactant: NC(=O)C12CCN(C(=O)c3ccc4ncsc4c3)C(Cc3ccc(O)cc31)C2
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N#CC12CCN(C(=O)c3ccc4ncsc4c3)C(Cc3ccc(O)cc31)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trifluoroacetic anhydride (43 μL) is added to a solution of 3-(benzothiazole-6-carbonyl)-8-hydroxy-2,3,4,5-tetrahydro-1H-2,6-methano-benzo[d]azocine-6-carboxylic acid amide (40 mg) and ethyldiisopropylamine (50 μL) in dichloromethane (0.5 mL) chilled in an ice bath. The ice bath is removed and the solution is stirred at ambient temperature for 4 h. Then, another portion of trifluoroacetic anhydride (43 μL) and ethyldiisopropylamine (50 μL) are added and the solution is stirred overnight. Methanol (1 mL) is added and the solution is stirred for another 10 min. The solution is concentrated under reduced pressure and the residue is purified by HPLC on reversed phase (water/MeCN) to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5]2[CH:14]=[CH:15][C:16]([C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])=[CH:17][C:4]=2[S:3]1.Br[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C>CO>[O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:9][CH2:10][N:11]([C:27]3[N:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH2:12][CH2:13]2)[C:5]2[CH:14]=[CH:15][C:16]([C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])=[CH:17][C:4]=2[S:3]1
Reactant: Brc1ncccn1
Reactant: N#Cc1ccccc1-c1ccc2c(c1)sc(=O)n2CC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN1CCCC1=O
Product: N#Cc1ccccc1-c1ccc2c(c1)sc(=O)n2CC1CCN(c2ncccn2)CC1
Temperature: 100 °C

Procedure:
To a microwave vial was added 2-[2-oxo-3-(piperidin-4-ylmethyl)-2,3-dihydro-1,3-benzothiazol-6-yl]benzonitrile (11-3) (0.029 g, 0.075 mmol), 2-bromopyrimidine (0.0143 g, 0.090 mmol), NMP (0.7 mL), and DIPEA (0.033 mL, 0.188 mmol). The reaction mixture was then heated under microwave irradiation at 100° C. for 10 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted with methanol, filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) gave 2-{2-oxo-3-[(1-pyrimidin-2-ylpiperidin-4-yl)methyl]-2,3-dihydro-1,3-benzothiazol-6-yl}benzonitrile (11-4) as a brown solid. HRMS (M+H)+: observed=428.1544, calculated=428.1540.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:17]3=[O:41])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:42].[CH:43]1[C:48](O)=[CH:47][CH:46]=[C:45]([CH3:50])[CH:44]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(N=NC(OCC)=O)=O>C(OCC)(=O)C.C1COCC1>[CH3:50][C:45]1[CH:46]=[CH:47][C:48]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[C:10]([CH2:15][CH:16]4[S:20][C:19](=[O:21])[NH:18][C:17]4=[O:41])[CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:42])=[CH:43][CH:44]=1
Reactant: O=C1CCc2c(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cccc2N1CCCO
Reactant: Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(OCCCN2C(=O)CCc3c(CC4SC(=O)NC4=O)cccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
A THF solution (2 ml) of 100 mg (0.18 mmol) of 5-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]-3-trityl thiazolidine-2,4-dione, 0.0363 ml (0.347 mmol) of p-cresol, and 91.1 mg (0.35 mmol) of triphenylphosphine was cooled with ice. 0.158 ml of azodicarboxylic acid diethyl (2.2 M toluene solution) was added to the solution in an argon atmosphere. The mixture was stirred at room temperature for two hours, and ethyl acetate was added to the reaction liquid. After washing with water, the organic layer was concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure, and 2 ml of a solution of 4N-hydrogen chloride/ethyl acetate was added to the residue. The mixture was stirred at room temperature overnight, and further stirred at 70° C. for 1.5 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure and evaporated to dryness, giving 27.1 mg (34.4% yield) of 5-{1-[3-(4-methylphenoxy)propyl]-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl}thiazolidine-2,4-dione as a colorless amorphous solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][OH:13].C(N(CC)CC)C.[CH3:21][O:22][C:23]([CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])=[O:24].Cl>C1COCC1.O>[OH:13][N:12]([CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:23]([O:22][CH3:21])=[O:24]
Reactant: COC(=O)CCCC(=O)O
Reactant: ONCc1ccc2ccccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCC(=O)N(O)Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Into a solution of 52 mg (0.3 mmol) of 2-naphthylmethylhydroxylamine in THF (5 ml) and water (1 ml) was added 30 mg (0.3 mmol) of triethylamine, and then a solution of 49 mg (0.3 mmol) of acid chloride of 4-methoxycarbonylbutanoic acid in THF (1 ml), followed by stirring at room temperature for 30 minutes. 1N-HCl (5 ml) was added and the desired product was extracted with methylene chloride. The extract was successively washed with water, aqueous NaCl, and then dried over anhydrous magnesium sulfate to give a purified product, which was then subjected to silica gel column chromatography to obtain 58 mg (64%) of the desired product.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH2:29]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[CH3:30].[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:29][CH3:30])=[CH:32][CH:33]=1)[CH3:28]
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(Oc2ccc(CC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 67.4 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.8 g), 4-ethylphenol (0.34 g), 8 M potassium hydroxide solution (0.34 mL) and dimethyl sulfoxide (10 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.59 g, 67%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:20]1CCOCC1.ClC(OCC)=O>C(Cl)Cl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:18])[NH2:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: NC(=O)C1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (30.0 g, 121 mmol) was dissolved in DCM (180 mL). The solution was cooled to 0° C. and N-methyl-morpholine (12.8 g, 127 mmol) was added over a period of 10 mins. The solution was then cooled to −15° C. and the ethyl chloroformate (13.7 g, 126 mmol) in DCM (30 mL) was added dropwise. The solution was then stirred for 2 hours at −25° C. Next, the solution was placed under NH3 (g) while maintaining the temperature below −20° C. The reaction mixture was then stirred for 1 hour while allowing the temperature to return to 0° C. The solution was poured in H2O (120 mL) and the organic layer was partitioned from the aqueous layer. The organic layer was then washed with 1N HCl (2×50 mL), 1N NaHCO3 (2×50 mL), dried over MgSO4 and concentrated under vacuo to afford 27.8 g (88%) of 2-carbamoyl-pyrrolidine-1-carboxylic acid benzyl ester, as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][CH2:11][CH:12]=[CH2:13].[C:14]12([C:24](O)=[O:25])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>>[CH2:10]([N:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5]/[C:4]/1=[N:8]\[C:24]([C:14]12[CH2:23][CH:18]3[CH2:17][CH:16]([CH2:22][CH:20]([CH2:19]3)[CH2:21]1)[CH2:15]2)=[O:25])[CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCBr
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1nc(N)sc1C
Product: C=CCCn1c(C)c(C)s/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2

Procedure:
4,5-Dimethylthiazol-2-ylamine, 4-bromo-but-1-ene and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 1.60-1.76 (m, 6H) 1.85 (d, J=2.50 Hz, 6H) 1.94-2.04 (m, 3H) 2.15 (s, 3H) 2.20 (s, 3H) 2.46 (q, J=7.18 Hz, 2H) 4.16 (t, 2H) 4.94-5.13 (m, 2H) 5.75-5.90 (m, 1H); MS (ESI) m/z 345 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([C:11]([OH:13])=O)[CH2:5]2.[NH2:14][C:15]([CH3:19])([CH3:18])[CH2:16]O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([C:11]1[O:13][CH2:16][C:15]([CH3:19])([CH3:18])[N:14]=1)[CH2:5]2
Reactant: O=C(O)C1Cc2ccc(Br)cc2C1
Reactant: CC(C)(N)CO
Solvent: Cc1ccccc1C
Product: CC1(C)COC(C2Cc3ccc(Br)cc3C2)=N1
Yield: 63 %

Procedure:
3.9 g of 5-bromo-2-indancarboxylic acid and 2 g of 2-amino-2-methyl-1-propanol were added to 100 ml of xylene. The mixture was heated under reflux for 24 hours while removing the water produced. The reaction mixture was concentrated in vacuo and 20 ml of water was added to the residue. The mixture was extracted with chloroform. The extract was washed with water, dried and then concentrated in vacuo. The residue was purified by silica gel column chromatography to give 3 g of 2-(5-bromoindan-2-yl)-4,4-dimethyloxazoline as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.[C:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C(#N)C.CCOC(C)=O>[N+:12]([C:8]1[C:6]2[N:7]=[C:3]([CH2:2][N:34]3[CH2:33][CH2:32][N:31]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:36][CH2:35]3)[O:4][C:5]=2[CH:11]=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2oc(CCl)nc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2nc3c([N+](=O)[O-])cccc3o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To room temperature solution of 2-(Chloromethyl)-4-nitrobenzo[d]oxazole (5.15 g, 24.2 mmol, 1.0 equiv) and DIPEA (4.2 mL, 24.2 mmol, 1.0 equiv) in dry acetonitrile (119 mL) was added N-Boc piperazine as a solid in one portion. The reaction was stirred at room temperature overnight. The mixture was diluted with EtOAc (120 mL), washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification on silica gel (20% EtOAc/80% hexanes—100% EtOAc) provided the title compound as a yellow solid (7.0 g, 68%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5](Br)=[CH:4][C:3]=1[CH3:10].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:26][CH2:27]O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:11]1([C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([C:27]3[CH:26]=[CH:4][CH:3]=[CH:2][CH:7]=3)=[CH:4][C:3]=2[CH3:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCO
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Br)c(C)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccccc2)c(C)cc1-c1ccccc1
Temperature: 90 °C
Yield: 84 %

Procedure:
A mixture of 52.8 g (200 mmol) of 1,4-dibromo-2,5-Dimethyl benzene, 53.6 g (440 mmol) of phenylboronic acid, 2.3 g (2 mmol) of tetrakis(triphenylphosphine)palladium, 400 ml of 2M Na2CO3, 400 ml of EtOH and 800 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 6 hours. After the reaction finish, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product 43.4 g (168 mmol, 84%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]1[CH:30]=[C:18]2[N:19]=[C:20]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=[C:22]([NH2:23])[N:17]2[N:16]=1.CCN(CC)CC>CC#N>[CH3:9][C:4]1[C:3]([CH2:2][N:27]2[CH2:26][CH2:25][N:24]([C:20]3[N:21]=[C:22]([NH2:23])[N:17]4[N:16]=[C:15]([C:11]5[O:10][CH:14]=[CH:13][CH:12]=5)[CH:30]=[C:18]4[N:19]=3)[CH2:29][CH2:28]2)=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: Nc1nc(N2CCNCC2)nc2cc(-c3ccco3)nn12
Reactant: Cc1noc(C)c1CCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1noc(C)c1CN1CCN(c2nc(N)n3nc(-c4ccco4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Chloromethyl-3,5-dimethyl-isoxazole (1.5 eq.) was directly added to a solution of 7-furan-2-yl-2-piperazin-1-yl-pyrazolo[1,5-a][1,3,5]triazin-4-ylamine (0.14 mmol) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.60 (d, J=1.0 Hz, 1 H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1 H), 6.2 (s, 1H) 3.8 (br s, 2H), 2.2-3.2 (m, 8H), 1.6 (br s, 6H). MS: m/z: 395 [M+H]+.