Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[CH3:17][C:18]1[NH:22][C:21]([C:23](O)=[O:24])=[N:20][C:19]=1[C:26]([F:29])([F:28])[F:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH3:17][C:18]1[NH:22][C:21]([C:23]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:24])=[N:20][C:19]=1[C:26]([F:29])([F:27])[F:28]
Reactant: Cc1[nH]c(C(=O)O)nc1C(F)(F)F
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(C(F)(F)F)c(C)[nH]1

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.22 g, 0.96 mmol), 5-methyl-4-(trifluoromethyl)-1H-imidazole-2-carboxylic acid obtained in Example (36d) (0.10 g, 0.51 mmol), WSC hydrochloride (0.30 g, 1.57 mmol) and HOBT (70 mg, 0.52 mmol), to obtain 0.17 g of the title compound as a white foamy substance (83%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][O:27][C:28](=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][OH:44])=[O:24].N1C=CC=CC=1>C(Cl)Cl>[Cl:6][CH2:5][O:4][C:2]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][O:27][C:28](=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:2]([O:4][CH2:5][Cl:6])=[O:3])=[O:24])=[O:3]
Reactant: O=C(CCCCCCCCCCCCCCCO)OCOC(=O)CCCCCCCCCCCCCCCO
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCCCCCCCCCCCCCCOC(=O)OCCl)OCOC(=O)CCCCCCCCCCCCCCCOC(=O)OCCl
Temperature: 0 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
Chloromethyl chloroformate (0.93 g, 7.2 mmol) was added to an ice-cooled solution of methylene bis(16-hydroxyhexadecanoate) (2.0 g, 3.6 mmol) in methylene chloride (80 ml). Pyridine (0.57 g, 7.2 mmol) was added and the reaction mixture was stirred for 15 minutes at 0° C. and 4 hours at room temperature The reaction mixture was washed with hydrochloric acid (1M, 50 ml) saturated aqueous sodium bicarbonate (50 ml), water (50 ml) and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography (silica/methylene chloride). Yield: 84% 1H NMR (200 MHz, CDCl3): δ 1.25 (m, 44H), 1.72 (m, 8H), 2.31 (t, 4H), 4.20 (t, 4H), 5.72 (m, 6H).
Reaction SMILES: Br[C:2]([CH3:8])([CH3:7])[C:3]([NH:5][CH3:6])=[O:4].[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C1(C)C=CC=CC=1.[Ag]=O>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][N:19]([C:2]([CH3:8])([C:3](=[O:4])[NH:5][CH3:6])[CH3:7])[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CNC(=O)C(C)(C)Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=[Ag]
Solvent: Cc1ccccc1
Product: CNC(=O)C(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 93.2 %

Procedure:
A mixture of 2-bromo-2, N-dimethyl-propionamide (312 mg), 1-BOC-piperazine (323 mg) and silver oxide (800 mg) was stirred in toluene (5 mL) at reflux. After 24 h the reaction mixture was cooled, filtered through celite, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent was removed in vacuo to yield 4-(1-methyl-1-methylcarbamoyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (461 mg). Removal of the BOC group with HCl yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:13]([F:20])=[C:14]([OH:19])[CH:15]=[C:16]([F:18])[CH:17]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:25]=O.C(O)(=O)C>CCO>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[C:17]3[C:16]([F:18])=[CH:15][C:14]([OH:19])=[C:13]([F:20])[C:12]=3[C:3]3[C:4]([CH3:11])=[N:5][N:6]([C:7]([CH3:9])([CH3:10])[CH3:8])[C:2]=3[N:1]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: Cc1nn(C(C)(C)C)c(N)c1-c1cc(F)cc(O)c1F
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nn(C(C)(C)C)c2nc(-c3ccc(OCc4ccccc4)c(Cl)c3)c3c(F)cc(O)c(F)c3c12
Temperature: 120 °C
Reaction time: 4.5 h
Yield: 46.6 %

Procedure:
To 3-[5-amino-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-4-yl]-2,5-difluorophenol (0.050 g, 0.178 mmol) and 3-chloro-4-[(phenylmethyl)oxy]benzaldehyde (0.044 g, 0.178 mmol) was added acetic acid (1 mL). The mixture was stirred at 120° C. for 4.5 h and then concentrated in vacuo to afford a residue which was co-evaporated with EtOH (2×) to afford a film which was purified by column chromatography (ether-dichloromethane 1:20) to afford 5-{3-chloro-4-[(phenylmethyl)oxy]phenyl}-3-(1,1-dimethylethyl)-6,9-difluoro-1-methyl-3H-pyrazolo[3,4-c]isoquinolin-8-ol as a light brown foam (0.042 g, 0.083 mmol, 47% yield). 1H NMR (400 MHz, CDCl3): 7.63 (t, 1H), 7.55-7.51 (m, 2H), 7.46-7.34 (m, 5H), 7.06 (d, 1H), 6.86 (dd, 1H), 5.25 (s, 2H), 2.81 (d, 3H), 1.84 (s, 9H); MS (EI) for C28H24ClF2N3O2: 508 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2].I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=C3C=2C(C2C4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C=CC=2)=CC=C3)C=CC=CC=1>[CH2:1]([NH:3][C:4]1[C:9]([NH:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: Ic1ccccc1
Reactant: CCNc1ncccc1N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCNc1ncccc1Nc1ccccc1
Yield: 34.1 %

Procedure:
N2-ethylpyridine-2,3-diamine (16.00 g, 117 mmol) and iodobenzene (19.61 mL, 175 mmol) were suspended in 300 mL of toluene. 8,8′-Bis(diphenylphosphino)-1,1′-binaphthalene (BINAP) (2.179 g, 3.50 mmol) and Pd2 dba3 (2.136 g, 2.333 mmol) were added, followed by sodium 2-methylpropan-2-olate (16.81 g, 175 mmol). The reaction flask was filled with nitrogen, stirred and refluxed overnight. The reaction mixture was cooled down, filtered through a silica plug and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate 4/1) to provide N2-ethyl-N3-phenylpyridine-2,3-diamine as a brown solid (8.5 g, 34%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[C:14](Cl)(=O)[C:15](Cl)=O.C(O)C>ClC(Cl)C.CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Br)cc2nc[nH]c12
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(Br)cc2nc[nH]c12
Reaction time: 0.17 h

Procedure:
To a suspension of crude 5-Bromo-1H-benzo[d]imidazole-7-carboxylic acid (247 mg, 0.81 mmol, 77% pure) in dichloroethane under N2 with stirring was added oxalyl chloride (0.5 mL, 5.6 equiv). Added one drop of DMF as catalyst. After 10 min, the suspension was treated with another 0.5 mL of oxalyl chloride. After 2.5 h, when effervescence ceased, added another 0.5 mL portion of oxalyl chloride and 2 drops of DMF and continued the reaction for another 1.5 h. The reaction mixture was added to 50 mL of ethanol carefully. The ethanol solution was maintained at ambient temperature for 30 min. It was then evaporated in vacuo. The residue was partitioned between EtOAc (75 mL) and satd aqueous bicarbonate (100 mL). The organic layer was washed with water (50 mL), dried (Na2SO4) and evaporated in vacuo. The crude product was coevaporated with hexane (50 mL). A suspension of the residual solid in hexane (50 mL) was filtered and washed with another 20 mL more hexane to give 200 mg. The crude product itself was used for subsequent reactions. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.53 (s, 1 H), 8.20 (s, 1 H), 7.93 (s, 1 H), 4.45 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H). 269(MH)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2.[O:14]=[C:15]1[NH:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:12]([C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([N:20]3[CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:16][C:15]3=[O:14])[N:3]=[CH:4]2)=[CH:9][CH:8]=1)#[N:13]
Reactant: N#Cc1ccc2cc(Cl)ncc2c1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cc3ccc(C#N)cc3cn2)C(=O)C1
Temperature: 100 °C

Procedure:
To a flask charged with 3-chloroisoquinoline-7-carbonitrile (250 mg, 1.3 mmol) and a stir bar was added tert-butyl 3-oxopiperazine-1-carboxylate (400 mg, 2.0 mmol), Pd2(dba)3 (120 mg, 0.13 mmol), Xantphos (150 mg, 0.26 mmol), cesium carbonate (650 mg, 2.0 mmol), and dioxane (20 mL). The mixture was purged three times with nitrogen, and heated to 100° C. for 16 hours. The mixture was diluted with EtOAc, washed with brine, dried over sodium sulfate, adsorbed onto silica gel, and purified by silica gel chromatography (Hexanes:EtOAc) to provide tert-butyl 4-(7-cyanoisoquinolin-3-yl)-3-oxopiperazine-1-carboxylate. LC-MS (IE, m/z): 353 [M+1]+.
Reaction SMILES: Br[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[Mg].[Cl:11][CH2:12][C:13]([C:15]1([Cl:18])[CH2:17][CH2:16]1)=[O:14].[Cl-].[NH4+]>C(OCC)C.O>[Cl:11][CH2:12][C:13]([C:15]1([Cl:18])[CH2:17][CH2:16]1)([OH:14])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3]
Reactant: O=C(CCl)C1(Cl)CC1
Reactant: C=C(Br)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: C=C(c1ccccc1)C(O)(CCl)C1(Cl)CC1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
##STR20## A solution of 5 g (25 mmol) of α-bromostyrene in 10 ml of absolute diethyl ether is added dropwise to a mixture of 0.7 g (30 mmol) of magnesium filings and 10 ml of diethyl ether under an argon atmosphere and with stirring at room temperature. After the addition has ended, the reaction mixture is refluxed for 1 hour. The resulting Grignard solution is added dropwise at room temperature with stirring to a solution of 3 g (20 mmol) of 1-chlorocyclopropyl chloromethyl ketone in 10 ml of diethyl ether. After the addition has ended, the mixture is refluxed for another 4 hours. The reaction mixture is subsequently treated with a saturated, aqueous ammonium chloride solution, the resulting mixture is poured into water, and this mixture is extracted repeatedly using diethyl ether. The combined organic phase are washed with saturated, aqueous sodium chloride solution, dried over sodium sulphate, and then concentrated by stripping off the solvent under reduced pressure. 5.0 g (97% of theory) of 1-chloro-2-(1-chlorocyclopropyl)-3-phenyl-but-3-en-2-ol are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[NH:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:16][C:17](C)([O-])[CH3:18].[K+].BrCCC.O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:15])[N:5]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH2:16][CH2:17][CH3:18])[CH3:2]
Reactant: CCOC(=O)Nn1ccc2ccccc21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCBr
Product: CCCN(C(=O)OCC)n1ccc2ccccc21
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a suspension of NaHCO3 (50 g) in 100 ml dichloromethane (DCM) was added a solution of 1H-indol-1-amine (36 g) in 200 ml DCM. After cooling to 0° C. with an ice bath, a solution of ethyl chloroformate (29 ml) in 50 ml DCM was added over a period of thirty minutes. After stirring at ambient temperature for three hours, the mixture was filtered, and the filtrate washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to an oil which was eluted on a silica gel column with DCM, via HPLC to give N-(1H-indol-1-yl) carbamic acid ethyl ester, 33.6 g (61%) as an oil. To a cold solution of N-(1H-indol-1-yl) carbamic acid ethyl ester (15 g) in 100 ml tetrahydrofuran, was added potassium t-butoxide (9 g) and the mixture stirred at 5° C. for one hour. To this was added 1-bromopropane (7.3 ml) and the mixture stirred at ambient temperature for five hours. The mixture was poured into 300 ml iced-water, stirred for five minutes, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated, NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to give N-(1H-indol-1-yl)-N-propylcarbamic acid ethyl ester as an oil, 16.5 g (91%). To a solution of N-(1H-indol-1-yl)-N-propylcarbamic acid ethyl ester (16.5 g) in 35 ml ethylene glycol, was added a solution of NaOH (10 g) in 30 ml water. After stirring at 120° C. for four hours, the mixture was poured into 300 ml ice water, stirred for five minutes, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to give N-(1H-indol-1-yl)-N-propylamine, 9.0 g (78%) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH2:19][C:20]2[C:28]3[C:23](=[N:24][N:25]=[CH:26][CH:27]=3)[NH:22][N:21]=2)=[CH:4][CH:3]=1.[CH2:29]=[O:30]>CO>[Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH2:19][C:20]2[C:28]3[C:23](=[N:24][N:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][OH:30])[N:21]=2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(Cc3n[nH]c4nnccc34)c2F)c1
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(Cc3nn(CO)c4nnccc34)c2F)c1
Temperature: 67 °C
Reaction time: 35 h

Procedure:
step 1—A suspension of 3-[6-bromo-2-fluoro-3-(1H-pyrazolo[3,4-c]pyridazin-3-ylmethyl)-phenoxy]-5-chloro-benzonitrile (R-73, 1.32 g, 2.88 mmol), 37% aqueous formaldehyde (100 mL) and MeOH (100 mL) was stirred at 67° C. for 35 h. The volatile solvents were evaporated and the residue diluted with H2O and the resulting precipitate filtered, washed with H2O and air-dried to afford 1.27 g of 3-[6-bromo-2-fluoro-3-(1-hydroxymethyl-1H-pyrazolo[3,4-c]pyridazin-3-ylmethyl)-phenoxy]-5-chloro-benzonitrile (12).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[O:15])([CH3:3])[CH3:2].C[Si]([N:20]=[N+:21]=[N-:22])(C)C.C1(C)C=CC=CC=1>O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[N:13]1[C:14](=[O:15])[NH:22][N:21]=[N:20]1)([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1-n1nn[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
37.1 g of 2,6-diisopropylphenyl isocyanate and 50 ml of trimethylsilyl azide are stirred for 24 hours at +140° C. The mixture is then cooled to room temperature and stirred with 250 ml of toluene and with 250 ml of water. After 1 hour, the phases are separated and the aqueous phase is extracted with toluene. The combined organic phases are extracted four times with 250 ml of 15% sodium hydroxide solution each time, and then the aqueous phases are combined and washed with ether. After acidification with semi-concentrated hydrochloric acid, crude 1-(2,6-diisopropylphenyl)-5-oxo-2-tetrazoline precipitates. This is recrystallised from a mixture of hexane and toluene in a ratio of 10:1. Melting point 177°-178.5°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([S:11]([NH:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])(=[O:13])=[O:12])[N:10]=[C:4]2[N:3]=1.[Br:23]N1C(=O)CCC1=O>C(O)(=O)C.C(OC(=O)C)(=O)C>[Br:23][C:7]1[C:2]([CH3:1])=[N:3][C:4]2[N:5]([N:8]=[C:9]([S:11]([NH:14][C:15]3[C:16]([Cl:22])=[CH:17][CH:18]=[CH:19][C:20]=3[Cl:21])(=[O:13])=[O:12])[N:10]=2)[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccn2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1nc2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn2cc1Br
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4.0 g (11 mmol) of 5-methyl-N-(2,6-dichlorophenyl)-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide in 50 ml of glacial acetic acid and 10 ml of acetic anhydride was stirred at 90° C. for 30 minutes. N-Bromosuccinimide (2.4 g, 13 mmol) was added to this hot solution, and the reaction mixture was stirred at 90° C. for 60 minutes. The solution was cooled and poured into 200 ml of ice water. A solid which separated was collected and dried. This crude product was purified by dissolving the sample in methylene chloride, filtering the solution through silica gel and triturating the fitrate with pentane. The desired product was obtained as a solid, m.p. 215°-216° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][N:8]2[C:10]([CH3:14])=[C:11]([CH3:13])[N:12]=[C:7]2[C:6](=O)[CH2:5]1.[NH2:16][C@H:17]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@@H:18]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C:19](OCC)=[O:20].C([N-]C(C)C)(C)C.[Li+].[Cl-].[NH4+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCC1.C1(C)C=CC=CC=1.O>[Si:25]([O:24][C@H:18]1[C:19](=[O:20])[C:5]2[CH:4]([CH2:3][O:2][CH3:1])[CH2:9][N:8]3[C:10]([CH3:14])=[C:11]([CH3:13])[N:12]=[C:7]3[C:6]=2[NH:16][C@@H:17]1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@H](N)c1ccccc1
Reactant: COCC1CC(=O)c2nc(C)c(C)n2C1
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COCC1Cn2c(nc(C)c2C)C2=C1C(=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](c1ccccc1)N2
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
By using a water separator, a mixture of 2.66 g of 6-methoxymethyl-2,3-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-one, 4.27 g of ethyl (2R, 3R)-3-amino-2-(t-butyldimethylsilyloxy)-3-phenylpropionate, 70 mg of p-toluenesulfonic acid and 15 ml of toluene is boiled at reflux for 1.5 h. After cooling, 15 ml of tetrahydrofuran are added. With introduction of argon, the mixture is cooled to an internal temperature of −25° C. 15.4 ml of a commercial 2 molar solution of lithium diisopropylamide (Aldrich) are then added. The solution is stirred at −25° C. for 30 min. The solution is then allowed to warm to room temperature (30 min.) and poured into 30 ml of saturated aqueous ammonium chloride solution, the mixture is extracted three times with in each case 20 ml of ethyl acetate and the combined extracts are concentrated to dryness in vacuo. Purification on silica gel (mobile phase: methylene chloride/methanol=100/3) gives 5.2 g of the title compound as a yellowish amorphous solid. 1H-NMR(CDCl3, δ), 7.33-7.45 (m, 5H), 5.95 (d, 1H), 4.55-4.65 (dd, 1H), 4.2-4.4 (dd, 2H), 3.2-3.75 (m, 3H), 3.3 (s, 3H), 2.91-3.1 (q, 1H), 2.15 (s, 6H), 0.6 (d, 9H), 0.08 (d, 3H), −0.3 (d, 3H).
Reaction SMILES: BrC1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[C:10](C(C)(C)C)[CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=CC=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:8]([C:10]1[CH:9]=[C:8]2[C:17]3=[C:16]4[C:5](=[CH:6][CH:5]=[C:16]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:15]4=[CH:14][CH:13]=[C:12]3[CH:11]=1)[CH:6]=[CH:7]2)([CH3:17])([CH3:9])[CH3:7]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)c1cc2ccc3ccc(Br)c4ccc(c1)c2c34
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc2ccc3ccc(-c4ccccc4)c4ccc(c1)c2c34
Temperature: 130 °C
Reaction time: 2 h
Yield: 131.5 %

Procedure:
A mixed solution of 2.3 g of 1-bromo-7-tert-butylpyrene, 1.1 g of phenylboronic acid, 3.8 g of tribasic potassium phosphate, 0.58 g of tetrabutylammonium bromide, 12 mg of palladium acetate, and 30 ml of dimethylformamide was then heated and stirred at 130° C. for 2 hours under a nitrogen stream. After the mixture was cooled to room temperature, 30 ml of water was added thereto, and the mixture was extracted with 50 ml of dichloromethane. The organic layer was washed twice with 20 ml of water, dried over magnesium sulfate, and then evaporated. The resulting residue was purified by silica gel column chromatography and dried under vacuum to give 1.5 g of 7-tert-butyl-1-phenylpyrene.
Reaction SMILES: [N+]([C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)([O-])=O.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(OCC)(=O)C.CCCCCC>[O:17]([C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1ccc([N+](=O)[O-])s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2ccccc2)s1
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 72.2 %

Procedure:
5-Nitro-thiophene-2-carbonitrile(1.5 g, 9.7 mmol), phenol (1.8 g, 19.4 mmol) and potassium carbonate(4.0 g, 29.1 mmol) were suspended in dimethylsulfoxide (20 mL), and the mixture was stirred for 50 minutes at 60° C., followed by further stirring overnight at room temperature. Water and ethyl acetate were added to the reaction mixture, which was then partitioned, the organic layer was washed 4 times with water, then, NH silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption, purification was carried out by NH silica gel column chromatography (hexane, then hexane:ethyl acetate=20:1, then 10:1), and the title compound (1.4 g, 7.0 mmol, 72.1%) was obtained as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[CH3:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:27][CH2:26][C:23]2[CH:24]=[N:25][C:20]([CH3:19])=[CH:21][CH:22]=2)[N:3]=1
Reactant: Cc1ccc(CO)cn1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(COc2nc(N)nc(-c3ccco3)c2C#N)cn1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (6-methyl-pyridin-3-yl)-methanol hydrochloride and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).