Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=O)(=[O:3])[CH3:2].Cl>CO>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:6]=1[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])(=[O:3])[CH3:2]
Reactant: COC(=O)CCCc1ccc(F)cc1NC(C)=O
Agent: Cl
Solvent: CO
Product: CC(=O)Nc1cc(F)cc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound obtained in (4) above (42 gm) was dissolved into 100 ml of methanol. After the addition of 200 ml of 1N hydrochloric acid, the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated to 200 ml and, after acidifying with the addition of concentrated hydrochloric acid, extracted three times with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated, and to the residue were added 100 ml of dichloromethane, then 17 gm of sodium carbonate and 12 ml of thionyl chloride. The mixture was heated under reflux for 2 hours, and then cooled to room temperature to remove insoluble substances by filtration. The filtrate was concentrated and 200 ml of 1,2-dichloromethane and 40 gm of aluminum chloride were added to the residue. The mixture was stirred for 3 hours at 70° C. then for 1 hour at 90° C. The reaction product was poured into ice-coled water and extracted with chloroform. The extract was washed with water, saturated sodium bicarbonate, and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column chromatography using chloroform-ethyl acetate (7:3) as an eluant to obtain fractions containing the target compound. The fractions were concentrated to obtain 17 gm of the title compound.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[C:20]1([CH2:33][CH2:34][NH2:35])[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(O)C>[C:20]1([CH2:33][CH2:34][NH:35][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: NCCc1cccc2c1Cc1ccccc1-2
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCc4cccc5c4Cc4ccccc4-5)ncnc32)[C@H](O)[C@@H]1O
Yield: 98 %

Procedure:
A reaction mixture of 1.75 g of 6-chlorpurine riboside, 1.78 g of fluorenylethylamine and 1.84 g of triethylamine is refluxed in 50 ml of ethanol under nitrogen for 20 hrs. Upon cooling, solid material crystallizes out. It is filtered and dried affording 2.75 g (95%) of N6 -fluorenylethyl adenosine having a melting point of 120°-123° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][C:19]4[N:24]=[C:23]([C:25]([O:27]C)=O)[CH:22]=[CH:21][CH:20]=4)=[O:17])[CH:11]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.O.[NH2:30][NH2:31]>C(O)C>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:25]([NH:30][NH2:31])=[O:27])[N:24]=4)=[O:17])[CH:11]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)c1cccc(NC(=O)c2cc(-c3ccc(C4CC4)nc3)ccn2)n1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cccc(NC(=O)c2cc(-c3ccc(C4CC4)nc3)ccn2)n1
Reaction time: 4 h
Yield: 47 %

Procedure:
The methyl 6-(6-cyclopropyl-3,4′-bipyridine-2′-carboxamido)picolinate from the previous step were suspended in ethanol (20 mL), hydrazine hydrate (700 μL, 14.4 mmol) was added, and the reaction was heated to relfux for 4 hours. The reaction mixture was concentrated and the resultant solids were suspended in acetronitrile and collected by filtration. The solids were washed with acetonitrile (2×100 mL) and diethyl ether (2×100 mL), and dried under reduced pressure to afford 1.21 g (47% yield) of 6-cyclopropyl-N-(6-(hydrazinecarbonyl)pyridin-2-yl)-3,4′-bipyridine-2′-carboxamide as a white solid.
Reaction SMILES: [C:1]1([C:15](O)=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].P([O-])([O-])(O)=O.[NH4+:22].[NH4+].S1(CCCC1)(=O)=O>O>[CH:5]1[C:1]([N+:2]([O-:4])=[O:3])=[C:15]([NH2:22])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: O=P([O-])([O-])O
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
Picric acid (10.0 g, 43.8 mmol), diammonium hydrogen phosphate (11.6 g, 87.6 mmol) and dry sulfolane (40 ml) are placed in a glass-lined, stainless steel reactor to form a 1.1M concentration reaction slurry. The reactor is sealed and the reaction slurry is stirred with heating for 2 hr as the temperature increases from 25 to 175° C. (20 psi pressure). The temperature is maintained at 175° C. and stirring is continued for an additional 20 hr. The cooled reaction mixture is mixed with water (400 ml) and the insoluble material is collected, washed with water and dried to produce picramide in 93% yield (Table 2, entry 5).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH2:24])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:29]([CH:26]4[CH2:28][CH2:27]4)=[O:30])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(N)sc3n2)c1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of tert-butyl{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]phenyl}carbamate (1.00 g, 2.79 mmol) in pyridine (30 mL) was added cyclopropanecarbonyl chloride (327 μL, 3.63 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate (100 mL, 30 mL). The combined organic layer was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran and hexane to give the title compound (1.02 g, 86%) as pale-yellow crystals.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:13]1[C@@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:16]3[C@@H:17]4[C@H:22]([C:21]5[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:20]=5[CH2:19][CH2:18]4)[CH2:13][CH2:14][CH2:15]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N#Cc1ccc2c(c1)[C@@H]1CCCN[C@H]1CC2
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: N#Cc1ccc2c(c1)[C@@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 18 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-9-carbonitrile following a procedure analogous to that described in Example 1. Yield: 18% of theory; LC (method 1): tR=2.49 min; Mass spectrum (ESI+): m/z=357 [M+H]+.
Reaction SMILES: N[C@H](C(O)=O)CCC(=O)N.P([O-])([O-])([O-])=O.Cl.NO.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[NH2:63][C@H:64]([C:70]([O-:72])=[O:71])[CH2:65][CH2:66][C:67]([O-:69])=[O:68]>>[NH2:63][C@H:64]([C:70]([OH:72])=[O:71])[CH2:65][CH2:66][C:67]([OH:69])=[O:68]
Reactant: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: NC(=O)CC[C@H](N)C(=O)O
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Glutaminase activity was measured by partly modifying the method described in Japanese Provisional Patent Publication No. 332553/1999. That is, to 250 μl of 2% (w/v) L-glutamine solution were added 500 μl of 0.2M phosphate buffer (pH 6.5) and 250 μl of an enzyme solution, and the mixture was reacted at 37° C. for 30 minutes, and then, the reaction was terminated by adding 250 μl of 0.75N perchloric acid solution, and 125 μl of 1.5N sodium hydroxide solution was added thereto to neutralize the reaction mixture. The above reaction mixture was then centrifuged (10,000 rpm, 10 minutes). To 100 μl of the resultant supernatant were added 1.0 ml of 0.1M hydrochloric acid-hydroxylamine buffer (pH 8.0), 1.0 ml of 20 mM NAD+ solution (available from Oriental Yeast Co.) and 50 μl of 500 U/ml L-glutamate dehydrogenase solution (available from SIGMA Co.), and the mixture was reacted at 37° C. for 30 minutes and the absorbance at 340 nm was measured with a spectrophotometer. An amount of the enzyme forming 1 μmol of glutamic acid per one minute under the above conditions is determined as 1 unit (U).
Reaction SMILES: [CH:1]([O:11][CH3:12])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[OH:15]>Cl>[CH3:12][O:11][CH:1]([O:15][CH:14]([CH3:16])[C:13]([O:18][CH2:19][CH3:20])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC=COC
Reactant: CCOC(=O)C(C)O
Agent: Cl
Product: CCCCCCCCCC(OC)OC(C)C(=O)OCC
Temperature: 40 °C
Reaction time: 2.3 h

Procedure:
Into a 50 ml. round-bottom flask equipped with a static nitrogen acid, thermometer, mantle, and magnetic stirrer, was charged 10.2 g. of methyl decenyl ether and 3.5 g. of ethyl lactate. One drop of HCl was added after heating the mixture to 40° C., whereupon an exotherm to 63° C. was experienced. Stirring was continued for 2.3 hours at between 40° and 53° C. The mixture was quenched with solid sodium carbonate. Another run made with 20.4 g. of the methyl decenyl ether and 7.1 g. of ethyl lactate was performed in a similar manner and combined with the above run for workup. The product was distilled on a one-foot micro-vigreaux column:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:22]([C:25]2[NH:29][N:28]=[N:27][N:26]=2)=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(-c2nnn[nH]2)ccc1OCc1ccccc1
Yield: 101.9 %

Procedure:
A solution of 436 mg (1.27 mmol) of benzyl 2-benzyloxy-5-cyanobenzoate, 91 mg (1.40 mmol) of sodium azide, and 68 mg (1.27 mmol) of ammonium chloride in 5 mL of DMF is heated at 120° C. for 24 hrs. The DMF was removed by rotoevaporation, the residue is taken up in water, and acidified. The white precipitate is collected by filtration and dried to give 500 mg of unpurified benzyl 2-benzyloxy-5-(1H-tetrazol-5-yl)benzoate, which is treated with 28% aqueous ammonium hydroxide in 5 mL of MeOH at 85° C. for 72 hrs. The reaction mixture was concentrated, taken up in water, and then acidified. Filtration of the precipitate gives 400 mg (1.04 mmol, 82% yield) of 2-benzyloxy-5-(1H-tetrazol-5-yl)benzamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](Cl)=[O:6].[C:13]1([C:19]2[O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(=S)=S>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([C:23]1[C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[O:20][C:19]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: COc1ccc(C(=O)Cl)cc1C
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Solvent: S=C=S
Product: COc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1C
Temperature: 25 °C

Procedure:
To a cooled, stirred solution of 10.8 g. (0.058 mol.) of 3-methyl-4-methoxybenzoic acid chloride and 9.6 g. (0.054 mol.) of 2-phenylbenzofuran in 40 ml. of carbon disulfide is added dropwise over a 20 minute interval 28.2 g. (0.108 mol.) of stannic chloride. After addition, the reaction mixture is warmed to ambient temperature and stirred for two hours. The mixture is then poured onto 100 ml. of ice-water and stirred for one hour. The solvent is removed, and the product extracted into chloroform and the extracts are washed with water, dried (Na2SO4) and concentrated under reduced pressure to give 3-(3-methyl-4-methoxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[C:13]1([CH:19]2[NH:24][CH2:23][CH2:22][NH:21][C:20]2=[O:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[O:25]=[C:20]1[NH:21][CH2:22][CH2:23][N:24]([C:7]([Cl:10])=[O:6])[CH:19]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C1NCCNC1c1ccccc1
Solvent: ClCCl
Product: O=C1NCCN(C(=O)Cl)C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
To a stirred solution of triphosgene (0.558 g) in DCM (10 ml) pyridine (0.46 mL) was added at 0° C. and, after 10 min, 3-phenyl-piperazine-2-one (1 g). The ice bath was removed and the mixture was stirred at room temperature overnight. The mixture was concentrated and the product was purified by flash chromatography (CH/AcOEt 1:1) to give the title compound (0.253 g) as a foam.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1
Reactant: CCC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: Nc1ccccc1
Solvent: CC(C)O
Solvent: CCCCO
Product: CCC(C)n1cnc2c(Nc3ccccc3)nc(Cl)nc21
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 9 starting from 200 mg of the product obtained in Stage 1 of Example 9 and 4 ml of butanol and using 0.091 ml of aniline in place of the benzylamine. Agitation is carried out at ambient temperature then the reaction medium is taken to a temperature of 80 to 85° C. for approximately 22 hours, left to return to ambient temperature, diluted with 4 ml of isopropanol and placed for two days at a temperature of approximately 0° C., followed by separating, washing with 5 ml of isopropanol and drying at a temperature of approximately 80° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 176 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([NH:17][C:18]([NH:20][C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:22])=[O:19])=[CH:16][C:11]=3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([NH:17][C:18]([NH:20][C@@H:21]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH3:22])=[O:19])=[CH:16][C:11]=3[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(-c1ccc(F)cc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(-c3ccc(F)cc3)c2cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To the solution of (R)-1-(3-(4-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (61 mg, 0.10 mmol) in DCM (0.5 mL) was added TFA (0.5 mL) and triethylsilane (0.05 mL, 0.313 mmol). The mixture was stirred at room temperature for 10 min, concentrated in vacuo and purified on reversed phase HPLC to afford (R)-1-(3-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (40 mg, 0.083 mmol, 83%) as a yellow solid. MS ESI calcd. for C21H19FN5O [M+H]+ 376, found 376. 1H NMR (600 MHz, DMSO-d6) δ 13.24 (s, 1H), 9.12 (s, 1H), 9.06 (s, 1H), 8.04 (dd, J=8.8, 5.5 Hz, 2H), 7.75 (s, 1H), 7.65 (s, 1H), 7.39-7.27 (m, 6H), 7.22-7.18 (m, 1H), 4.86 (m, 1H), 1.39 (d, J=6.9 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CC(C)([O-])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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[CH:3]=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Br)c2)CC1
Temperature: 100 °C
Yield: 62.3 %

Procedure:
To a suspension of 3,5-dibromopyridine (2 g, 8.44 mmol), 1,1-dimethylethyl 1-piperazinecarboxylate (1.572 g, 8.44 mmol), BINAP (0.210 g, 0.338 mmol) and sodium tert-butoxide (1.136 g, 11.82 mmol) in Toluene (50 mL) at RT, was added Pd2dba3 (0.42 g, 0.459 mmol). The reaction mixture was heated at 100° C. for 3 hours and was cooled to RT, followed by filtration through a short pad of celite (washed with ethyl acetate). The filtrate was concentrated in vacuo to give a residue, which was purified on silica gel, eluting with a gradient of 0-20% ethyl acetate in cyclohexane, to give the title compound (1.8 g). LCMS (A): m/z (M+H)+ 342/344, C14H20BrN3O2 requires 341/343 (acidic).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18](O)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:23]=4[OH:22])[CH2:28]3)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(C)cc3)nc3ccccc13)C2
Yield: 36 %

Procedure:
Reaction of 2-(4-methylphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 12 (36% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.41 (s, 3H), 2.63 and 2.90 (2t, 2H), 3.47 and 4.03 (2t, 2H), 3.74 and 3.80 (2s, 3H), 4.38 and 4.92 (2s, 2H), 6.32 and 6.77 (2d, 1H), 6.70 and 6.91 (2d, 1H), 7.36-7.41 (m, 2H), 7.67-7.77 (m, 1H), 7.84-7.95 (2d, 1H), 8.04-8.15 (m, 2H), 8.39-8.45 (m, 2H), 8.68 and 8.72 (2s, 1H); MS (ESI) m/z 426 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:25][CH:26]([CH2:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1)[C:27]([O:29][CH2:30][CH3:31])=[O:28]>[Pd]>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:36]5[CH:35]=[N:34][N:33]([CH2:32][CH:26]([CH3:25])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:37]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: CCOC(=O)C(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: [Pd]
Product: CCOC(=O)C(C)Cn1cc(-c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)cn1

Procedure:
9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411 and ethyl 2-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate were reacted under Suzuki palladium coupling conditions to give ethyl 3-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate LC/MS (ESI+): m/z 490 (M+H), which was hydrolyzed with lithium hydroxide in water then the corresponding acid was treated with ammonium chloride, HATU, diisopropylethylamine, and DMF to give 243. LC/MS (ESI+): m/z 461 (M+H). 1H NMR (500 MHz, DMSO) δ 8.35 (d, J=8.4, 1H), 8.15 (s, 1H), 7.95 (s, 1H), 7.86 (s, 1H), 7.36 (dd, J=8.4, 1.7, 2H), 7.25 (d, J=1.7, 1H), 6.83 (s, 1H), 5.82 (dt, J=13.2, 6.6, 1H), 4.51 (s, 4H), 4.30 (dd, J=13.5, 7.6, 1H), 4.02 (dd, J=13.5, 7.0, 1H), 2.91 (dd, J=14.3, 7.1, 1H), 2.25 (s, 3H), 1.47 (d, J=6.6, 5H), 1.01 (d, J=7.0, 3H)
Reaction SMILES: [C:1]([N:5]1[CH2:11][CH:10]([N:12]2[C:16]3[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)[CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>C(Cl)Cl>[C:41]([N:8]1[CH2:9][CH:10]([N:12]2[C:16]3[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)[CH2:11][N:5]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:6][CH2:7]1)(=[O:43])[CH3:42]
Reactant: C=CC(=O)N1CCNCC(n2c(NC(=O)c3ccnc(C)c3)nc3cccc(Cl)c32)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N1CCN(C(C)=O)CC(n2c(NC(=O)c3ccnc(C)c3)nc3cccc(Cl)c32)C1
Reaction time: 0.08 h

Procedure:
A solution of Example 13 (30 mg, 0.068 mmol), N,N-dimethylaminopyridine (17 mg, 0.137 mmol), and N,N-diisopropylethylamine (0.024 mL, 0.137 mmol) in CH2Cl2 (0.75 mL) was treated at room temperature with acetic anhydride (0.01 mL, 0.103 mmol) and stirred for 5 min. The reaction was then added directly to a RediSep dry loader cartridge and purified by column chromatography (9:1:0.175 M CH2Cl2/MeOH/NH3 in CH2Cl2, 0-50%) to afford the title compound (Example 14). 1H NMR (400 MHz, MeOD) δ 8.53-8.41 (m, 1H), 7.96-7.88 (m, 1H), 7.88-7.77 (m, 1H), 7.50-7.36 (m, 1H), 7.31-7.13 (m, 2H), 6.91-6.60 (m, 1H), 6.30-6.08 (m, 1H), 5.87-5.72 (m, 1H), 5.72-5.65 (m, 1H), 4.43-4.24 (m, 4H), 4.24-3.94 (m, 2H), 3.64-3.48 (m, 2H), 2.55 (s, 3H), 2.12-1.99 (m, 3H); MS calculated for C24H26ClN6O3 (M+H+) 481.17. found 481.2.