Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:6][C:5]=12>[Pd].C(O)(=O)C>[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][CH2:6][C:5]=12
Reactant: COC(=O)c1ccc2nccn2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C1CCc2nccn2C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a 50 ml pressure bottle were placed methyl imidazo[1,2-a]pyridine-6-carboxylate (0.26 g), acetic acid (10 ml), and wet 5% palladium on carbon (0.052 g). The reaction mixture was stirred for 16 hours at 30 psi and 50° C. The solid was filtered off, and the filtrate was concentrated. The residue was taken up in ethyl acetate. It was then washed with saturated sodium bicarbonate, brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel using 10-100% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [OH-:1].[Na+].Br.[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:7]=1)#[N:5]>CO.O1CCCC1>[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:7]=1)(=[O:1])[NH2:5]
Reactant: N#Cc1ccnc(-c2csc(N=C(N)N)n2)c1
Reactant: [OH-]
Agent: Br
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1ccnc(-c2csc(N=C(N)N)n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1N-Aqueous sodium hydroxide (10 ml) was added to a suspension of 4-(4-cyanopyridin-2-yl)-2-(diaminomethyleneamino)thiazole hydrobromide (1.00 g) in a mixture of methanol (10 ml) and tetrahydrofuran (10 ml). After the mixture was stirred for one day at ambient temperature, the solvent was evaporated in vacuo and the residue was mixed with water (10 ml). The resulting precipitate was collected by filtration, washed with water and recrystallized from a mixture of N,N-dimethylformamide and water to give 4-(4-carbamoylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.45 g).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][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][CH3:21])[CH2:2][CH:3]=[CH2:4].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[CH2:6]([O:5][CH2:1][CH2:2][CH:3]1[CH2:4][O:30]1)[CH2:7][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][CH3:21]
Reactant: C=CCCOCCCCCCCCCCCCCCCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOCCC1CO1
Reaction time: 72 h
Yield: 79.1 %

Procedure:
To a solution of 100 g of 1-(3-butenyloxy)hexadecane in 640 ml of methylene chloride was added portionwise 69 g of m-chloroperbenzoic acid. The mixture was stirred under argon for 72 hours and then the solvents were removed. The residue was dissolved in ether and washed with saturated aqueous sodium bicarbonate, dried and evaporated to an oil. This oil was distilled (140°-150° C., 0.05 mm Hg) giving 83.4 g of the desired compound as an oil.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:10]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][CH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][NH2+:15]1)#[N:9].C(N(CC)CC)C.[N:34]1[CH:39]=[CH:38][C:37]([CH2:40][NH:41][C:42](=O)[O:43]C2C=CC([N+]([O-])=O)=CC=2)=[CH:36][CH:35]=1.O>ClCCl>[C:8]([C:10]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][CH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[C:42]([NH:41][CH2:40][C:37]1[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=1)=[O:43])#[N:9]
Reactant: O=C(NCc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: N#Cc1c(OC[C@H]2CCCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1c(OC[C@H]2CCCCN2C(=O)NCc2ccncc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 23 h
Yield: 30.9 %

Procedure:
To a solution of (R)-2-((2-cyano-3-nitrophenoxy)methyl)piperidinium 2,2,2-trifluoroacetate (Example 16c, 1.12 g, 2.99 mmol) in dichloromethane (5 mL), was added triethylamine (420 uL, 3.01 mmol). To that mixture was added a suspension of 4-nitrophenyl pyridin-4-ylmethylcarbamate (Example 27d, 980 mg, 3.59 mmol) in dichloromethane (5 mL), followed by triethylamine (420 uL, 3.01 mmol). After stirring for 23 h at room temperature, additional portions of 4-nitrophenyl pyridin-4-ylmethylcarbamate (980 mg, 3.59 mmol) and triethylamine (420 uL, 3.01 mmol) were added, and the resulting reaction mixture was stirred for 1 h. at which time it was poured into water, and washed successively with saturated aqueous NaHCO3 water and brine, dried over MgSO4, filtered, concentrated and purified by flash chromatography (0-100% ethyl acetate in hexanes followed by 0-10% methanol in dichloromethane) to provide (R)-2-((2-cyano-3-nitrophenoxy)methyl)-N-(pyridin-4-ylmethyl)piperidine-1-carboxamide (365 mg, 32%). MS=396 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][C:7]2=O)([O-])=O.[C:20](OC(=O)C)(=[O:22])[CH3:21]>[Pd]>[C:20]([NH:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:8][CH2:7]2)(=[O:22])[CH3:21]
Reactant: CCOC(=O)c1cc(=O)c2cc([N+](=O)[O-])ccc2o1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Product: CCOC(=O)C1CCc2cc(NC(C)=O)ccc2O1
Temperature: 80 °C

Procedure:
A hydrogenation apparatus is charged with 6 g of ethyl 6-nitrochromone-2-carboxylate (Example 10), 3.5 mL of acetic anhydride, 1 g of 10% palladium on carbon, 4.0 g of dry, powdered 3A molecular sieves, and 30 mL of glacial acetic acid. After purging several times with nitrogen, the apparatus is purged several times with hydrogen. Under continuous stirring, the apparatus is maintained at about 70 psi with hydrogen and about 80° C. for about 10-12 h. The apparatus is then cooled to about 50° C., evacuated of hydrogen, and purged several times with nitrogen. Trifluororoacetic acid (3.5 mL) is added to the mixture, then the apparatus is resealed, purged several times with hydrogen, and pressurized to 70 psi with hydrogen. The stirred reaction mixture is heated to 80° C. until the reaction is complete by HPLC (intermediate:product≦3%), then cooled to room temperature. After filtering the mixture through Celite, the catalyst and molecular sieves are washed with 10 mL aliquots of glacial acetic acid, and the washes combined with the filtrate. These combined filtrates are concentrated by mild distillation to an oil, which is dissolved in ethyl acetate and washed with saturated NaHCO3. The aqueous fraction is extracted with ethyl acetate, then made strongly acidic with concentrated HCl and extracted several times with ethyl acetate. The combined ethyl acetate fractions are combined and concentrated to a solid. The solid is washed with acetonitrile, filtered, and dried to afford about 3.5-4.0 g of ethyl 6-acetamidochromane-2-carboxylate as a white solid.
Reaction SMILES: [SH:1][C:2]([CH3:12])([CH3:11])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Tc]([O-])(=O)(=O)=O.[Na+]>[CH2:10]([S:1][C:2]([CH3:12])([CH3:11])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:4][CH2:3][C:2]([SH:1])([CH3:12])[CH3:11])/[CH:5]=[CH:6]/[CH3:7]
Reactant: CC(C)(S)CNc1ccccc1
Agent: O=[Tc](=O)(=O)[O-]
Agent: [Na+]
Product: C/C=C/CSC(C)(C)CNc1ccccc1NCC(C)(C)S

Procedure:
1-(2-trans-2-Butenylthio)-2-methylpropylamino)-2-(2-mercapto-2-methylpropylamino) benzene was reacted with Tc-99m sodium pertechnetate by the procedure of Example 7 to produce the Tc-99m complex of 1-[2-(trans-2-butenylthio)-2-methylpropylamino]-2-(2-mercapto-2-methylpropylamino) benzene. HPLC (90% ethanol//H2O, 1.5 ml/min, Waters Radial-Pak C-18) Rt 4.06 min, radiochemical purity 100%. TLC (70% hexane/diethyl ether) RF 0.26, radiochemical purity 94%. Electrophoresis (0.05 M NaH2PO4, pH 4.5, 300 volts, 45 min) neutral.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>C(O)C.O1CCOCC1>[ClH:25].[ClH:25].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nccc(C(F)(F)F)n2)CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: FC(F)(F)c1ccnc(NC2CCNCC2)n1

Procedure:
A solution of 4-(4-trifluoromethyl-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (3.47 g, 10.02 mmol) in ethanol (50 mL) and 4 M HCl in dioxane (75 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 247.1 [M+H]+.
Reaction SMILES: C(OCC1C=CC=CC=1)C1C=CC=CC=1.C([O:23][C:24]1[CH:29]=[C:28]([O:30]CC2C=CC=CC=2)[C:27]([CH:38]([CH3:40])[CH3:39])=[CH:26][C:25]=1[C:41]1[N:42]([C:47]2[CH:48]=[C:49]3[C:53](=[CH:54][CH:55]=2)[N:52]([CH2:56][CH2:57][NH:58][CH3:59])[CH:51]=[CH:50]3)[C:43]([OH:46])=[N:44][N:45]=1)C1C=CC=CC=1>>[OH:46][C:43]1[N:42]([C:47]2[CH:48]=[C:49]3[C:53](=[CH:54][CH:55]=2)[N:52]([CH2:56][CH2:57][NH:58][CH3:59])[CH:51]=[CH:50]3)[C:41]([C:25]2[CH:26]=[C:27]([CH:38]([CH3:40])[CH3:39])[C:28]([OH:30])=[CH:29][C:24]=2[OH:23])=[N:45][N:44]=1
Reactant: CNCCn1ccc2cc(-n3c(O)nnc3-c3cc(C(C)C)c(OCc4ccccc4)cc3OCc3ccccc3)ccc21
Solvent: c1ccc(COCc2ccccc2)cc1
Product: CNCCn1ccc2cc(-n3c(O)nnc3-c3cc(C(C)C)c(O)cc3O)ccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The benzylether[5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-(2-(methylamino)ethyl)-1H-indol-5-yl)-4H-1,2,4-triazol-3-ol; 294 mg, 0.5 mmol) was dissolved in 6 ml degassed ethyl acetate and ethanol (1:1). 50 mg Pd/C (10%) was added and the mixture stirred under hydrogen (balloon) at rt for 6 h. After filtration the solvent was removed and the crude purified by chromatography on silica with DCM/MeOH (5-20%)/NH4OH (0.5%) to yield 203 mg (0.5 mmol) 4-(5-hydroxy-4-(1-(2-(methylamino)ethyl)-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol. This amine (203 mg) was added to 4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanoic acid (110 mg, 0.6 mmol), EDC (154 mg, 0.8 mmol) and HOBt (108 mg, 0.8 mmol) in 9 ml DCM/DMF (2:1) at rt. The mixture was stirred for 12 h and then ethyl acetate and water added. The aq. Phase was extracted twice with ethyl acetate and the combined organic extracts washed with brine and dried over MgSO4. The crude was purified by chromatography on silica with DCM/MeOH (0-8%) to yield 133 mg (0.23 mmol) N-(2-(5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-1H-indol-1-yl)ethyl)-4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-methylbutanamide.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[NH2:11][C:12]1[C:13]([S:24][CH2:25][C@@H:26]([C:35](O)=[O:36])[NH:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1.CN(C=O)C>CCOC(C)=O>[CH3:31][C:30]([CH3:32])([CH3:33])[C:29]([O:28][NH:27][C@@H:26]1[C:35](=[O:36])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:13]=2[S:24][CH2:25]1)=[O:34]
Reactant: CC(C)(C)C(=O)ON[C@@H](CSc1c(N)cccc1-c1ccccc1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)ON[C@H]1CSc2c(cccc2-c2ccccc2)NC1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
0.269 mL of diethyl cyanophosphonate (289.4 mg, 1.774 mmol) are placed in a 25 mL three-necked flask containing 580 mg of 39 (1.493 mmol) and 7 mL of DMF, at 0° C., followed, 10 minutes later, by addition of 0.201 mL of TEA (1.43 mmol). The reaction medium is stirred at 0° C. for 2 hours. 20 mL of EtOAc are added and the mixture is then washed with twice 20 mL of distilled water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. The crude product (600 mg of yellow oil) is chromatographed on a silica cartridge (30 g) with a heptane/EtOAc eluent (as an EtOAc gradient: 10% to 50%). 410 mg of expected product 40 are obtained (white solid).
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].C(O[CH:15](OCC)[CH2:16][CH2:17][CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])C>C(O)(=O)C>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[CH2:18][CH2:17][CH2:16][CH:15]=[N:2][NH:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH2:9])=[O:8])=[CH:10][CH:11]=1
Reactant: CCOC(CCCN1C(=O)c2ccccc2C1=O)OCC
Reactant: NNc1ccc(C(N)=O)cc1
Solvent: CC(=O)O
Product: NC(=O)c1ccc(NN=CCCCN2C(=O)c3ccccc3C2=O)cc1
Yield: 91.5 %

Procedure:
A solution of 4-hydrazinobenzamide (0.26 g), in 25% aqueous acetic acid (20 ml) was added to 4-[1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl]-butanal diethyl acetal (0.5 g). The mixture was heated on a steam bath for 2 hours and then cooled. The mixture was decanted to leave an oil which was triturated with methanol (3 ml). The solid that resulted was washed with water (5 ml) and dried in vacuo at 50° C. to give the title compound (0.55 g) as a yellow crystalline solid m.p. 147°-152° C. (decomp).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:21][CH2:20][C:19]2[S:22][C:23]([NH:25][C:26](=[O:28])[CH3:27])=[N:24][C:18]=2[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)(Cl)Cl>[S:22]1[C:19]2[CH2:20][CH2:21][NH:15][CH2:16][CH2:17][C:18]=2[N:24]=[C:23]1[NH:25][C:26](=[O:28])[CH3:27]
Reactant: CC(=O)Nc1nc2c(s1)CCN(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc2c(s1)CCNCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
35 mL trifluoroacetic acid was added to 2.4 g 2-acetylamino-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6-carboxylic acid tert-butyl ester in 80 mL chloroform. The reaction was stirred 3 h at RT and concentrated. The residue was dissolved in 75 mL chloroform and basified with 2.5 M potassiumcarbonate solution. The chloroform layer was separated and concentrated to give 1.3 g of the desired product. (M+H)+=212
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[Br-].[O:16]1CCO[CH:17]1[CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC>ClCCl.C([O-])([O-])=O.[K+].[K+]>[F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:21][CH:17]=[O:16]
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1F
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Product: O=CC=Cc1ccc(-n2cccn2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A mixture of 2-fluoro-4-(1H-pyrazol-1-yl)benzaldehyde (1.06 g, 5.57 mmol, prepared as described in Reference Example 8), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (3.60 g, 8.39 mmol), and TDA-1 (1.80 mL, 5.63 mmol) in dichloromethane (30 mL) and sat. aq. K2CO3 (30 mL) was heated to reflux for 20 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×15 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried (Na2SO4), and concentrated. THF (15 mL) and 10% HCl (15 mL) were added and the mixture was stirred for 1 h at rt. The mixture was cooled to 0° C., the precipitated solids were removed by filtration, washed with water and dried in vacuo. Recrystallization from IPA provided 0.84 g (70%) of the title compound as tan needles. MS 217 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][C:9]([CH3:14])([CH3:13])[C:10](=O)[NH:11][C:6]=2[CH:5]=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>C1COCC1>[F:1][C:2]1[C:7]2[O:8][C:9]([CH3:14])([CH3:13])[C:10](=[S:19])[NH:11][C:6]=2[CH:5]=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1(C)Oc2c(F)cc([N+](=O)[O-])cc2NC1=O
Solvent: C1CCOC1
Product: CC1(C)Oc2c(F)cc([N+](=O)[O-])cc2NC1=S
Yield: 69 %

Procedure:
To a solution of 8-Fluoro-2,2-dimethyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.75 g, 3.1 mmol) in 25 ml anhydrous THF, P2S5 (2.8 g, 6.25 mmol) was added and the reaction mixture was heated to reflux for 12 hours. Analysis of LC-MS indicated the completion of the reaction. Volatiles were removed in vacuo and the crude reaction mixture was partitioned in EtOAc (100 ml) and saturated aqueous NH4Cl (100 ml). Layers were separated and the organic layer was washed (×2) with saturated aqueous NH4Cl (50 ml). EtOAc layer was dried over Na2SO4 and concentrated to give the product in 69% yield (0.55 g). LCMS (m/z) 257 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]([C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1)([CH:18]([CH3:20])[CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(C(C)C)C(C)C)C>C(OCC)(=O)C>[CH3:20][CH:18]([CH3:19])[C:12]([C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1)([NH:11][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C(N)(c1nc(OC)cc(OC)n1)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(NC(=O)c1ccccc1Cl)(c1nc(OC)cc(OC)n1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
2-Chlorobenzoyl chloride (0.35 g) in ethyl acetate (3 ml) was added to a stirred solution of ethyl 2-amino-3-methyl-2-(4,6-dimethoxypyrimidin-2-yl)butanoate (0.566 g) and ethyl diisopropylamine (0.258 g) in ethyl acetate (15 ml). The mixture was stirred at room temperature for 2 hours, filtered, and the filtrate was washed with water, dried and evaporated to dryness under vacuum. The residual solid was triturated with 60°-80° petroleum ether to give 0.4 g of the desired product as a white solid, mp 94°-95° C.
Reaction SMILES: CC([PH+](C(C)(C)C)CCCS([O-])(=O)=O)(C)C.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[N:22][CH:23]=1.Br[C:28]1[CH:45]=[C:44]2[C:31]([CH2:32][C:33]3([C:37]42[N:41]=[C:40]([NH2:42])[C:39]([CH3:43])=[N:38]4)[CH2:36][CH2:35][CH2:34]3)=[CH:30][CH:29]=1.CC1CCCO1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([C:28]2[CH:45]=[C:44]3[C:31]([CH2:32][C:33]4([C:37]53[N:41]=[C:40]([NH2:42])[C:39]([CH3:43])=[N:38]5)[CH2:36][CH2:35][CH2:34]4)=[CH:30][CH:29]=2)[CH:21]=[N:22][CH:23]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC1
Agent: Cl[Pd]Cl
Agent: CC(C)(C)[PH+](CCCS(=O)(=O)[O-])C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CC1CCCO1
Solvent: ClCCl
Product: CC1=NC2(N=C1N)c1cc(-c3cncc(Cl)c3)ccc1CC21CCC1
Temperature: 90 °C
Yield: 76.5 %

Procedure:
Sodium tetrachloropalladate (II) (2.77 mg, 9.43 μmol), 3-(di-tert-butylphosphonium)propane sulfonate (5.06 mg, 0.02 mmol), 5-chloropyridin-3-ylboronic acid (40.6 mg, 0.25 mmol) and 6′-bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 54, 60 mg, 0.19 mmol), was added to a vial. 2-Methyl-tetrahydrofuran (1 mL) and 2 M aq. K2CO3 (0.283 mL, 0.57 mmol) was added and the mixture was degassed by bubbling N2 (g). The vial was sealed and heated in a microwave reactor at 90° C. for 30 min. EtOAc (5 mL) and water (5 mL) were added and the phases were separated. The aq phase was extracted with EtOAc and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography using a gradient of 0-10% MeOH, containing 1.2% 7M NH3 in MeOH, in DCM, afforded 51 mg of the title compound (77% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.62 (m, 4H) 1.83 (d, 1H) 2.16 (s, 1H) 2.21 (s, 3H) 3.23 (d, 2H) 6.60 (s, 2H) 6.94 (d, 1H) 7.43 (d, 1H) 7.58 (dd, 1H) 8.10 (t, 1H) 8.57 (d, 1H) 8.71 (d, 1H); MS (ES+) m/z 351 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[O:25][CH3:24])=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: COc1ccccc1B(O)O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: COc1ccccc1-c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)sc1CCO2
Yield: 54 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 2-methoxyphenylboronic acid were reacted to give 234 (0.087 g, 54%). 1H NMR (400 MHz, DMSO) δ 8.60 (s, 1H), 8.10 (s, 1H), 7.39 (dd, J=31.7, 7.5, 3H), 7.09 (dt, J=14.7, 9.8, 3H), 5.82-5.69 (m, 1H), 4.41 (s, 2H), 3.79 (s, 3H), 3.47 (s, 2H), 1.51 (d, J=6.5, 6H). MS (ESI(+)): m/z 419.1 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[C:6]([NH2:8])[CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].Cl>N1C=CC=CC=1>[CH3:12][S:13]([NH:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[C:6]([NH:8][S:13]([CH3:12])(=[O:15])=[O:14])[CH:7]=1)(=[O:15])=[O:14]
Reactant: Nc1cc(N)cc([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(NS(C)(=O)=O)cc([N+](=O)[O-])c1

Procedure:
To a solution of 1.5 g. (0.01 mol) of 3,5-diaminonitrobenzene in 3 ml. of pyridine cooled to 5° C. was added 1.6 ml. (0.02 mol) of methanesulfonyl chloride, dropwise, and the mixture was stirred for 90 minutes at room temperature. The reaction mixture was decomposed by adding dilute hydrochloric acid and ice. The solid was filtered, washed with water and dried to give 3,5-bis-methylsulfonamidonitrobenzene, m.p. 223°-224° C.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]([CH2:29][C:30]([CH3:33])([OH:32])[CH3:31])[C:15]2[C:20]([N:21]=1)=[C:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[N:18]=[C:17]([CH3:28])[N:16]=2.N1C=CC=CC=1>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]([CH2:29][C:30]([OH:32])([CH3:31])[CH3:33])[C:15]2[C:20]([N:21]=1)=[C:19]([N:22]1[CH2:23][CH2:24][N:25]([C:2]([O:4][CH3:5])=[O:3])[CH2:26][CH2:27]1)[N:18]=[C:17]([CH3:28])[N:16]=2
Reactant: Cc1nc(N2CCNCC2)c2nc(-c3ccccc3Cl)n(CC(C)(C)O)c2n1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N1CCN(c2nc(C)nc3c2nc(-c2ccccc2Cl)n3CC(C)(C)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
Add methyl chloroformate (0.29 g, 0.0031 mol) to a solution of 1-[8-(2-chlorophenyl)-2-methyl-6-piperazin-1-yl-purin-9-yl]-2-methyl-propan-2-ol (0.001 mol, 0.5 g) and pyridine (2.0 mL) in dry dichloromethane (3 mL) at 0° C. and stir for 2 h at room temperature. Quench the reaction mixture with saturated sodium bicarbonate solution and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column using methanol:dichloromethane (3:97) as eluent to give Methyl 4-[8-(2-chlorophenyl)-9-(2-hydroxy-2-methyl-propyl)-2-methyl-purin-6-yl]piperazine-1-carboxylate (0.3 g). ES/MS m/z 459 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=[O:12])=[CH:6][CH:5]=1>C1COCC1>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1
Reactant: COCc1ccc(CC(=O)O)cc1
Solvent: C1CCOC1
Product: COCc1ccc(CCO)cc1
Reaction time: 6 h

Procedure:
[4-(Methoxymethyl)phenyl]acetic acid (3.6 g, 20 mmole) was dissolved in THF (100 ml) and cooled on an ice-bath. BH3xTBT (1M, 40 ml, 40 mmole) was added. The reaction mixture was stirred for 6 h and then quenched with HCl (1M, 80 ml) and water (˜100 ml). THF was evaporated and the residue extracted with dicloromethane and ethyl acetate. The phases were separated and the organic phase was washed with HCl (0.3M, 100 ml and dried with Na2SO4. Evaporation gave 3.31 g, 99.6%, of the desired product.