Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([C:15]([O:17][CH3:18])=[O:16])[CH:8]=[C:9]([CH:14]=1)[C:10]([O:12]C)=[O:11])[CH:2]=[CH2:3].[OH-].[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:14]=[C:9]([CH:8]=[C:7]([C:15]([O:17][CH3:18])=[O:16])[CH:6]=1)[C:10]([OH:12])=[O:11])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCOc1cc(C(=O)O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
A mixture of dimethyl 5-allyloxy-isophthalate (3.7 g, 14.9 mmol) in methanol (75 mL) was treated with 1M sodium hydroxide (13.4 mL, 13.4 mmol) and the reaction stirred at room temperature for 16 hours. The mixture was concentrated under vacuum and the resulting residue was dissolved in water. The aqueous layer was washed with ethyl acetate (3×), and then acidified (pH 1) by the addition of aqueous HCl. The aqueous solution was then extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated to afford 2.6 g (74%) of 3-allyloxy-5-(methoxycarbonyl)benzoic acid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]4[CH2:20][O:21][C:22](=[O:23])[C:12]3=4)[CH:9]=2)[NH:4][N:3]=1.[CH3:24][CH:25]([O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[CH3:26].C(=O)(O)[O-].[Na+]>O1CCOCC1.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>[CH3:19][C:15]1[NH:14][C:13]2[CH2:20][O:21][C:22](=[O:23])[C:12]=2[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[C:31]2[CH:32]=[N:33][C:28]([O:27][CH:25]([CH3:26])[CH3:24])=[CH:29][CH:30]=2)[C:16]=1[C:17]#[N:18]
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(Br)c3c2)C2=C(COC2=O)N1
Reactant: CC(C)Oc1ccc(B(O)O)cn1
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: C1COCCO1
Product: CC1=C(C#N)C(c2ccc3[nH]nc(-c4ccc(OC(C)C)nc4)c3c2)C2=C(COC2=O)N1
Temperature: 100 °C
Reaction time: 12 h
Yield: 19.6 %

Procedure:
To a degassed solution of 120 mg (0.323 mmol) 4-(3-bromo-1H-indazol-5-yl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile (Example 24) and 70.2 mg (0.388 mmol) [6-(propan-2-yloxy)pyridin-3-yl]boronic acid in anhydrous 1,4-dioxane (3.5 ml) were added under inert gas atmosphere 37.4 mg (0.032 mmol) tetrakis(triphenylphosphine)palladium(0) and aqueous sodium bicarbonate solution (2 M, 0.77 ml). The resulting mixture was stirred at 100° C. for 12 h. After cooling to room temperature and concentration under reduced pressure, the remaining solid was dissolved in ethyl acetate (20 ml). The solution was subsequently washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (acetonitrile/water gradient, final mixture 95:5 v/v) to yield the title compound as a white solid (27 mg, 19% of th.).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:25]1[S:29][N:28]=[CH:27][N:26]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH:20]2[CH2:24][CH2:23][CH2:22][NH:21]2)[CH:11]=1)(=[O:9])=[O:8].COC(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1>CCOC(C)=O.C1(C)C=CC=CC=1>[N:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[N:21]1[CH2:22][CH2:23][CH2:24][CH:20]1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH:18]=[CH:19][C:10]([S:7]([NH:6][C:25]1[S:29][N:28]=[CH:27][N:26]=1)(=[O:9])=[O:8])=[CH:11]2
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(C4CCCN4)cccc3c2)c(OC)c1
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1ncns1)c1ccc2c(C3CCCN3c3ccccn3)cccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.8 %

Procedure:
A vial was charged with N-(2,4-dimethoxybenzyl)-5-(pyrrolidin-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (INTERMEDIATE KK) (34.01 mg, 0.067 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (Strem Chemical, Newburyport, Mass., 2.72 mg, 3.33 mmol), and cesium carbonate (65.1 mg, 0.200 mmol). The vial was flushed with Ar (g), then toluene (0.3 mL) and 2-bromopyridine (19.05 μl, 0.200 mmol) were added. The vial was sealed and placed in a 100° C. heating bath. After 4 h, an additional portion of catalyst (about 3 mg) was added, and the vial was heated for an additional 16 h. Additional portions of catalyst (6 mg) and cesium carbonate (about 55 mg) were added, and the vial was returned to the heat for 5 h. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through diatomaceous earth. The filtrate was concentrated. The residue was purified by chromatography on silica gel (12-g column, 0 to 10% MeOH/DCM) to give 5-(1-(pyridin-2-yl)pyrrolidin-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (9.7 mg, 0.022 mmol, 33.3% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=8.54 (d, J=2.0 Hz, 1H), 8.45 (s, 1H), 8.38 (d, J=9.2 Hz, 1H), 8.12 (d, J=8.2 Hz, 1H), 8.02-7.88 (m, 2H), 7.72 (br. s., 1H), 7.56-7.48 (m, 1H), 7.33 (d, J=6.9 Hz, 1H), 6.79 (t, J=6.4 Hz, 1H), 6.61 (br. s., 1H), 5.91 (d, J=7.8 Hz, 1H), 4.04 (t, J=8.6 Hz, 1H), 3.77-3.62 (m, 1H), 2.71-2.59 (m, 1H), 2.17-2.05 (m, 1H), 2.01-1.84 (m, 2H); m/z (ESI) 438.4 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)=[O:5])C.C(O)C>>[N+:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)([O-:17])=[O:16]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Solvent: CCO
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
To a solution of ethyl-5-nitro-1H-indole-2-carboxylate (22.7 g, 96.83 mg) in ethanol (EtOH) (150 ml) sodium hydroxide (11.62 g, 290.5 mmol) was added. The mixture was stirred at room temperature for 16 h. During this time a brown solid formed. After evaporation of the solvent under reduced pressure the residue was suspended in water and HCl was added. The color of the precipitate changed from brown to yellow. After filtration the residue was washed with water and dried in a vacuum oven at 50° C. to give the product as a brown powder (19.53 g, 98%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(Cl)Cl>O>[CH2:28]([O:27][C:25](=[O:26])[N:10]([CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCC(NCCCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C1CCC(N(CCCc2ccccc2)C(=O)OCc2ccccc2)CC1
Reaction time: 1.5 h

Procedure:
A mixture of 4-(3-phenyl-propylamino)-cyclohexanone (1.9 g, 8.21 mmol), K2CO3 (1.15 g, 8.3 mmol), benzyl chloroformate (1.42 g, 8.3 mmol) and CH2Cl2 (20 ml) was stirred at r.t for 1.5 h. H2O (50 ml) was added, and the mixture was extracted with CH2Cl2. The organic layer was dried (Na2SO4), evaporated and the residue was purified by chromatography (SiO2, CH2Cl2—MeOH 95:5) to give (4-Oxo-cyclohexyl)-(3-phenyl-propyl)-carbamic acid benzyl ester as a yellow oil (2.7 g, 90%, MS: m/e=365(M+)).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.Br[CH2:11][CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[OH:13][CH2:12][CH2:11][N:6]1[CH2:7][CH2:8][C:9]2[S:1][CH:2]=[CH:3][C:4]=2[CH2:5]1
Reactant: c1cc2c(s1)CCNC2
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: OCCN1CCc2sccc2C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 54.8 %

Procedure:
A mixture of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (0.86 g), 2-bromoethanol (0.66 g), potassium carbonate (2.58 g) and potassium iodide (3.10 g) in N,N-dimethylformamide (20 ml) was stirred at 70° C. for 2 hours. After cooling, ethyl acetate and water were added thereto. The organic layer was separated, washed with water twice, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of methanol and dichloromethane (1:10) as an eluent. The fractions containing the objective compound were collected and evaporated under reduced pressure to give 5-(2-hydroxyethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (0.53 g) as an oil.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2OCC[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.Cl.C(=O)([O-])O.[Na+]>CO>[CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CSc2ccc(C3OCCO3)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=Cc1ccc(SCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of 2-(4-benzylsulfanyl-phenyl)-[1,3]dioxolane (1.06 g, 3.89 mmol) described in Manufacturing Example 205-1-1 in methanol (5 mL) and tetrahydrofuran (5 mL) was added 1 N hydrochloric acid (4.16 mL), which was stirred for 30 minutes at room temperature. The mixture was cooled to 0° C. and neutralized with a saturated sodium hydrogencarbonate aqueous solution, and then extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (840 mg). The title compound was used in the following reaction without any further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][C:11](Cl)=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][O:21][C:22](=[O:25])[CH2:23][NH2:24].C(N(C(C)C)CC)(C)C>C(O)CCC>[CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][C:11]([NH:24][CH2:23][C:22]([O:21][CH3:20])=[O:25])=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CN
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COC(=O)CNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 150 °C
Reaction time: 19 h
Yield: 17.2 %

Procedure:
9-Benzyl-2-chloroadenine (0.30 g, 1.12 mmol), glycine methyl ester hydrochloride (0.72 g, 5.73 mmol) and diisopropylethylamine (1.48 g, 11.47 mmol) were added to n-butanol (10 ml), and the mixture was stirred in an autoclave at 150° C. for 19 hours. The solvent was removed and the residue was poured into water. The solution was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated and the residue was purified by column chromatography to give 9-benzyl-2-methoxycarbonylmethylaminoadenine (0.06 g) as a brown tar. Thus obtained 9-benzyl-2-methoxycarbonylmethylaminoadenine was dissolved in dichloromethane (10 ml) and to the solution was added bromine (0.05 ml) in an ice bath. The mixture was stirred at room temperature for 1 hour. After removing the solvent, the residue was poured into water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated and the residue was purified by column chromatography to give 9-benzyl-8-bromo-2-methoxycarbonylmethylaminoadenine (0.06 g) as a yellow solid.
Reaction SMILES: [BH4-].[Na+].CC(C)=O.[CH3:7][C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH:11]=[C:10]([CH3:25])[C:9]=1[SH:26].Cl.[N+:28]([CH3:31])([O-:30])=[O:29]>C(O)C.O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:7][C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH:11]=[C:10]([CH3:25])[C:9]=1[S:26][CH2:31][N+:28]([O-:30])=[O:29]
Reactant: Cc1ccccc1CC(=O)Nc1cc(C)c(S)c(C)c1
Reactant: C[N+](=O)[O-]
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: Cl
Agent: [BH4-]
Solvent: CCO
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccccc1CC(=O)Nc1cc(C)c(SC[N+](=O)[O-])c(C)c1
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Sodium borohydride (0.24 g, 6.3 mM) was added in portions to a stirred suspension of 2,6-dimethyl-4-[2-(2-metbylphenyl)acetamidophenyl thiocyanate (0.5 g, 1.6 mM), in ethanol (20 mL). After 30 minutes, acetone (0.47 mL, 6.4 mM) was added to remove excess sodium borohydride and the mixture stirred for 10 minutes to give a clear yellow solution containing 2,6-dimethyl-4-[2-(2-methylphenyl)acetamido]benzenethiol. Nitromethane (0.09 mL, 1.6 mM) was then added followed, after 10 minutes, by a solution of potassium ferricyanide (0.53 g, 1.6 mM) in water (10 mL). Progress of the reaction was followed by standard thin layer chromatographic (tlc) analysis. After 1 hour, unreacted thiol remained and so further nitromethane (0.45 mL, 0.8 mM) and a solution of potassium ferricyanide (0.27 g, 0.8 mM) in water (5 mL) was added. After about a further 1 hour, thiol was no longer detectable by tlc analysis. Water (500 mL) was then added. The reaction mixture was acidified to pH4 with 2M HCl and extracted with ethyl acetate. The extracts were dried (MgSO4) and the solvent evaporated. The sticky, orange solid was triturated with ether. The orange filtrate was separated and the solid residue discarded. The filtrate was evaporated to give (2,6-dimethyl-4-[2-(2-methylphenyl)acetamido]phenylthio)nitromethane as an orange/brown solid, m.p. 152° C. (decomposition) in 20% yield and which was used without purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH3:22])=[CH:10][CH:9]=2.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[CH3:22][O:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:23])[N:6]([CH3:24])[C:5]([CH2:4][CH2:3][NH:2][C:32](=[O:34])[CH3:33])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc2c(=O)n(C)c(CCN)c(-c3ccccc3)c2c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(=O)n(C)c(CCNC(C)=O)c(-c3ccccc3)c2c1
Reaction time: 0.75 h

Procedure:
To a solution of 3-(2-aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one hydrochloride (75 mg, 0.22 mmol) in 2 mL of dichloromethane was added triethylamine (0.076 mL, 0.54 mmol), followed by acetyl chloride (0.017 mL, 0.24 mmol). After 45 minutes, the mixture was partitioned between EtOAc and 10% citric acid solution, and the organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC to provide the titled product as a colorless oil. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C21H22N2O3 (M+H+): 351.1703. Found 351.1681.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:11][C:12](=[O:30])[C:13]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2)=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10].O>CS(C)=O>[N:25]1[C:26]2[C:21](=[C:20]([C:13]3([C:12]([O:11][CH2:9][CH3:10])=[O:30])[CH2:4][CH:14]3[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)C=C(C(=O)OCC)c1cccc2ncccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1CC1(C(=O)OCC)c1cccc2ncccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Sodium hydride (0.93 g) was added in small portions to a stirred suspension of trimethylsulfoxonium iodide (5.12 g) in DMSO (50 mL) at room temperature. After 0.5 h, the clear reaction mixture was cooled to 0° C. and a solution of diethyl-2-(5-quinolinyl)-2-butenedioate (P24, 3.48 g) in DMSO (25 mL) was quickly added and the stirring continued for 0.5 h after which time water (30 mL) was added. The mixture was extracted twice with ether (30 mL), the organic phase was washed with saturated ammonium chloride, dried over sodium sulphate and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluting with cyclohexane-ethyl acetate from 100 to 70%) to give 3.02 g of the title compound as a slightly yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.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>[Br:8][C:4]1[N:3]=[C:2]([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])[CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C)OB(c2ccccc2C#N)OC1(C)C
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1-c1cccc(Br)n1
Temperature: 80 °C
Yield: 100 %

Procedure:
2,6-Dibromopyridine (0.47 g, 2.0 mmol), 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (0.69 g, 3.0 mmol) and potassium phosphate (0.85 g, 4.0 mmol) were dissolved in N,N-dimethylformamide (10 ml) and degassed with nitrogen for 15 min. Tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol) was added then the mixture heated at 80° C. for 16 h. The mixture was allowed to cool to ambient temperature, diluted with water (200 ml) and extracted into ethyl acetate (2×150 ml). The combined organics were washed with brine (200 ml), dried over anhydrous sodium sulfate and evaporated to give a yellow oil. Purification by flash column chromatography on silica eluting with isohexane on a gradient of ethyl acetate (10-30%) gave 2-(6-bromopyridin-2-yl)benzonitrile (0.518 g, 100%) as a waxy solid: δH (360 MHz, CDCl3) 7.53-7.57 (2H, m), 7.68-7.72 (2H, m), 7.80 (1H, d, J 8), 7.86-7.90 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][S:18]([NH2:21])(=[O:20])=[O:19])[C:12](=[O:22])[N:11]([CH3:23])[C:10]=3[N:9]=[C:8]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=2)=[CH:4][CH:3]=1.IC.[C:40](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][S:18]([NH:21][CH3:40])(=[O:20])=[O:19])[C:12](=[O:22])[N:11]([CH3:23])[C:10]=3[N:9]=[C:8]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:34])([F:33])[F:35])[CH:26]=2)=[CH:36][CH:37]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=O)n(CS(N)(=O)=O)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNS(=O)(=O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)methanesulfonamide (0.1 g, 0.18 mmol, example 18) in DMF (3 mL) was added iodomethane (16 mg, 0.18 mmol) and potassium carbonate (36 mg, 0.26 mmol). The reaction was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative-HPLC to give 1-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8 (3-(trifluoromethoxy)-phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-methylmethanesulfonamide (23 mg, 22.3% yield) as a white solid. 1H-NMR (DMSO-d6) δ 7.63(t, 1H), 7.50(d, 1H), 7.41-7.46(m, 4H), 7.34-7.37(m, 1H), 7.19-7.23(m, 1H), 5.45(s, 2H), 5.20(s, 2H), 3.31(s, 3H), 2.60(d, 3H). LCMS retention time 3.097 min; LCMS MH+ 574
Reaction SMILES: [CH3:1][C:2]1O[C:4](=[O:15])[C:5]2[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.Br.[NH2:17][C@:18]1([CH3:26])[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25].N1C=CN=C1.C1(OP(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[CH3:26][C@@:18]1([N:17]2[C:4](=[O:15])[C:5]3[C:6](=[CH:8][CH:9]=[CH:10][C:11]=3[N+:12]([O-:14])=[O:13])[N:7]=[C:2]2[CH3:1])[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25]
Reactant: C[C@@]1(N)CCC(=O)NC1=O
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1
Agent: Br
Agent: c1c[nH]cn1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1[C@]1(C)CCC(=O)NC1=O
Temperature: 45 °C
Reaction time: 40 h
Yield: 18.7 %

Procedure:
A mixture of 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one (2.0 g, 9.7 mmol), (R)-3-amino-3-methylpiperidine-2,6-dione hydrobromide (2.2 g, 9.7 mmol), imidazole (1.5 g, 21 mmol), and triphenylphosphite (3.7 g, 12 mmol) in DMF (20 mL) was stirred under nitrogen at 45° C. for 40 hours. The mixture was evaporated, and the residue was chromatographed on silica gel using a dichloromethane-acetonitrile gradient. The product eluted at 60% acetonitrile, providing (R)-3-methyl-3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione as a yellow solid (0.60 g, 19% yield); 1H NMR (DMSO-d6) δ 1.94 (s, 3H, CH), 2.35-2.40 (m, 1H, CHH), 2.45-2.59 (m, 2H, 2CHH), 2.71-2.83 (m, 4H, CH3, CHH), 7.75-7.82 (m, 2H, Ar), 7.95 (dd, J=8, 8 Hz, 1H, Ar), 10.86 (s, 1H, NH).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]2[C:7](=[O:18])[C:8]3[O:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:16]=3[O:17][C:5]=2[CH:4]=1.N1C(=O)CC[C@H]1C(O)=O.Cl>>[OH:2][C:3]1[CH:20]=[CH:19][C:6]2[C:7](=[O:18])[C:8]3[O:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:16]=3[O:17][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(=O)c3oc4ccccc4c3oc2c1
Agent: Cl
Agent: O=C1CC[C@@H](C(=O)O)N1
Product: O=c1c2ccc(O)cc2oc2c1oc1ccccc12
Temperature: 25 °C
Yield: 54.8 %

Procedure:
The starting methyl ether 18 (0.55 g, 2.1 mmol) was heated at 200° C. with Pyr-HCl (5 g) for one hour. The reaction mixture was allowed to cool to rt and worked up by partitioning between 2N HCl and EtOAc/MeOH. The organic layer was washed with NaHCO3 aq and brine and dried over MgSO4. Concentration gave 24 (0.29 g) as a tan solid: MP>300° C.; 1H NMR (DMSO-d6) δ 11.2 (br s, 1H), 8.14-8.07 (m, 2H), 7.87 (d, 1H, J=8.5 Hz), 7.76-7.70 (m, 1H), 7.55-7.52 (m, 1H), 7.09 (d, 1H, J=1.9 Hz), 7.02 (dd, 1H, J=8.8 Hz, 1.9 Hz); MS APCI 253 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:11]2[CH:21]=[CH:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[CH3:29])[C:12]=2[C:13](=[O:18])[N:14]([CH2:16][CH3:17])[N:15]=1>CN(C=O)C.O>[CH3:29][C:23]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=1[N:19]1[C:12]2[C:13](=[O:18])[N:14]([CH2:16][CH3:17])[N:15]=[C:10]([O:6][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[C:11]=2[CH:21]=[CH:20]1
Reactant: CCn1nc(Cl)c2ccn(-c3ccc(C)cc3C)c2c1=O
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)Oc1nn(CC)c(=O)c2c1ccn2-c1ccc(C)cc1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
To a solution of 3-pentanol (0.079 ml, 0.73 mmol) in DMF (1 ml) was added sodium hydride (60% in oil, 29 mg, 0.73 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-(2,4-dimethylphenyl)-6-ethyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (55 mg, 0.18 mmol). The mixture was stirred at 60° C. for 4 hours, then diluted with water (30 ml) and extracted with ethyl acetate (50 ml). The extract were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (10:1) to give 48 mg (48%) of the title compound as an oil.