Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][O:16][CH3:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>CCOC(C)=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>[F:21][C:22]1[N:23]=[CH:24][C:25]([C:2]2[CH:7]=[N:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][O:16][CH3:17])=[CH:10][CH:9]=3)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=2)=[CH:26][CH:27]=1
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Reactant: COCOc1ccc(-c2ncc(Br)cc2[N+](=O)[O-])cc1
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
Solvent: CCOC(C)=O
Product: COCOc1ccc(-c2ncc(-c3ccc(F)nc3)cc2[N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 67.5 %

Procedure:
A mixture of 5-bromo-2-(4-(methoxymethoxy)phenyl)-3-nitropyridine (68 mg, 0.2 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (45 mg, 0.2 mg), tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol), Na2CO3 (0.5 mL, 1 M aqueous solution) and dioxane (1.5 mL) was heated at 100° C. for 10 min in a microwave reactor. After cooling to rt, the reaction was diluted with EtOAc (20 mL) and washed with brine (20 mL) and water (2×20 mL) and dried over MgSO4. Solvent was removed under reduced pressure and the residue was purified by silica chromatography (EtOAc in hexane, 5% to 40%) to afford 6′-fluoro-6-(4-(methoxymethoxy)phenyl)-5-nitro-3,3′-bipyridine as a yellow solid (48 mg, 67%). MS (ESI) m/z [M+H]+356.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=2)(=[O:10])=[O:9])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: Nc1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(S(=O)(=O)Nc2ccc(Br)cc2)ccc1Cl
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of 4-chloro-3-nitrobenzenesulfonyl chloride (2.561 g, 10 mmol) in acetic acid (20 mL) was treated with 4-bromoaniline (1.72 g, 10 mmol) and anhydrous sodium acetate (1.23 g, 15 mmol), then heated at 100° for 30 minutes. The reaction was cooled to room temperature and the acetic acid removed by rotary evaporation under vacuum. The residue was taken up in ethyl acetate (100 mL) and washed with water (2×25 mL) and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum, co-evaporating the oil with methylene chloride/hexanes. Purification by silica gel chromatography using methylene chloride followed by 5% ethyl acetate/methylene chloride as eluent provided the title compound as a yellow solid (2.038 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:7]
Reactant: CCCNCCC
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1ccnc(Cl)c1
Yield: 76.5 %

Procedure:
Stir a solution of 2-chloroisonicotinic acid (1.0 g, 6.3 mmol), 1-hydroxybenzotriazole (850 mg, 6.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.21 g, 6.3 mmol), dipropyl amine (862 μL, 6.3 mmol), and triethylamine (1.75 mL, 12.6 mmol) in dichloromethane (63 mL) at room temperature over the weekend. Wash the solution with 0.1 N citric acid (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), saturated aqueous sodium chloride (50 mL), dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:hexanes) to give the title compound (1.16 g, 76%).
Reaction SMILES: Cl.C(OC(=O)[NH:8][C:9]([CH3:37])([CH3:36])[CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[C:20]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:13]=[C:12]1[CH2:32][O:33][CH2:34][CH3:35])(C)(C)C>C(O)C>[CH2:25]([O:24][C:20]1[CH:19]=[CH:18][C:17]2[N:16]=[CH:15][C:14]3[N:13]=[C:12]([CH2:32][O:33][CH2:34][CH3:35])[N:11]([CH2:10][C:9]([NH2:8])([CH3:36])[CH3:37])[C:23]=3[C:22]=2[CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)N
Temperature: 25 °C
Yield: 93.2 %

Procedure:
A 50 mL solution of HCl in ethanol (4.3 M) was added to a solution of tert-butyl[2-(8-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]carbamate (8.4 g, 16.6 mmol) in ethanol (50 mL) and heated at reflux temperature for 1 hour. The reaction was cooled to ambient temperature and nitrogen was bubbled through the solution. The solvent was removed under reduced pressure and water was added to the residue. The solution was made basic and then extracted with three portions of dichloromethane. The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated to yield 6.26 g of 2-(8-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethylamine as a brown solid.
Reaction SMILES: CS[C:3]1[N:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][CH:11]=[C:7]2[CH:6]=[C:5]([S:18][CH3:19])[N:4]=1.[CH3:20][O-:21].[Na+]>>[CH3:20][O:21][C:3]1[N:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][CH:11]=[C:7]2[CH:6]=[C:5]([S:18][CH3:19])[N:4]=1
Reactant: CSc1cc2cnc(-c3ccccc3)n2c(SC)n1
Reactant: C[O-]
Agent: [Na+]
Product: COc1nc(SC)cc2cnc(-c3ccccc3)n12

Procedure:
Using the method of Example 61, 5,7-bis(methylthio)-3-phenylimidazo[1,5-c]pyrimidine (from Example 30) was reacted with sodium methoxide to provide 5-methoxy-7-methylthio-3-phenylimidazo[1,5-c]pyrimidine as a pale yellow solid after recrystallization from cyclohexane, m.p. 134°-135°0 C. Analysis: Calculated for C14H13N3OS: %C, 62.0; %H, 4.8; %N, 15.5; Found; %C, 62.0; %H, 4.7; %N, 15.7.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4]O)[CH3:2].[ClH:10]>O>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][Cl:10])[CH3:2]
Reactant: Cl
Reactant: CCCCC(CC)CO
Solvent: O
Product: CCCCC(CC)CCl

Procedure:
A 1 l jacketed glass reactor with a glass paddle stirrer, an immersed tube for reactant metering and an attached water separator is initially charged with 200 g of N-n-butylalkylpyridinium chloride (prepared according to Example 1 as catalyst and adjusted to a temperature of 135° C. 519.8 g of 2-ethylhexanol are introduced uniformly via the immersed tube within 5 h. Over the entire reaction time, gaseous hydrogen chloride is likewise metered in via the immersed tube in a slight stoichiometric excess (223 g). The water of reaction is distilled off azeotropically with the target product and removed as the lower phase in the water separator, while the upper phase is recycled into the reactor. After a total reaction time of 22 h, the conversion based on the 2-ethylhexanol is 99.3%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([CH3:10])=[CH:4][C:3]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[O:25]1CCC[CH2:26]1>>[C:8]([C:6]1[C:5]([CH3:10])=[CH:4][C:3]2[N:11]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[C:26](=[O:25])[NH:1][C:2]=2[CH:7]=1)#[N:9]
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1C#N
Reactant: C1CCOC1
Product: Cc1cc2c(cc1C#N)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 100 %

Procedure:
A solution of 1,1-dimethylethyl 4-[(2-amino-4-cyano-5-methylphenyl)amino]-1-piperidinecarboxylate (D92) (2.55 mmol, 840 mg) in tetrahydrofuran (8 mL) was treated with N,N′-carbonyldiimidazole (3.83 mmol, 613 mg, 1.5 eq) under argon at room temperature, then the mixture was heated at 50° C. for 1 h, concentrated under reduced pressure, and the residue was treated with 10% aqueous sodium carbonate solution and extracted twice with ethyl acetate. The organics were combined, dried and concentrated under reduced pressure to give the title compound (3.23 mmol, 1.15 g, >100% yield). M+H 357.3, 301.2 (full molecule and fragment for loss of the tert-butyl group).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].Cl[C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][N:29]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][N:29]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)c1ccnc(Cl)c1
Reactant: COc1cc(B(O)O)cc(OC)c1OC(C)C
Product: CCOC(=O)c1ccnc(-c2cc(OC)c(OC(C)C)c(OC)c2)c1

Procedure:
To a solution of 3,5-dimethoxy-4-isopropoxyphenylboronic acid (1.23 g) and ethyl 2-chloroisonicotinate (0.95 g) were condensed in the same manner as described in Preparation Example 1 to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][C:15]([O:17]C)=[CH:16][C:10]=2[O:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)[CH3:2].C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:10]=2[O:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CN1Cc2ccc(OC)cc2Oc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: CCOC(=O)CN1Cc2ccc(O)cc2Oc2ccccc21
Reaction time: 0.5 h

Procedure:
A solution of 1-5 (400 mg, 1.27 mmol) in dichloromethane (5 mL) was cooled to −5° C. and treated with ethanethiol (419 mg, 6.75 mmol) and aluminum chloride (815 mg, 6.11 mmol). After 30 min, the reaction was quenched with aqueous ammonium chloride solution. The solvent was removed in vacuo and the residue dissolved in 1M HCl. The aqueous layer was extracted with three portions of dichloromethane and the combined organic extracts were washed with brine and dried (Na2SO4). The solvent was removed in vacuo. Preparative centrifugal chromatography (SiO2, 4 mm, 10% EtOH; 90% CH2C2) afforded 1-6.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([NH2:24])[CH:17]=[CH:16][C:15]=1[C:25]1[CH:29]=[CH:28][O:27][C:26]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl.N1C=CC=CC=1>[NH2:13][C:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([NH:24][S:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Br:1])(=[O:11])=[O:10])[CH:17]=[CH:16][C:15]=1[C:25]1[CH:29]=[CH:28][O:27][C:26]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)c1occc1-c1ccc(N)c(C(=O)OC)c1N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1occc1-c1ccc(NS(=O)(=O)c2ccc(F)cc2Br)c(C(=O)OC)c1N
Reaction time: 1 h
Yield: 83.1 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.584 g) was added to a solution of ethyl 3-(2,4-diamino-3-methoxycarbonylphenyl)-furan-2-carboxylate (Intermediate 89, 0.650 g) in DCM (30 mL) and pyridine (10 mL). The resultant mixture was stirred at room temperature for 45 minutes. A further amount of 2-bromo-4-fluorobenzene-sulfonyl chloride (0.584 g) was added and the mixture stirred for a further 1 hour. A further amount of 2-bromo-4-fluorobenzenesulfonyl chloride (0.300 g) was added and the mixture stirred for a further 30 minutes. The mixture was concentrated in vacuo and the residue was partitioned between water and DCM. The organic layer was dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was triturated with methanol and the resultant solid was collected by filtration and air dried to give ethyl 3-[2-amino-4-(2-bromo-4-fluorobenzenesulfonylamino)-3-methoxycarbonylphenyl]-furan-2-carboxylate (0.960 g) as a powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:24][O:23][N:22]([CH3:21])[C:17]([CH:14]1[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15]1)=[O:19]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
A mixture of 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (10 g, 38.0 mmol), N,O-dimethylhydroxylamine hydrochloride (5.56 g, 57.0 mmol), and CH2Cl2 (120 mL) was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.92 g, 57.0 mmol) and 4-(dimethylamino)pyridine (0.464 g, 3.80 mmol). The mixture was cooled in an ice bath and treated with N,N-diisopropylethylamine (13.23 mL, 76 mmol) over 3 min. After 10 min, the cooling bath was removed and the mixture was stirred at RT overnight (˜14 h). The mixture was diluted with CH2Cl2 (150 mL), washed with saturated NaHCO3 (3×50 mL), 2 M HCl (2×50 mL) and brine, dried over MgSO4, and concentrated to provide a residue. The residue was purified by flash chromatography using a 120 g silica gel cartridge and 10:1 Hex/EtOAc to elute the product. The fractions containing the product were pooled and concentrated on a rotary evaporator to give the title compound (7.8 g, 25.5 mmol, 67% yield) as a pale yellow oil. LC-MS: 307.1, (M+H)+. 1H-NMR (400 MHz, CDCl3) δ ppm 7.25-7.37 (5H, m), 5.11 (2H, s), 4.21 (2H, s), 3.66-3.71 (3H, m), 3.16 (3H, s), 2.83 (3H, d, J=5.93 Hz), 1.64-1.75 (4H, m).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][N:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[C:16]([F:15])[CH:17]=1
Reactant: Nc1cccc(F)c1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Product: N#Cc1cnc2cnc(F)cc2c1Nc1cccc(F)c1
Yield: 45.2 %

Procedure:
Following the procedure described above in Example 13, 4-chloro-6-fluoro-1,7-naphthyridine-3-carbonitrile (0.300 g, 1.45 mmol) was reacted with 3-fluoroaniline (0.15 mL, 0.18 g, 1.6 mmol). The crude product was purified by flash chromatography over silica gel (10% EtOAc in CH2Cl2) to give pure 6-fluoro-4-(3-fluorophenylamino)-1,7-naphthyridine-3-carbonitrile (0.185 g, 45% yield): 1H NMR (400 MHz, DMSO-D6) δ 7.16 (td, J=8.5, 2.7 Hz, 1 H) 7.22 (ddd, J8.0, 2.0, 0.9 Hz, 1 H) 7.27 (dt, J=10.2, 2.2 Hz, 1 H) 7.43-7.53 (m, 1 H) 8.17 (s, 1 H) 8.72 (s, 1 H) 9.10 (s, 1 H) 10.16 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)[N:3]=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]2[CH:13]=[C:14]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][C:20]([F:19])([F:32])[F:31])[CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: CCOC(=O)c1cn(-c2cccc(Br)c2)nc1N
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)nc1N
Yield: 74 %

Procedure:
To a solution of the product from Step 1 (0.452 g, 1.45 mmol) in toluene (4 mL) were added 2-trifluoromethoxyphenylboronic acid (0.450 g, 2.18 mmol), tetrakis(triphenylphosphine)palladium (0.050 g, 3 mol %) and 2M sodium carbonate (1.45 mL, 2.9 mmol). The reaction was refluxed for 16 hours, then cooled and partitioned between EtOAc and water. The organic phase was washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. The filtrate was concentrated in vacuo, and the crude product was purified by silica-gel chromatography using 4% EtOAc in hexanes to yield 0.42 g of the product (73% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:23]=[CH:22][C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[NH:17][C:18](=[O:20])[S:19]/2)=[CH:12][CH:11]=1)[CH3:8].Br[CH2:25][CH2:26][CH3:27]>CN(C=O)C>[CH2:7]([O:9][C:10]1[CH:23]=[CH:22][C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[N:17]([CH2:25][CH2:26][CH3:27])[C:18](=[O:20])[S:19]/2)=[CH:12][CH:11]=1)[CH3:8]
Reactant: CCCBr
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)S/C(=C\c2ccc(OCC)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Potassium carbonate (93 mg, 0.60 mmol) was added to a solution of compound 2 (75 mg, 0.30 mmol) in 3 mL of anhydrous DMF at 0° C. After stifling of the reaction mixture for 20 min, a solution of 1-bromopropane (30 μL, 0.33 mmol) in 1 mL of anhydrous DMF was added and then the reaction mixture was stirred at room temperature overnight. The reaction was quenched by adding water and extracted with ethyl acetate. The ethyl acetate layer was washed with water (4×20 mL) and dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (15% ethyl acetate in hexanes) to afford 82 mg (93.9%) as a light-yellow solid.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C@H:8]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[C:11](=[O:21])[N:10]([CH2:22][CH2:23][CH2:24][Br:25])[C@H:9]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(O)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Br:25][CH2:24][CH2:23][CH2:22][N:10]1[C:9]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[C:5](=[O:6])[C:8]=2[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[C:11]1=[O:21]
Reactant: O=C(O)[C@H]1c2ccc([N+](=O)[O-])cc2C(=O)N(CCCBr)[C@H]1c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C1c2ccccc2-c2c1c1ccc([N+](=O)[O-])cc1c(=O)n2CCCBr
Temperature: 25 °C
Yield: 45.3 %

Procedure:
Thionyl chloride (5 mL) was added to a solution of cis-4-carboxy-3,4-dihydro-N-(3-bromopropyl)-3-phenyl-7-nitro-1(2H)isoquinolone (8b) (1.000 g, 2.308 mmol) in benzene (50 mL). The reaction mixture was heated at reflux for 30 min, allowed to cool to room temperature, and concentrated. The residue was diluted with nitrobenzene (30 mL), chilled in an ice bath, and aluminum chloride (0.616 g, 4.616 mmol) was added. The reaction mixture was removed from the bath and heated at 100° C. for 1 h. Ice water (100 mL) was added and the solution was extracted with CHCl3 (3×100 mL). The combined organic layer was washed with sat NaHCO3 (3×50 mL), sat NaCl (50 mL) and dried over sodium sulfate. The solution was concentrated, hexanes (900 mL) were added, and liquid was decanted. The obtained solid was washed with hexanes (100 mL) and the liquid was again decanted. The crude solid was purified by flash column chromatography (SiO2), eluting with chloroform, to provide an orange solid (0.432 g, 45%): mp 258-260° C. (dec). IR (film) 1672, 1612, 1560, 1503, 1428, and 1337 cm−1; 1H NMR (CDCl3) δ 9.20 (d, J=2.4 Hz, 1H), 8.89 (d, J=8.9 Hz, 1H), 8.52 (dd, J=9.0 Hz and 2.4 Hz, 1H), 7.92 (m, 1H), 7.75 (m, 1H), 7.57-7.52 (m, 2H), 4.76 (m, 2H), 3.70 (t, J=6.2 Hz, 2H), 2.54 (m, 2H); CIMS m/z (rel intensity) 413/415 (MH+, 100/82). Anal. (C19H13BrN2O4) C, H, N.
Reaction SMILES: [N:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:9]1([CH2:12][CH2:13][NH:14][C:15]([C:17]2[N:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1>>[CH:9]1([CH2:12][CH2:13][NH:14][C:15]([C:17]2[N:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:7])[CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)N1CCCC1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)N3CCCC3)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use pyrrolidine-1-carbonyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (54% yield). 1H NMR (400 MHz, CDCl3) δ 8.04, 7.98, 6.99, 3.79, 3.56, 3.47-3.45, 3.40, 1.87-1.85, 1.52, 0.80-0.72, 0.48-0.46, 0.10-0.09.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH3:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>C(N(CC)CC)C.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][C:20]([OH:24])([C:22]#[C:23][C:12]1[C:13]2[C:4]([N:5]=[C:6]3[C:11]=1[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=[CH:7]3)=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)[CH3:21]
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2nc3cc(Cl)ccc3c(C#CC(C)(C)O)c2c1

Procedure:
A mixture of 6,9dichloro-2-methoxyacridine (3.5 g, 12.6 mmol), 2-methyl-3-butyn-2-ol (1.27 g, 15 mmol), dichlorobis(triphenylphosphine)palladium (100 mg), and cuprous iodide (25 mg) in triethylamine (35 mL) and dimethylformamide (20 mL) was heated at 90° for 12 h. The mixture was cooled and diluted with aqueous potassium carbonate to give the title compound. MS(ES) m/e 326.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][CH2:9][CH2:10][CH2:11]O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[I:33]C>C(#N)C.C(OCC)C>[CH2:13]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])[CH2:8][CH2:9][CH2:10][CH2:11][I:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N(CCCCO)Cc1ccccc1
Reactant: CI
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CCCCI)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
To a solution of benzyl-(4-hydroxy-butyl)-carbamic acid tert butyl ester (6.06 g 21.7 mmol) in acetonitrile (25 mL), carbonyldiimidazole (3.52 g 21.7 mmol) and iodomethane (6.8 mL 109 mmole) were added. The reaction mixture became lukewarm and was stirred for an hour at room temperature followed by another 2 h under reflux. The reaction mixture was allowed to cool to room temperature and additional iodomethane (6.8 mL) was added and the reaction was refluxed for an additional hour. The reaction mixture was allowed to cool to room temperature and was diluted with diethyl ether (150 mL) resulting in a white suspension that was washed with of water (100 mL). The organic layer was washed successively with, 1N HCl (50 mL), saturated NaHCO3 (50 mL), 5% Na2S2O3 (50 mL), and brine. The organic layer was dried on Na2SO4 and the resulting yellow oil crude was purified by flash chromatography using a 95:5 mixture of ethyl acetate-petroleum ether as eluent to give N-benzyl-N-(t-butoxycarbonyl)-4-amino-1-iodobutane (4.49 g, 53%) as colorless, viscous oil. 1H NMR (CDCl3) δ 7.24-7.35 (m, 5H); 4.42 (bs, 2H); 3.19 (bs, 4H); 1.76 (bs, 2H); 1.6 (bs, 2H); 1.51 (s, 9H).