Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[CH:3]=1.[Cl:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Cl:10][CH2:11][CH2:12][CH2:13][C:14]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[S:8][CH3:9])=[O:15]
Reactant: CSc1cccc(F)c1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1cc(F)ccc1C(=O)CCCCl
Temperature: 20 °C
Reaction time: 12 h
Yield: 81 %

Procedure:
To a solution of 1-fluoro-3-(methylsulfanyl)benzene (1.98 g, 14.0 mmol) and 4-chlorobutyryl chloride in CH2Cl2 (15 mL) was added AlCl3 (2.06 g, 15.4 mmol) at 20° C. under N2. The reaction mixture was stirred for 15 h at 20° C. for 12 h then quenched by addition of H2O and extracted with Et2O. The combine organic solution was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting white solid was recrystalized to give 4-chloro-1-[4-fluoro-2-(methylsulfanyl)phenyl]-1-butanone (2.80 g, 81%) as a white needle shape crystal.
Reaction SMILES: [O:1]([C@H:9]([CH3:13])[CH2:10][CH2:11][OH:12])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:24][C:25]1[CH:26]=[C:27]([N:32]2[C:37](=[O:38])[C:36](Br)=[C:35]([Br:40])[CH:34]=[N:33]2)[CH:28]=[CH:29][C:30]=1[F:31]>C1COCC1>[F:24][C:25]1[CH:26]=[C:27]([N:32]2[C:37](=[O:38])[C:36]([O:12][CH2:11][CH2:10][C@H:9]([O:1][Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:4])[CH3:3])[CH3:13])=[C:35]([Br:40])[CH:34]=[N:33]2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: C[C@H](CCO)O[Si](C)(C)C(C)(C)C
Reactant: O=c1c(Br)c(Br)cnn1-c1ccc(F)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](CCOc1c(Br)cnn(-c2ccc(F)c(F)c2)c1=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
To a stirred, 0° C. solution of the product from Example 545B (3.4 g, 10 mmol) in THF (20 mL) was added 1M sodium bis(trimethylsilyl)amide in THF (12 mL, 12 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, then it was transferred to a stirred, −30° C. solution of 2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone (3.66 g, 10 mmol) in THF (100 mL). The reaction mixture was stirred at −30° C. for 1 hour, then overnight while warming to room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was washed with brine (2×20 mL), then dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 90:10 hexane/ethyl acetate) to provide the title intermediate (2.5 g, 51%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>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.O>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccnc(Cl)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: COCCOC
Solvent: O
Product: O=C(O)c1ccnc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 40.2 %

Procedure:
A mixture of 2-chloro-pyrimidine-4-carboxylic acid (2.0 g, 13 mmol), 4-trifluoromethyl phenyl boronic acid (2.4 g, 13 mmol), tetrakis(triphenylphosphine)palladium(0) (0.7 g, 0.6 mmol), potassium phosphate (5.3 g, 25 mmol), 1,2-dimethoxyethane (40 mL) and water (8 mL) was heated to 80° C. under a blanket of nitrogen in a sealed tube. After 5 h, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were discarded, and the aqueous layer was acidified with concentrated HCl to pH 2. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified directly by FCC to afford a white solid (1.4 g, 42%). MS (ESI): mass calcd. for C12H7F3N2O2, 268.0 m/z found, 269.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C([O-])(=O)C.[Na+]>CO.[Pd]>[N:8]1([C:7]2[CH:6]=[CH:5][N:4]=[N:3][CH:2]=2)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: Clc1cc(N2CCNCC2)c(Cl)nn1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: c1cc(N2CCNCC2)cnn1

Procedure:
9.3 g of 3,6-dichloro-4-piperazin-1-yl-pyridazine (see 10.2) and 6.5 g sodium acetate are suspended in 100 ml of methanol and hydrogenated with 1 g Pd/C 10% and ambient temperature. The catalyst is suction filtered and the filtrate evaporated to dryness. The product is extracted with chloroform, washed with sodium hydroxide solution and precipitated as the hydrochloride with an ethereal HCl solution. 8.6 g of (V-4) are obtained. M.p>300° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:12][C:11]2[C:10](=[O:13])[N:9]([CH2:14][CH2:15][CH2:16][OH:17])[C:8](=[O:18])[N:7]([CH2:19][CH3:20])[C:6]=2[N:5]=1)[CH3:2].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:12]2[C:11]3[C:10](=[O:13])[N:9]([CH2:14][CH2:15][CH2:16][OH:17])[C:8](=[O:18])[N:7]([CH2:19][CH3:20])[C:6]=3[N:5]=[C:4]2[O:3][CH2:1][CH3:2])=[CH:24][CH:25]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CCOc1nc2c([nH]1)c(=O)n(CCCO)c(=O)n2CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1nc2c(c(=O)n(CCCO)c(=O)n2CC)n1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 14.9 %

Procedure:
To a solution of 8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (70 mg, 0.248 mmol, intermediate 26) in DMF (3 mL) was added 1-(bromomethyl)-4-chlorobenzene (80 mg, 0.390 mmol), followed by potassium carbonate (60 mg, 0.435 mmol). The mixture was stirred at 60° C. for 4 h, then diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (15 mg, 14.9% yield) as white solid. 1H-NMR (DMSO-d6) δ 7.43-7.41(d, 2H), 7.34-7.32(d, 2H), 5.21(s, 2H), 4.53-4.44(m, 3H), 3.99-3.88(m, 4H), 3.45-3.39(m, 2H), 1.71-1.64(m, 2H), 1.37-1.33(t, 3H), 1.23-1.19(t, 3H). LCMS retention time 2.654 min; LCMS MH+ 407.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[N+](C)=CCl.[Cl-].C(Cl)(=O)[C:17](Cl)=[O:18]>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:17]=[O:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc2[nH]ccc2c1
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=Cc1cc2ccccc2[nH]1

Procedure:
In Step 1 of Scheme F, indole compound a is treated with the Vilsmeier reagent formed by mixing oxalyl chloride with dimethyl formamide to form indole aldehyde w, which in turn is reacted with Meldrum's acid in Step 2 to yield indole compound x. Indole x is then treated with Grignard reagent y in Step 3 to afford indole compound z. In Step 4 compound z is reacted with amine d in the presence of pyridine to give indole amide r, which is then reduced in Step 5 to provide aminopropyl indole compound s. Compound s is a compound of formula I in accordance with the invention.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=CC=CC=4)[CH:27]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:25]=[CH:24][C:23]4[C:18](=CC=CC=4)[CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C([Li])CCC.C[O:42][B:43]([O:46]C)OC>C1COCC1>[C:26]1([C:5]2[C:6]3[C:11]([C:12]([C:16]4[CH:17]=[CH:18][CH:23]=[CH:24][CH:25]=4)=[C:13]4[C:4]=2[CH:3]=[C:2]([B:43]([OH:46])[OH:42])[CH:15]=[CH:14]4)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:35]=[CH:34][CH:33]=[CH:28][CH:27]=1
Reactant: Brc1ccc2c(-c3ccc4ccccc4c3)c3ccccc3c(-c3ccc4ccccc4c3)c2c1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
In an argon atmosphere, 100 mL of dehydrated THF were added to 10 g (20 mmol) of 2-bromo-9,10-di(2-naphtyl)anthracene, and the temperature of the mixture was cooled to −78° C. Then, 14 mL of n-butyllithium (in hexane, 1.6 mol/L) were dropped. After the mixture had been stirred at −78° C. for 1 hour, the temperature of the mixture was increased to 0° C. The temperature of the mixture was cooled to −78° C. again, and 6.6 mL (60 mmol) of trimethoxyborane were added. The mixture was stirred at −78° C. for 1 hour, and was then stirred at room temperature for 2 hours. 100 mL of 10-mass % hydrochloric were added, and the whole was stirred for 1 hour, followed by filtration. The resultant solid was washed with toluene to obtain 4.7 g of 9,10-diphenylanthracene-2-boronic acid (50% yield).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Cl-].[Al+3].[Cl-].[Cl-]>[CH2:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: ClCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: c1ccc(Cc2ccccc2Cc2ccccc2)cc1
Reaction time: 2 h
Yield: 106.2 %

Procedure:
To a reaction vessel were added 2500 g of diphenylmethane and 40 g of aluminum chloride and reaction was carried out for 2 hours at room temperature with further adding 600 g of benzyl chloride with stirring. After the reaction, the catalyst was deactivated and 1300 g of a dibenzylbenzene isomer mixture (Composition I) was obtained by reduced pressure distillation.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>CN(C)C=O>[Br:3][C:4]1[C:9]([O:10][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Oc1cccnc1Br
Reactant: BrC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ncccc1OC1CCCCC1
Yield: 30 %

Procedure:
Sodium hydride (160 mg) was dissolved in dimethylformamide (5 ml) and 2-bromo-3-pyridinol (500 mg) dissolved in dimethylformamide is slowly added dropwise. Then, bromocyclohexane (0.7 ml) was added to the solution and reacted for 5 hours at room temperature. Water was added to the suspension to dilute and extracted with ethyl acetate to separate an organic layer. The separated organic layer was dried with anhydrous magnesium sulfate and distilled under reduced pressure. As a result, 2-bromo-3-cyclohexyloxy pyridine (220 mg, yield: 30%) was obtained as an oil phase.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=[O:9])(=[O:4])=[O:3]>Cl.CCOCC>[CH3:1][S:2]([O:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: COC(=O)c1ccccc1OS(C)(=O)=O
Agent: Cl
Solvent: CCOCC
Product: CS(=O)(=O)Oc1ccccc1C(=O)O
Yield: 94.1 %

Procedure:
A mixture of methyl 2-(methylsulphonyloxy)benzoate (6.9 g) in hydrochloric acid (6M) was heated at reflux for 0.75 hours. The cooled mixture was diluted with ether and extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-(methylsulphonyloxy)benzoic acid (6.1 g) as a white solid m.p. 125°-126° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].Cl.Cl[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nn(Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1CCC(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 86.1 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (360 mg), 2-chloromethylquinoline hydrochloride (270 mg), potassium carbonate (300 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). After a mixture of the resulting oily substance, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(2-quinolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (420 mg, yield: 86%). This was recrystallized from acetone-hexane. Melting point: 140–141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:12][CH2:13][CH3:14])[C:9](Cl)=[S:10].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:12][CH2:13][CH3:14])[C:9]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[S:10]
Reactant: c1c[nH]cn1
Reactant: CCCN(C(=S)Cl)c1ccccc1Cl
Solvent: C1CCOC1
Product: CCCN(C(=S)n1ccnc1)c1ccccc1Cl
Reaction time: 8 h

Procedure:
12.4 g. N-2-chlorophenyl-N-propyl(thiocarbamoyl) chloride and 6.8 g. imidazole were refluxed in 75 ml. dry tetrahydrofuran for 16 hours. A further 2 g. imidazole was then added and the heating continued for 8 hours. After separating the solid formed evaporation of the tetrahydrofuran left an oil which was dissolved in methylene chloride. The resulting organic phase was washed with water, dried with soldium sulphate and the solvent evaporated to leave an oil which crystallised on treatment with light petroleum and chilling to give the product, 1-[N-2-chlorophenyl-N-propyl (thiocarbamoyl)]imidazole, m.p. 59°-61° C.
Reaction SMILES: [CH:1]1([C@H:7]2[N:12]3[CH:13]=[C:14]([C:19]([OH:21])=O)[C:15]4[CH:16]=[CH:17][CH:18]=[C:10]([C:11]=43)[O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:25])=O>ClCCl>[CH:1]1([C@H:7]2[N:12]3[CH:13]=[C:14]([C:19]([Cl:25])=[O:21])[C:15]4[CH:16]=[CH:17][CH:18]=[C:10]([C:11]=43)[O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cn2c3c(cccc13)OC[C@H]2C1CCCCC1
Solvent: ClCCl
Product: O=C(Cl)c1cn2c3c(cccc13)OC[C@H]2C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (362 mg, 1.23 mmol) in dichloromethane (20 ml) was added oxalyl chloride (0.215 ml, 2.46 mmol). The deep blue mixture was stirred at room temperature for 2 h and then the solvent was removed in vacuo to afford (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid chloride (380 mg, 1.23 mmol) as a blue solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:18]1[C:31]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=2)[C:27](Br)=[CH:26][C:25](Br)=[C:24]4[CH:23]=[CH:22][C:21]3=[C:20](Br)[CH:19]=1>C1C=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>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[C:31]3[C:32]4=[C:33]5[C:28](=[CH:29][CH:30]=3)[C:27]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:26][C:25]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:24]5[CH:23]=[CH:22][C:21]4=[C:20]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=3)[CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Brc1cc(Br)c2ccc3c(Br)cc(Br)c4ccc1c2c43
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: c1ccccc1
Product: Clc1cccc(-c2cc(-c3cccc(Cl)c3)c3ccc4c(-c5cccc(Cl)c5)cc(-c5cccc(Cl)c5)c5ccc2c3c54)c1

Procedure:
4.4 equivalents of 3-chlorophenylboronic acid, 10 equivalents of sodium carbonate in a 2 mol/L aqueous solution, and 0.12 equivalents of tetrakis(triphenylphosphine)palladium (0) were added to one equivalent of 1,3,6,8-tetrabromopyrene obtained in the same way as for EXAMPLE 1, and the mixture was subjected to heating under refluxing to allow reaction for three hours, using benzene as a solvent. 1,3,6,8-tetra(3-chlorophenyl)pyrene was obtained after deposition and purification through recrystallization of the product.
Reaction SMILES: NC(N)=O.[NH2:5][C:6]1[C:7]([OH:17])=[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:9]([Cl:12])=[CH:10][CH:11]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]=[C:27]=[O:28]>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:27]([NH:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])=[O:28])=[C:7]([OH:17])[C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: COc1ccccc1N=C=O
Agent: NC(N)=O
Product: COc1ccccc1NC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 34.4 %

Procedure:
Following the general procedure for urea formation outlined in example 12, 3-amino-6-chloro-2-hydroxybenzenesulfonamide (40 mg, 0.18 mmol) and 2-methoxyphenylisocyanate (33 mg, 0.22 mmol) ) were coupled to form the desired urea (23 mg, 34%). EI-MS (m/z) 370.3, 372.1(M).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[NH:5][C:6]([NH:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[C:7]([F:12])[C:8](=[N:10][NH2:11])[N:9]=1.[CH:20]1([CH2:25][C@H:26]([CH2:30][N:31]([CH:39]=[O:40])[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:27](O)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:3][C:4]1[N:9]=[C:8]([NH:10][NH:11][C:27](=[O:28])[C@H:26]([CH2:25][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:30][N:31]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH:39]=[O:40])[C:7]([F:12])=[C:6]([NH:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[N:5]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Reactant: NN=c1nc(Cl)[nH]c(NCc2nccs2)c1F
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCc2nccs2)c1F)OC1CCCCO1
Reaction time: 8 h
Yield: 61.8 %

Procedure:
2-Chloro-5-fluoro-6-[(1,3-thiazol-2-ylmethyl)amino]-4(1H)-pyrimidinone hydrazone dihydrochloride (0.3052 g, 0.882 mmol) and (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (0.457 g, 1.059 mmol) were dissolved in DMF (8 mL). NMM (0.58 mL, 5.2753 mmol) was added, followed by HOAt (0.144 g, 1.059 mmol) and EDC (0.203 g, 1.059 mmol). After stirring overnight, the reaction mixture was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(1,3-thiazol-2-yl methyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as a beige solid (0.3031 g, 62%). LCMS: (M+H)+=556.2.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:22]([O:24]C)=[O:23])(=[O:10])=[O:9].C(N(CC)CC)C.[CH2:33]([N:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][NH2:39])[CH3:34].Cl>C(#N)C>[CH2:33]([N:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][NH:39][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:22]([OH:24])=[O:23])(=[O:10])=[O:9])[CH3:34]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1CCCC2
Reactant: CCN(CC)CCCN
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2
Temperature: 200 °C

Procedure:
A mixture of Example 229A (143 mg, 0.393 mmol), triethylamine (0.165 mL), acetonitrile (1.2 mL), and N,N-diethyl-1,3-propanediamine (0.37 mL, 2.36 mmol) was sealed and heated in microwave for fifteen hundred seconds at 200° C. The solution was cooled and adjusted to pH 5 with 1N HCl. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic fractions were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by preparative HPLC to provide the desired product. MS (ESI(+)) m/e 460 (M+H)+; (ESI(−)) m/e 458 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.15 (br s, 1H), 9.54 (s, 1H), 9.02 (br s, 1H), 7.51 (dd, 1H), 7.41 (dt, 1H), 6.96 (2, 1H), 6.86 (d, 1H), 6.64 (m, 2H), 6.00 (t, 1H), 3.29 (q, 2H), 3.09 (m, 7H), 2.65 (br s, 4H), 1.89 (m, 2H), 1.67 (br s, 4H), 1.14 (t, 6H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:49][CH:50]1[C@H:54]2[C@H:55](OC3CCCCO3)[N:56](C(OC(C)(C)C)=O)[C:57]3[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][C:58]=3[C:59](=[O:60])[N:53]2[CH2:52][C:51]1=[CH2:81])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH:17]1[C@H:21]2[C@H:22](OC3CCCCO3)[N:23](C(OC(C)(C)C)=O)[C:24]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:25]=3[C:26](=[O:27])[N:20]2[CH2:19][C:18]1=[CH2:48].C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:15]([O:16][CH:17]1[C@@H:21]2[CH:22]=[N:23][C:24]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:25]=3[C:26](=[O:27])[N:20]2[CH2:19][C:18]1=[CH2:48])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:49][CH:50]1[C@@H:54]2[CH:55]=[N:56][C:57]3[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][C:58]=3[C:59](=[O:60])[N:53]2[CH2:52][C:51]1=[CH2:81]
Reactant: C=C1CN2C(=O)c3cc(OC)ccc3N(C(=O)OC(C)(C)C)[C@@H](OC3CCCCO3)[C@@H]2C1OCCCCCCCCOC1C(=C)CN2C(=O)c3cc(OC)ccc3N(C(=O)OC(C)(C)C)[C@@H](OC3CCCCO3)[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=C1CN2C(=O)c3cc(OC)ccc3N=C[C@H]2C1OCCCCCCCCOC1C(=C)CN2C(=O)c3cc(OC)ccc3N=C[C@@H]12
Reaction time: 1 h
Yield: 83.8 %

Procedure:
95% TFA (2 mL) was added dropwise to dimer compound 28a (77 mg, 0.074 mmol) at 0° C. which was stirred for 1 h and then poured into saturated aqueous NaHCO3 (30 mL). The mixture was extracted with chloroform (3×20 mL) and the organic layer was then washed with water (20 mL), brine (20 mL), dried (MgSO4) and filtered. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 29a (39 mg, 0.062 mmol, 84%) as a solid: [α]29D=+428° (c=0.07, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.33-1.54 (m, 8H, 14-H, 15-H), 1.78-1.93 (m, 4H, 13-H), 2.86-2.97 (m, 2H, 1-H), 3.04-3.17 (m, 2H, 1-H), 3.83-3.89 (m, 2H, 11a-H), 3.93 (s, 6H, 7-OMe), 3.99-4.12 (m, 4H, 12-H), 4.28 (s, 4H, 3-H), 5.16-5.19 (m, 4H, 2a-H), 6.79 (s, 2H, 9-H), 7.49 (s, 2H, 6-H), 7.66 (d, 2H, J=4.42 Hz, 11-H); 13C NMR (CDCl3, 100 MHz): δ 25.2, 25.8, 28.8, 29.2, 35.5, 51.3, 53.8, 56.1, 58.4, 69.0, 109.3, 110.4, 111.4, 119.6, 140.7, 141.7, 147.9, 151.0, 162.4, 164.8; IR (neat): 3310, 2932, 2855, 1598, 1503, 1463, 1451, 1429, 1381, 1260, 1216, 1096, 1013, 911, 786, 729 cm−1; MS (ES+) m/z (relative intensity) 627 ([M+H]+., 100), 628 ([M+2H]+., 53), 332 (92), 323 (61).