Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)=[CH:3][CH:2]=1.[C:13](Cl)(=[O:17])[CH2:14][CH2:15][CH3:16].C(N(CC)CC)C>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:8][N:9]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][O:12]2)=[CH:3][CH:2]=1
Reactant: CCCC(=O)Cl
Reactant: c1cc(C2CNCCO2)ccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N1CCOC(c2ccncc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-(pyridin-4-yl)morpholine in dry dichloromethane are added 1.5 eq butanoyl chloride and 2.5 eq triethylamine. After stirring for 6 hours at room temperature the solvent is removed in vacuo and the residue redisolved in ethyl acetate. The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, ethyl acetate is removed in vacuo and the crude 1-(2-(pyridin-4-yl)morpholino)butan-1-one is purified by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH2:10].C(N(CC)CC)C.C1C=[CH:20][C:21](=[O:34])[C:22]2C=1C(C(Cl)=O)=C1C=2C=CC=C1>ClCCl>[CH:21]([O:34][CH:7]([CH3:6])[CH3:2])([CH3:22])[CH3:20].[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH-:10]
Reactant: Nc1cc(F)c(Cl)cc1N
Reactant: O=C(Cl)C1=c2ccccc2=C2C(=O)C=CC=C12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(C)C
Product: [NH-]c1cc(Cl)c(F)cc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 301.9 %

Procedure:
The procedure used in stage 1 of Example 1 is followed, but starting from 1 g of 1,2-diamino-4-chloro-5-fluorobenzene, 1.75 ml of triethylamine and 1.5 g of fluoren-4-one-9-carboxylic acid chloride in 45 ml of dichloromethane. After stirring for 20 hours at room temperature, the precipitate that formed is filtered off, and washed with dichloromethane, with water, then with a 10% saturated aqueous solution of sodium hydrogen carbonate and, finally, with water. After formation of a paste with diisopropyl ether, in this way we obtain 1.5 g of (2-amino-5-chloro-4-fluorophenyl)amide of 9-oxo-9H-fluorene-4-carboxylic acid, in the form of a yellow powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH:24]=O)=[C:19]2[C:23]=1[O:22][CH:21]=[CH:20]2.C(OCC)(=O)C>O1CCCC1.[Cl-].[Na+].O>[Cl:14][C:15]1[C:23]2[O:22][CH:21]=[CH:20][C:19]=2[C:18](/[CH:24]=[CH:3]/[C:1]#[N:2])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(Cl)c2occc12
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#C/C=C/c1ccc(Cl)c2occc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of diethyl cyanomethylphosphonate (7.34 g) in dry tetrahydrofuran (20 ml) was added to a suspension of sodium hydride (60% oil dispersion; 1.65 g) in THF (40 ml) over 5 mins with ice cooling. After 15 min, a solution of 7-chloro-benzofuran-4-carbaldehyde in THF (20 ml) was added and after 5 mins the solution was warmed up and stirred at room temperature for 2 h. Brine (40 ml) and ethyl acetate (40 ml) were added, the phases separated and the aqueous extracted with ethyl acetate (2×20 ml). The extracts were dried (MgSO4) and evaporated and the residue crystallised from ethanol to give off-white fluffy needles (2.95 g) of (E)-3-(7-Chloro-benzofuran-4-yl)-acrylonitrile.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:22]=[CH:21]C(C(O)=O)=[CH:16][CH:15]=2)[S:12][CH:13]=1.CN(C=O)C>C(Cl)Cl>[Cl:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:22]=[CH:21][C:1]([C:2]([Cl:4])=[O:3])=[CH:16][CH:15]=2)[S:12][CH:13]=1
Reactant: O=C(O)c1ccc(-c2nc(CCl)cs2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(-c2nc(CCl)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxalyl chloride (3.2 mL, 36.6 mmol, 5 eq.) was added dropwise to a suspension of 4-[4-(chloromethyl)-1,3-thiazol-2-yl]benzoic acid (1.86 g, 7.32 mmol, 1 eq.) in DCM (10 mL) followed by a catalytic amount of DMF at RT. The reaction mixture was allowed to stir at RT overnight and then evaporated to give the title compound as the crude product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[PH:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28].CCN(CC)CC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:27]([O:26][P:25]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)([O:29][CH2:30][CH3:31])=[O:32])[CH3:28]
Reactant: CCO[PH](=O)OCC
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2ccc(Br)cc2)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(-c2ccc(C(C)(C)NC(=O)OC(C)(C)C)cn2)cc1
Yield: 92.4 %

Procedure:
To a solution of tert-butyl 2-(6-(4-bromophenyl)pyridin-3-yl)propan-2-ylcarbamate, 33-f, (850 mg, 2.17 mmol) in toluene (15 ml) was added diethyl phosphonate (900 mg, 6.52 mmol) and Et3N (660 mg, 6.52 mmol) and PdCl2(dppf) (85 mg) under N2, and the reaction mixture was refluxed for 8 hours. The reaction solution was then evaporated and diluted with EtOAc. The organic phase was washed with brine, dried and concentrated. Purified by silica gel (DCM-DCM:MeOH=50:1) to give tert-butyl 2-(6-(4-(diethoxyphosphoryl)phenyl)pyridin-3-yl)propan-2-ylcarbamate (900 mg, 92.4%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C:8]3[CH:19]=[CH:20][C:21](Br)=[CH:22][C:7]2=3)[N:6]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.[C:35]([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[C:16]([CH3:35])[C:11]=3[CH2:10][CH2:9][C:8]3[CH:19]=[CH:20][C:21]([C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[CH:22][C:7]2=3)[N:6]=1
Reactant: COc1ccc2c(c1)CCc1ccc(Br)cc1C21N=C(N)N(C)C1=O
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1cccnc1
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2c(c1C)CCc1ccc(-c3cccnc3)cc1C21N=C(N)N(C)C1=O
Temperature: 25 °C
Yield: 44 %

Procedure:
A mixture of 2′-amino-2-methoxy-1′-methyl-7-bromo-10,11-dihydrospiro[dibenzo[a,d][7]annulene-5,4′-imidazol]-5′(1′H)-one (0.130 g; 0.314 mmol), dioxane (5 mL, de-oxygenated), 3-pyridineboronic acid (77.1 mg; 0.628 mmol) and 2.0 N Na2CO3 solution (0.63 mL; 4.0 eq.) was stirred at reflux temperature for one hour, cooled to ambient temperature and concentrated in vacuo. The resultant residue was partitioned in chloroform and water. The organic phase was dried over sodium sulfate, filtered, and evaporated. This residue was purified by HPLC with a Phenomenex CN column using a solvent system consisting of A) hexane and B) dichloromethane/methanol (4:1). A gradient starting at 50% B and increasing to 100% B was used for purification. The purified solid was crystallized from hot ethyl acetate and hexane to yield the title compound as tan crystals, 57 mg (44% yield), mp 235-9° C.; identified by NMR and mass spectral analyses. MS (ES) m/z 413.15 [M+H]+.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=3[NH:8][C:9](=[O:10])[C:4]2=[N:3][CH:2]=1.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CS(C)=O.C(O)(=O)C>[CH2:20]([C:17]1([CH2:7][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]2[N:5]3[CH:1]=[CH:2][N:3]=[C:4]3[C:9](=[O:10])[NH:8][C:7]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]1=2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1ccccc1)(Cc1ccccc1)c1ccccc1-2
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of 0.45 g of 5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one in 20 ml of dimethyl sulphoxide under nitrogen are added, at a temperature in the region of 20° C. and with stirring, 60 mg of sodium hydride. The stirring is continued for 2 hours and a further 66 mg of sodium hydride are then added. The reaction medium is heated to 45° C. for 30 minutes, cooled to 20° C. and 0.25 ml of benzyl bromide are added. After continuing the stirring for 3 hours, the reaction mixture is poured into 150 ml of water, acidified to pH 4 with acetic acid and extracted with three times 60 ml of chloroform. The organic phases are combined, washed with twice 100 ml of water, dried over magnesium sulphate, filtered and concentrated on a rotary evaporator. The black solid obtained (0.78 g) is purified by chromatography on a column of silica (70 g) with a mixture of dichloromethane and methanol (95/5 by volume) to give 0.1 g of 10,10-dibenzyl-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one in the form of a pale green solid melting above 260° C. [N.M.R. spectrum: (200 MHz; DMSO d6 ; δ in ppm): 3.63 and 3.85 (2d, J=14 Hz, 2H each: --CH2 --Ar); 6.36 (d, J=7 Hz, 4H: ortho-H of the benzyls); from 6.75 to 6.95 (mt, 6H: meta-H and para-H of the benzyls); from 7.29 to 7.45 (2t, J=7.5 Hz, 1H each: --H7 and --H8); 7.82 and 8.80 (2s broad, 1H each: --H of the imidazole); 7.38 and 8.02 (2d, J=7.5 Hz, 1H each: --H6 and --H9); 11.9 (cplx, 1H: --NH--)].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:5]#[N:6].C(N(CC)CC)C.N1C=CC=CC=1.[SH2:26]>O>[CH3:1][O:2][CH2:3][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:5]([NH2:6])=[S:26]
Reactant: COCC(C#N)c1ccccn1
Reactant: S
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COCC(C(N)=S)c1ccccn1
Temperature: 100 °C

Procedure:
2 grams of 3-methoxy-2-(2-pyridyl)propionitrile is dissolved in 1.5 g. of triethylamine and 2 g. of dry pyridine, saturated with hydrogen sulfide. The mixture is heated at 100°C. in a sealed bomb for 15 hours. The mixture is cooled, diluted with water and extracted with ether. The organic phase is dried, the solvent is removed and the residue is recrystallized from benzene/petroleum ether to give 3-methoxy-2-(2-pyridyl)thiopropanamide.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2.[BH4-].[Na+].Cl.[CH3:25]O>>[CH3:25][O:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)Cc1ccc2c(c1)C(OC)c1ccccc1CO2

Procedure:
A mixture of 5.64 g. of methyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate, 0.4 g. of sodium borohydride and 250 ml. of methanol is stirred at 0°-2° for four hours. The reaction product is treated with 1 N hydrochloric acid and extracted with chloroform, and the chloroform extracts are washed with saturated sodium bicarbonate solution and dried with sodium sulfate. The chloroform is evaporated to leave methyl 6, 11-dihydro-11-methoxydibenz[b,e]oxepin-2-acetate as an oil;
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH3:19])[CH:8]=[CH:7][C:5]=2[N:6]=1.[O:34]1[CH:38]=[C:37]([C:39](O)=[O:40])[N:36]=[CH:35]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C)C=O.O>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([CH:13]=1)[O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:39]([C:37]3[N:36]=[CH:35][O:34][CH:38]=3)=[O:40])[S:3][C:4]=2[CH:10]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: O=C(O)c1cocn1
Reactant: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)c3cocn3)sc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.1 %

Procedure:
A solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methoxyphenyl}-3-(1-cyano-1-methylethyl)benzamide (230 mg, 0.50 mmol) produced in Example A21(iv), 1,3-oxazole-4-carboxylic acid (113 mg, 1.00 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 1.00 mmol), 1-hydroxybenzotriazole (135 mg, 1.0 mmol) and N-ethyl-N-isopropylpropane-2-amine (260 mg, 2.00 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (183 mg, 66%) as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[N:12]1[C:16](=[O:17])[NH:15][N:14]=[N:13]1.I[CH2:19][CH2:20][CH3:21]>CN(C)C=O.O1CCOCCOCCOCCOCCOCC1>[CH2:19]([N:15]1[C:16](=[O:17])[N:12]([C:5]2[CH:6]=[C:7]([Cl:11])[C:8]([Cl:10])=[CH:9][C:4]=2[Cl:3])[N:13]=[N:14]1)[CH2:20][CH3:21]
Reactant: O=c1[nH]nnn1-c1cc(Cl)c(Cl)cc1Cl
Reactant: CCCI
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nnn(-c2cc(Cl)c(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.5 %

Procedure:
To a stirred mixture of 0.24 g (0.005 mole) of sodium hydride (60% oil suspension) in 45 mL of N,N-dimethylformamide was added 1.3 g (0.005 mole) of 1,4-dihydro-1-(2,4,5-trichlorophenyl)-5H-tetrazol-5-one. The mixture was stirred at room temperature for 15 minutes, then 0.85 g (0.005 mole) of 1-iodopropane and several drops of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) were added. After complete addition, the reaction mixture was stirred at room temperature for 4 days. The reaction mixture was poured into ice water and the resulting mixture extracted with diethyl ether. The ether extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to leave a solid. The solid was purified by column chromatography on silica gel, eluting with methylene chloride. Recrystallization from ethanol gave 0.3 g of 1,4-dihydro-4-propyl-1-(2,4,5-trichlorophenyl)-5H-tetrazol-5-one as a solid, mp 89°-90° C.
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[CH:14][C:15](Cl)=[N:16][CH:17]=1.O>CN(C)C=O.C(OCC)(=O)C>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([S:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:16][CH:17]=1
Reactant: Clc1ccc(Br)cn1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(SCc2ccccc2)nc1
Reaction time: 2 h

Procedure:
A solution of phenylmethanethiol (1 ml, 8 mmol) in N,N-dimethylformamide (15 ml) under an atmosphere of argon was treated with sodium hydride (352 mg, 8.8 mmol, 60% dispersion in oil). After stirring at room temperature for 15 minutes a solution of 5-bromo-2-chloropyridine (1.84 g, 9.6 mmol) in N,N-dimethylformamide (5 ml) was added. After 2 hours, water and ethyl acetate were added. The organic layer was separated and washed with water, brine and dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was then purified by chromatography on silica gel eluting with 5% ethyl acetate in pentane to give the title compound. MS (ES+) 280/282 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([OH:38])=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:45][C:46]1[CH:47]=[N:48][C:49](Cl)=[N:50][CH:51]=1.Cl>CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([O:38][C:49]4[N:50]=[CH:51][C:46]([Br:45])=[CH:47][N:48]=4)=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncc(Br)cn1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(O)cn2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(Oc3ncc(Br)cn3)cn2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 4-tert-butyl-N-{6-[2-(5-hydroxypyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (200 mg) in dimethylformamide (4 ml)is added potassium carbonate (154 mg), 5-bromo-2-chloropyrimidine (216 mg), and the mixture is stirred at 50° C. for two hours. The reaction mixture is acdified with cold hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water and brine, and dried over anhydrous sodium sulfate, and evaporated to remove the solvent. The oily residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=50:1), and the fractions are evaporated to remove the solvent. The resulting crude crystals are recrystallized from methylene chloride/isopropyl ether to give 4-tert-butyl-N-{6-[2-(5-(5-bromopyrimidin-2-yloxy)pyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (238 mg) as colorless needles.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1.C([O-])(O)=O.[Na+]>COCCOC.CCO.CCOC(C)=O.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>[OH:30][C:27]([CH:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:35]3[CH:36]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1)([CH3:29])[CH3:28]
Reactant: OB(O)c1cncnc1
Reactant: CC(C)(O)C1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(O)C1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
5-Bromo-6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 113.1, 98 mg, 0.2 mmol) and pyrimidin-5-ylboronic acid (49.6 mg, 0.4 mmol) were dissolved in DME (0.8 mL) and EtOH (0.12 mL). A solution of 2 M NaHCO3 (0.3 mL, 0.6 mmol) was added, the RM was flushed with argon, then Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol) was added. The RM was stirred under argon at 95° C. for 2 h in a sealed pressure safe tube. After cooling at RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH) and treated with Si-Thiol (80 mg) in MeOH to afford the title compound as a white solid. HPLC (Condition 4) tR=4.94 min, UPLC-MS (Condition 3) tR=1.01 min, m/z=532.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.90-1.08 (m, 6H) 1.58-1.83 (m, 2H) 1.99-2.15 (m, 1H) 3.05-3.23 (m, 3H) 3.25-3.35 (m, 1H) 4.29 (s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.75-7.87 (m, 2H) 8.07 (d, J=2.35 Hz, 1H) 8.77 (d, J=2.35 Hz, 1H) 8.87 (s, 2H) 9.17 (s, 1H) 10.14 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:8][C:9]1[C:10]([C:16](OC)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][N:14]=1.N12CCCN=C1CCCCC2>O>[NH2:8][C:9]1[C:10]([C:16]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][N:14]=1
Reactant: Nc1cccnc1
Reactant: COC(=O)c1nc(Br)cnc1N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Nc1ncc(Br)nc1C(=O)Nc1cccnc1
Reaction time: 4 h
Yield: 59.3 %

Procedure:
To 3-aminopyridine (10 g, 106 mmol) at 70° C. were added methyl 3-amino-6-bromo-2-pyrazinecarboxylate (1.0 g, 4.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (645 μL, 4.3 mmol). The reaction solution was stirred for 4 h, diluted with water (75 mL) and extracted with methylene chloride. The combined organic layers were washed with a saturated ammonium chloride solution, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified on a silica gel column using methylene chloride/ethanol, (9:1), as the eluent to give 750 mg (59% yield) of the title compound as a yellow solid: 1H NMR (CDCl3, 400 MHz) δ 9.50 (br s, 1H) 8.82 (d, J=3 Hz, 1H), 8.43 (dd, J=5 and 1 Hz, 1H), 8.31 (s, 1H), 8.23 (ddd, J=8, 3 and 2 Hz, 1H), 7.34 (dd, J=8, 5 Hz, 1H); MS (TSP) m/z 294 (M++1).
Reaction SMILES: [C:1]([NH:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:28]([O:31][CH:32]([C:41]([CH3:48])([CH3:47])[CH2:42][O:43][C:44](=[O:46])[CH3:45])[C:33]([NH:35][CH2:36][CH2:37][C:38](O)=[O:39])=[O:34])(=[O:30])[CH3:29]>>[C:1]([NH:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:38](=[O:39])[CH2:37][CH2:36][NH:35][C:33](=[O:34])[CH:32]([O:31][C:28](=[O:30])[CH3:29])[C:41]([CH3:47])([CH3:48])[CH2:42][O:43][C:44](=[O:46])[CH3:45])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(=O)OCC(C)(C)C(OC(C)=O)C(=O)NCCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccccc1N
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccccc1NC(=O)CCNC(=O)C(OC(C)=O)C(C)(C)COC(C)=O
Yield: 61.7 %

Procedure:
2-Oleoylaminoaniline (744 mg) and 606 mg of 3-[N-(2,4-diacetoxy-3,3-dimethyl-1-oxobutyl)amino]propionic acid were reacted in the same manner as in Example 1 to obtain 810 mg of the title compound (yield: 65%).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[CH:22]=[CH:21][C:20]2[C:19](=O)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Br:24])[CH:17]=3)[C:12](=O)[C:11]=2[CH:10]=1>CCOCC.CC(O)=O>[Br:8][C:9]1[CH:22]=[CH:21][C:20]2[C:11](=[C:12]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:13]3[C:18]([C:19]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:17][C:16]([Br:24])=[CH:15][CH:14]=3)[CH:10]=1
Reactant: [Li]c1ccccc1
Reactant: O=C1c2ccc(Br)cc2C(=O)c2ccc(Br)cc21
Solvent: CC(=O)O
Solvent: CCOCC
Product: Brc1ccc2c(-c3ccccc3)c3cc(Br)ccc3c(-c3ccccc3)c2c1
Temperature: 130 °C
Reaction time: 24 h
Yield: 67.5 %

Procedure:
6 g of phenyl lithium was dissolved in Et2O, and the resulting solution was gradually added dropwise to a solution containing 5 g of 2,6-dibromoanthraquinone dissolved in Et2O. This reaction was carried out on a dry ice bath. Then, the temperature of the reaction material was elevated to room temperature, thereby obtaining white solids. The obtained solids were dissolved in 100 mL of AcOH, followed by addition of KI and NaH2PO2 and the resulting mixture was stirred at 130° C. for 24 hours. After the reaction was complete, the resulting material was filtered with addition of water. The filtrate was then recrystallized from MC and MeOH, thereby obtaining 4.5 g of 2,6-dibromo-9,10-diphenylanthracene.