Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][CH2:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:3]1.[N+](C1C=CC([O:30][C:31]([N:33]2[CH:37]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=3)[CH2:36][O:35][C:34]2=[O:46])=O)=CC=1)([O-])=O>C1COCC1>[CH3:1][CH:2]1[CH2:3][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][C:31]([N:33]1[CH:37]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=2)[CH2:36][O:35][C:34]1=[O:46])=[O:30]
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H]1CN(c2ccccc2[N+](=O)[O-])CCN1CCCN
Solvent: C1CCOC1
Product: CC1CN(c2ccccc2[N+](=O)[O-])CCN1CCCNC(=O)N1C(=O)OCC1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of (S)-(+)-3-methyl-1-(2-nitrophenyl)-4-(3-aminopropyl)-piperazine (35 mg, 0.126 mmol) in 10 mL of THF, 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester (50 mg, 0.137 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by MeOH:EtOAc=1:9 (Rf =0.58, MeOH:EtOAc=1:3) to obtain 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid {3-[2-methyl-4-(2-nitro-phenyl)-piperazin-1-yl)-propyl}-amide (55 mg, 87%) The compound was dissolved in CH2Cl2 (3 mL) and was treated with 1N HCl in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a pale yellow solid. M. P. 115-119° C.; [α]D =+38.3, (c=0.22, CH2Cl2); Anal. Calcd. For C24H28N5O5F2Cl.0.72 C6H12 : C, 56.50; H, 6.38; N, 11.63. Found: C, 56.63; H, 6.35; N, 10.08.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]([CH3:10])=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[OH:21])[CH2:16][OH:17].C(Cl)C#C>ClCCl>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH2:10][C:8]#[CH:7])[CH2:16][OH:17]
Reactant: COc1cc(CO)ccc1O
Reactant: CC(C)=O
Agent: C#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C#CCOc1ccc(CO)cc1OC
Yield: 94 %

Procedure:
Finely powdered K2CO3, 10.4 grams (0.075 moles), and KI, 9.1 grams (0.060 moles), were placed in a 300 mL round-bottomed flask equipped with a magnetic stir bar, and 150 mL acetone was added. 3-methoxy-4-hydroxybenzyl alcohol, 7.71 grams (0.050 moles), and propargyl chloride, 4.10 grams (0.055 moles), were then added, and the mixture stirred and refluxed for approximately 48 hours. The results from thin layer chromatography showed no starting material (3-methoxy-4-hydroxybenzyl alcohol) as well as the presence of a new compound. The solution was then filtered. The acetone of the resulting filtrate was removed by rotary evaporation, leaving an oily residue. The oily residue was dissolved in 50 mL dichloromethane and washed with water (30 mL×2) and then dried over anhydrous potassium carbonate. After filtering the organic phase, the solvents were removed by rotary evaporation, leaving a liquid product. 9 grams of product was obtained, which corresponds to a 94% yield.
Reaction SMILES: Cl.Cl.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[C:17]([CH3:29])[CH:16]=1.[O:30]1[CH:34]=[CH:33][C:32](B(OC(C)C)OC(C)C)=[CH:31]1>>[O:30]1[CH:34]=[CH:33][C:32]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][N:8]=[C:7]3[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([CH3:29])[CH:16]=2)=[CH:31]1
Reactant: Cc1cc(Nc2ncnc3ccc(Br)cc23)ccc1OCc1ccccn1
Reactant: CC(C)OB(OC(C)C)c1ccoc1
Agent: Cl
Product: Cc1cc(Nc2ncnc3ccc(-c4ccoc4)cc23)ccc1OCc1ccccn1
Yield: 55 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-bromo-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline dihydrochloride salt was reacted with di-isopropyl 3-furylboronate to give 6-(3-furyl)-4-[3-methyl-4-(2-pyridylmethoxy)anilino]-quinazoline in 55% yield, m.p. 206°-208° C.;
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9][CH2:10]O)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:45]I>C1COCC1>[C:1]([O:5][C:6](=[O:20])[C@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9][CH2:10][I:45])([CH3:4])([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(C)(C)OC(=O)N[C@H](CCCO)C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCI)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 72 %

Procedure:
A solution of the title E compound, (2R)-(t-butyioxycarbonylamino)-5-hydroxy-pentanoic acid t-butyl ester (9.12 g, 31.5 mmol), imidazole (3.22 g, 47.3 mmol) and triphenylphosphine (12.40 g, 47.3 mmol) in 300 mL of THF is treated portionwise over 5 min with iodine (9.60 g, 37.8 mmol) at RT. After 2 h, the mixture is filtered and concentrated. The residue is first filtrated though silica gel (eluant; ethyl acetate) then purified by chomatography on silica gel (eluant; 10% ethyl acetate in hexane) affording 9.05 g (72%) of (2R)-(t-butyloxycarbonylamino)-5-iodopentanoic acid t-butyl ester as a colorless oil: NMR(CDCl3) 1.42 (s, 9H), 1.46 (s, 9H), 1.65-1.95 (m, 4H), 3.14-3.28 (m, 2H), 4.19-4.26 (m, 1H), 5.06 (br d, 1H, J=7.4); IR 1712, 1500, 1155; ESI-MS 400 (M++1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O>[CH2:24]([N:14]1[CH2:15][CH2:16][N:12]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)[C:13]1=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(N2CCN(Cc3ccccc3)C2=O)nc1C
Yield: 93 %

Procedure:
To a suspension of ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate (0.51 g, 2.00 mmol) and potassium carbonate (0.49 g, 3.54 mmol) in acetone (30 mL) was added benzyl bromide (0.30 mL, 0.25 mmol). The reaction mixture was heated to reflux for 16 hours. The solvent was removed in vacuo, and the residue was washed with water (100 mL) and hexanes (30 mL) to afford the title compound in 93% yield (0.65 g): mp 122-124° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.35-7.26 (m, 5H), 4.40 (s, 2H), 4.19 (q, J=7.2 Hz, 2H), 3.97 (t, J=7.5 Hz, 2H), 3.42 (t, J=7.5 Hz, 2H), 2.48 (s, 3H), 1.23 (t, J=7.2 Hz, 3H); MS (ES+) m/z 346.0 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7](=[O:16])[CH2:8][CH2:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1>C(OC(=O)C)(=O)C>[CH3:5][O:6][C:7](=[O:16])[CH2:8][CH2:9][CH2:10][C:11]1[S:12][C:13]([N+:1]([O-:4])=[O:2])=[CH:14][CH:15]=1
Reactant: COC(=O)CCCc1cccs1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)CCCc1ccc([N+](=O)[O-])s1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 8 mL of acetic anhydride at −20° C. is added 1.2 mL of nitric acid (d=1.5). The mixture is kept at −20° C., and a solution of 4-thiophen-2-yl-butyric acid methyl ester (1.84 g, 10.0 mmol) in 12 mL of acetic anhydride is added dropwise. The reaction mixture is stirred for 10 minutes after completion of addition, and poured into an ice-water mixture. The product is extracted with ethyl acetate and the organic layer is washed with 10 N aqueous sodium hydroxide solution, dried and concentrated. The residue is purified by flash column chromatography eluting with 1:4 ethyl acetate:hexane to provide 1.32 g of 4-(5-nitro-thiophen-2-yl)-butyric acid methyl ester as a yellow oil; 1H NMR (DMSO-d6) δ 1.93 (quintet, J=7 Hz, 2H), 2.41 (t, J=7 Hz, 2H), 2.88 (t, J=7 Hz, 2H), 3.59 (s, 3H), 7.04 (d, J=5 Hz, 1H), 8.01 (d, J=5 Hz, 1H); MS 229.0 (M)+
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=[N:10][OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:14][CH2:15][CH2:16][O:11][N:10]=[C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:2]([F:12])([F:13])[F:1]
Reactant: BrCCBr
Reactant: ON=C(c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)C(=NOCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of the above oxime (13.5 g, 71 mmol), 1,2-dibromoethane (65 ml), potassium carbonate (29.4 g, 213 mmol) and acetone (100 ml) was heated at reflux for 16 h and then stirred at room temperature for 7 days. The mixture was filtered and the solvent was evaporated from the filtrate in vacuo to give 20.7 g of 2,2,2-trifluoroacetophenone O-(2-bromoethyl)oxime.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[NH:5][C:4]=2[CH:3]=1.[CH:14]([C:16]1[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:19]=[CH:18][C:17]=1B(O)O)=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[CH3:12][C:6]1([CH3:13])[NH:5][C:4]2[CH:3]=[C:2]([C:17]3[CH:18]=[N:19][N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:16]=3[CH:14]=[O:15])[S:10][C:9]=2[C:8](=[O:11])[NH:7]1
Reactant: CC1(C)NC(=O)c2sc(Br)cc2N1
Reactant: C[Si](C)(C)CCOCn1ncc(B(O)O)c1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CC1(C)NC(=O)c2sc(-c3cnn(COCC[Si](C)(C)C)c3C=O)cc2N1
Yield: 54.1 %

Procedure:
A mixture of 6-bromo-2,2-dimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.444 g, 1.70 mmol), (5-formyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)boronic acid (0.554 g, 2.05 mmol), cesium carbonate (2.77 g, 8.50 mmol), 1,2-dimethoxyethane (15 mL) and water (4 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (0.139 g, 0.17 mmol) was added, and the mixture was purged with argon again. The mixture was refluxed for 2 h. Then, the mixture was poured into water (100 mL) and EtOAc (100 mL). The insoluble materials were filtered off, and the organic layer was collected from the filtrate. This organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residual oil was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc) to afford the title compound (374 mg, 54%) as a yellow solid:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH:25]=O)[C:22]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[N:21]2)=[CH:17][CH:16]=1.[C:34]([O:42][CH2:43][CH3:44])(=[O:41])[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].N1CCCCC1.C(O)(=O)C1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:34]([O:42][CH2:43][CH3:44])=[O:41])[C:22]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[N:21]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C=O)c(-c3cccs3)n2)cc1
Agent: Cl
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1cccs1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A mixture of 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (5.02 g), diethyl malonate (2.12 g), piperidine (0.35 ml), benzoic acid (0.27 g), and toluene (50 ml) was subjected to azeotropic dehydration for 1 hour. The reaction mixture was poured into dilute hydrochloric acid, 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-chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). Sodium borohydride (170 mg) was added to a mixture of the obtained colorless oily substance, ethanol (20 ml), and tetrahydrofuran (20 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into dilute hydrochloric acid, 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 chromatography to obtain diethyl [1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]methylmalonate (6.08 g, yield: 92%) as a pale yellow oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[C:11]([O:26][C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:28]=2[CH3:35])[N:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[CH:23]([C:12]1[C:13](=[O:15])[NH:14][C:9](=[O:8])[NH:10][C:11]=1[O:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:28]=1[CH3:35])([CH3:25])[CH3:24]
Reactant: [H][H]
Reactant: Cc1cc(C)c(C)c(Oc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C)c(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 59 %

Procedure:
2,4-Bis-benzyloxy-5-isopropyl-6-(2,3,5-trimethyl-phenoxy)-pyrimidine was dissolved in 6 mL ethyl acetate and 6 mL ethanol mixture. 10% Pd/C (52 mg) was added to the mixture. Then hydrogen balloon was applied. The reaction was stirred at room temperature for 40 minutes. The reaction crude was filtered through celite. The filtrate was concentrated down and purified (silica gel, 0-50% EtOAC/hexane) followed by reverse phase HPLC (MeCN/water) to give white solid (94 mg, 59%). LC-MS shows 289.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 9.6 (br, 1H), 8.9 (br, 1H), 6.88 (s, 1H), 6.58 (s, 1H), 3.12 (m, 1H), 2.18 (s, 6H), 2.12 (s, 3H), 1.22 (d, 6H).
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([I:8])[N:3]=1.[CH3:9][NH:10][CH3:11]>CO>[I:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:10]([CH3:11])[CH3:9])[N:3]=1
Reactant: Ic1cncc(I)n1
Reactant: CNC
Solvent: CO
Product: CN(C)c1cncc(I)n1

Procedure:
A solution of 2,6-diiodopyrazine (6 g, 18.1 mmol) in methanol (50 ml) and dimethylamine (40% aqueous solution, 200 ml) was heated at reflux for 1 h. The methanol was removed under vacuum, the aqueous saturated with potassium carbonate and extracted with dichloromethane (3×100 ml). The combined extracts were dried (Na2SO4), evaporated and the residue purified by chromatography through silica-gel eluting with dichloromethane. The product (4 g) was obtained as a low melting solid, m.p. 46°-48° C., m/e 249 (M+); δ (360 MHz, CDCl3) 3.10 (6H, s, 2×Me); 7.87 (1H, s, pyrazine-H); 8.01 (1H, s, pyrazine-H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([F:17])[C:13](F)=[N:14][CH:15]=1.CCOC(C)=O>CN(C=O)C>[Br:9][C:10]1[CH:11]=[C:12]([F:17])[C:13]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[N:14][CH:15]=1
Reactant: Nc1cc(O)ccn1
Reactant: Fc1cc(Br)cnc1F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ncc(Br)cc2F)ccn1
Temperature: 120 °C
Reaction time: 3 h
Yield: 46.1 %

Procedure:
Mix 2-aminopyridin-4-ol (1.13 g, 10.3 mmol), 5-bromo-2,3-difluoro-pyridine (2 g, 10.3 mmol) in DMF (10 mL). Stir the mixture at 120° C. for 3 hrs. TLC (EtOAc:PE=1:1) shows the reaction is complete. Filter, add water (50 mL) to the filtrate, extract with EtOAc (50 mL×3). Combine the organic layers, dry over anhydrous Na2SO4. Concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:4) affords the title compound (1.35 g, 46.3%). MS: (M+1): 284.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH3:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][C:21]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]1)=[N:7][N:6]=[CH:5]2
Reactant: Cc1ccc(C(N)=O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1CN(c2nncc3cc(Br)ccc23)CCN1
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: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(C(N)=O)cc1-c1ccc2c(N3CCNC(=O)C3)nncc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
A mixture of 4-(6-bromophthalazin-1-yl)piperazin-2-one (0.1 g, 0.3 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.09 g, 0.3 mmol), and tetrakis(triphenylphosphine)palladium (0.02 g, 0.02 mmol) in 5 mL DME/EtOH (4:1) was treated with 2M potassium carbonate (0.5 mL, 1.0 mmol). The mixture resulted was warmed up to 90° C. and stirred for 1 h under nitrogen. The mixture was cooled down to room temperature, and the crude product was purified via flash chromatography (silica gel) eluting with a gradient of 4% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give the title compound (60 mg) as a pale yellow solid. Found MS (ES+): 362(M+H)+.
Reaction SMILES: N1(C2CCCCCCCCCC2)CCCCCCCCCN1.[C:23]1([CH2:33][NH:34][C:35]2[N:43]=[C:42]([C:44]#[N:45])[N:41]=[C:40]3[C:36]=2[N:37]=[CH:38][NH:39]3)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.[C:46]([O:54][C@H:55]1[C@@H:59]([O:60][C:61](=[O:68])[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C@@H:58](OC(=O)C)[O:57][C@@H:56]1[C:73]([NH:75][CH2:76][CH3:77])=[O:74])(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(O[C@H]1[C@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C)O[C@@H]1C(NCC)=O)(=O)C1C=CC=CC=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C.C(OCC)(=O)C>[C:61]([O:60][C@@H:59]1[C@H:55]([O:54][C:46](=[O:53])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:56]([C:73]([NH:75][CH2:76][CH3:77])=[O:74])[O:57][C@H:58]1[N:39]1[CH:38]=[N:37][C:36]2[C:40]1=[N:41][C:42]([C:44]#[N:45])=[N:43][C:35]=2[NH:34][CH2:33][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: N#Cc1nc(NCc2cccc3ccccc23)c2nc[nH]c2n1
Reactant: CCNC(=O)[C@H]1O[C@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Agent: CCNC(=O)[C@H]1O[C@@H](OC(C)=O)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
Diazabicycloundecane (0.18 ml, 1.2 mmol) was added to a solution of (6-[(1-naphthylmethyl)amino]-9H-purine-2-carbonitrile (200 mg, 0.67 mmol) (Preparation 10) and (2S,3S,4R,5R)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3furanyl benzoate and (2S,3S,4S,5S)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (309 mg, 0.70 mmol) (Preparation 18) in acetonitrile (5 ml). Trimethylsilyl trifluoromethanesulfonate (0.24 ml, 1.33 mmol) was added and the reaction mixture heated under reflux for 30 minutes. The reaction mixture was then allowed to cool to room temperature, diluted with ethyl acetate (20 ml) and washed twice with water (20 ml). The ethyl acetate layer was then washed with 10% w/w aqueous citric acid and saturated aqueous sodium chloride solution (20 ml). The organic phase was dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane increasing in polarity to dichloromethane:methanol (98:2 by volume). The solvent was removed under reduced pressure to give the title compound (235 mg) as a foam.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][N:12]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=3)=[CH:22][C:17]=2[CH:16]=[C:15]([C:36]([OH:38])=O)[CH2:14][CH2:13]1.S(Cl)(Cl)=O>O1CCCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][N:12]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=3)=[CH:22][C:17]=2[CH:16]=[C:15]([C:36]([NH:12][C:18]2[CH:19]=[CH:20][C:21]([CH2:4][N:2]([CH3:1])[CH:3]3[CH2:31][CH2:30][O:29][CH2:26][CH2:25]3)=[CH:22][CH:17]=2)=[O:38])[CH2:14][CH2:13]1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cccc(OC)c2)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2cccc(OC)c2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 1-(3-methoxybenzyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (110 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (80 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (60 mg) and triethylamine (273 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 1-(3-methoxybenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 53) (62 mg) as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11]
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(Br)ccc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a cold (0° C.) solution of 2-bromo-6-nitrotoluene (43.2 g, 0.2 mol) in con H2SO4 (600 mL) was added HNO3 (37 g, 0.24 mol) in small portions with efficient agitation while maintaining the temperature at 0-10° C. The reaction mixture was allowed to slowly warm to RT with stirring overnight then poured into crushed ice (1600 g). The solid was collected by filtration, thoroughly washed with water and dried in air. The crude material was recrystallised from EtOAc/hexanes to afford 40 g (77%) of 1-bromo-2-methyl-3,4-dinitrobenzene (154) as a pale white solid: MS (ESI) m/z=262 [M+1]+.