Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH2:2]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=1Br)[CH3:3].[CH2:14]=[O:15].Cl>II.BrCCBr.O1CCCC1>[CH2:2]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=1[CH2:14][OH:15])[CH3:3]
Reactant: C=O
Reactant: CCc1cc(C)cc(CC)c1Br
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1CO
Temperature: 60 °C

Procedure:
Under a nitrogen atmosphere, 11.24 g of magnesium, 200 g of tetrahydrofuran, 0.1 g of iodine and 1.0 g of 1,2-dibromoethane were mixed. This mixture was heated to 60° C. To this mixture, a small amount of 2,6-diethyl-4-methylbromobenzene was added. To this mixture, 0.1 g of iodine and 1.0 g of 1,2-dibromoethane were added. Then, 2,6-diethyl-4-methylbromobenzene (the total amount including the amount added first: 100.12 g) was added dropwise over 2.5 hours. After completion of addition, the resultant mixture was stirred at 50° C. for 1.5 hours. This mixture was cooled to 30° C. To this mixture, 14.84 g of paraformaldehyde was added portionwise in five additions over 30 minutes. The resultant mixture was stirred at 30° C. for 2 hours. To the reaction mixture, 143 g of 10% hydrochloric acid was added, followed by extraction with 300 g of tert-butyl methyl ether. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to obtain 77.56 g of 2,6-diethyl-4-methylbenzyl alcohol as a yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][NH:6][C:7](=[O:36])[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][NH:6][C:7](=[O:36])[C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:12][CH:13]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(=Cc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)CC(C)C)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCNC(=O)c1ccc(C(Cc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
3-{4-[1-(4′-tert-Butyl-biphenyl-4-ylmethylene)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester (240 mg) is taken into ethanol (20 ml) and 10% Pd/C (20 mg) is added: The system is purged with nitrogen, followed by the introduction of hydrogen (30 psi). The mixture is stirred at room temperature for 4 h, filtered through Celite®, and concentrated. The resulting residue is purified by silica gel column chromatography, eluting with EtOAc/hexanes to afford 160 mg of the titled compound. MS (ES): 500.3 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[CH2:18](I)[CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:18][CH2:19][CH3:20])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:15])[F:16]
Reactant: FC(F)(F)c1cc(C2CCNCC2)ccc1Cl
Reactant: CCCI
Product: CCCN1CCC(c2ccc(Cl)c(C(F)(F)F)c2)CC1

Procedure:
Beginning with 4-(4-Chloro-3-trifluoromethyl-phenyl)-piperidine and 1-propyliodide, the title compound was re-covered by the procedure described in Example 2. m.p. 218-220° C. (HCl), MS m/z (rel. intensity, 70 eV) 305 (M+, 4), 278 (35), 277 (13), 276 (bp), 70 (40).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][S:13][C@H:12]2[CH2:16][CH2:17][CH2:18][C@@H:19]([C:20]([O:22]C)=[O:21])[N:11]2[C:10]1=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][S:13][C@H:12]2[CH2:16][CH2:17][CH2:18][C@@H:19]([C:20]([OH:22])=[O:21])[N:11]2[C:10]1=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)O)N2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of (4S,7S,10aS)-methyl 4-(tert-butoxycarbonylamino)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (0.139 g, 0.387 mmol) in MeOH (6 mL) was added NaOH (1 N in water, 387 μL, 0.387 mmol). The mixture was stirred at rt overnight. HPLC showed only 20% conversion. Additional NaOH (1 N in water, 387 μL, 0.387 mmol) was added and the reaction was stirred for an additional 3 days. The mixture was cooled with ice-water and the reaction was carefully neutralized with aqueous 1 N HCl to pH<7. The reaction was extracted with DCM. The organic layer was washed with water, dried over MgSO4, filtered and concentrated to give (4S,7S,10aS)-4-(tert-butoxycarbonylamino)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid (133 mg, 0.386 mmol, 99% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[OH-].[Na+].[O-:14][C:15]#[N:16].[Na+].C(O)(=O)C>O.O1CCOCC1>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:15]([OH:14])[N:16]=[C:4]2[OH:5]
Reactant: N#C[O-]
Reactant: Nc1ccc(I)cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: Oc1nc(O)c2cc(I)ccc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of commercially available 2-amino-5-iodobenzoic acid (1 g, 3.80 mmol) in water (5 mL) and 2N aqueous sodium hydroxide (1.9 mL, 3.80 mmol), was added sodium cyanate (272 mg, 4.18 mmol). The reaction mixture was then diluted with dioxane (3 mL). The reaction mixture was maintained at approximate pH 6-7 over the course of 3 hours, by the addition of acetic acid (228 μl). The mixture was stirred at room temperature for 18 hours then cooled to 0 C. The pH of the reaction was adjusted to 13-14 with the addition of 6N aqueous sodium hydroxide (1 mL), then the mixture was heated at 55 C for 3.5 hours. The reaction mixture was cooled to 0 C and the precipitate was collected, washed with water, then dried by lyophilization to give 6-iodo-quinazoline-2,4-diol as a lavender solid, (849 mg, 78%). HNMR (500 MHz, DMSO) 6.72 (d, 1H), 7.53 (d, 1H), 7.95 (s, 1H), LCMS m/e 286.98 (M+H).
Reaction SMILES: C([N:8]([C@@H](C1C=CC=CC=1)C)[C@@H:9]1[CH2:13][CH2:12][CH2:11][C@:10]1([CH2:18][OH:19])[C:14]([O:16][CH3:17])=[O:15])C1C=CC=CC=1.C(O)=O>CO.[Pd]>[NH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@:10]1([CH2:18][OH:19])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)[C@@]1(CO)CCC[C@H]1N(Cc1ccccc1)[C@H](C)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: COC(=O)[C@@]1(CO)CCC[C@H]1N

Procedure:
According to the procedure of Example 53, Step 2,using crude methyl (1S,2R)-2-{benzyl[(1R)-1-phenylethyl]amino}-1-(hydroxymethyl)cyclopentanecarboxylate (800 mg), 4.4% formic acid in methanol (50 mL) and 10% Pd/C (421 mg), methyl (1S,2R)-2-amino-1-(hydroxymethyl)cyclopentanecarboxylate was obtained (404 mg, 1.93 mmol) as a colorless solid. 1H NMR (400 MHz, MeOD) δ ppm 1.76-1.82 (m, 2H) 1.84-1.92 (m, 1H) 2.09-2.18 (m, 1H) 2.20-2.30 (m, 1H) 3.58-3.68 (m, 2H) 3.81 (s, 3H) 3.97-4.02 (m, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)[CH:2]=[CH2:3].[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH2:25][NH:24][C:23]2=[O:28])[CH2:18][CH2:17]1>C(O)C>[CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH2:25][NH:24][C:23]2=[O:28])[CH2:18][CH2:17]1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccccc1OCC1CO1
Reactant: O=C1NCCCN1C1CCNCC1
Solvent: CCO
Product: C=CCOc1ccccc1OCC(O)CN1CCC(N2CCCNC2=O)CC1

Procedure:
A solution of 10.3 g of 1-(o-allyloxy-phenoxy)-2,3-epoxy-propane and 9.15 g of 1-(4-piperidyl)-2-oxo-hexahydropyrimidine in 7 ml abs. ethanol is heated for 5 hours to 95° C and then evaporated in vacuo. The residue is recrystallised from isopropanol to yield the 1-[3-(o-allyloxy-phenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine, which melts at 122°-125° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC1C=CC(C[O:21][CH2:22][C:23]2([CH3:34])[O:27][C:26]3=[N:28][C:29]([N+:31]([O-:33])=[O:32])=[CH:30][N:25]3[CH2:24]2)=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1>C(Cl)Cl>[CH3:34][C:23]1([CH2:22][OH:21])[O:27][C:26]2=[N:28][C:29]([N+:31]([O-:33])=[O:32])=[CH:30][N:25]2[CH2:24]1
Reactant: CC1(COCc2ccc(OCc3ccccc3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(CO)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (25.4 mL, 0.342 mol) was added dropwise to a stirred mixture of 2-({[4-(benzyloxy)benzyl]oxy}methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (26) (see Example 2Z) (2.53 g, 6.40 mmol) and anisole (7.0 mL, 64 mmol) in CH2Cl2 (100 mL) (water bath cooling). After stirring at room temperature for 4 h, the solvents were removed by blowing under a stream of N2. The oily residue was treated with excess solid NaHCO3, then diluted with 15% MeOH/CH2Cl2 (100 mL), and the mixture was stirred at room temperature for 30 min and then filtered. The filtrate was evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-1% MeOH/CH2Cl2 firstly gave foreruns, and then further elution with 1-2% MeOH/CH2Cl2 gave (2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazol-2-yl)methanol (101) (reported by Tsubouchi et al., WO 2004033463A1 via 3 steps, starting from 2-chloro-4(5)-nitroimidazole (81) and 2-[methoxymethoxy)methyl]-2-methyloxirane) (1.215 g, 95%) as a cream solid: mp (MeOH/CH2Cl2/hexane) 174-176° C.; 1H NMR [(CD3)2SO] δ 8.09 (s, 1H), 5.41 (t, J=5.7 Hz, 1H), 4.24 (d, J=10.6 Hz, 1H), 4.03 (d, J=10.7 Hz, 1H), 3.64 (dd, J=12.2, 5.6 Hz, 1H), 3.54 (dd, J=12.2, 5.9 Hz, 1H), 1.51 (s, 3H). Anal. (C7H9N3O4) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.[N:14]#[C:15]Br>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[C:5]2[N:6]([C:15]([NH2:14])=[N:9][N:8]=2)[N:7]=1
Reactant: N#CBr
Reactant: CS(=O)(=O)c1cc(Cl)nnc1NN
Solvent: CO
Product: CS(=O)(=O)c1cc(Cl)nn2c(N)nnc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(6-Chloro-4-methanesulfonylpyridazin-3-yl)hydrazine (W3.126; 200 mg, 0.9 mmol) was dissolved in methanol (5 ml), cyanogen bromide (360 μl, 3 M in DCM) was added and the mixture was stirred at RT for 4 h. The mixture was concentrated and the residue was purified by flash chromatography (dichloromethane:methanol). Yield: 111 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]([C:16](=[O:17])[C:5]=2[CH2:4][CH2:3]1)=[O:15].OC1C(=O)C2C(C(=O)C=1)=CC=CC=2.BrCC=C(C)C.[I-].[Na+]>CS(C)=O.C(N(CC)CC)C>[CH3:1][C:2]([CH3:18])=[CH:3][CH2:4][C:5]1[C:6](=[O:7])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14](=[O:15])[C:16]=1[OH:17]
Reactant: CC1(C)CCC2=C(O1)c1ccccc1C(=O)C2=O
Agent: CC(C)=CCBr
Agent: O=C1C=C(O)C(=O)c2ccccc21
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)=CCC1=C(O)C(=O)c2ccccc2C1=O
Yield: 40 %

Procedure:
β-lapachone, as well as its intermediates, derivatives and analogs thereof (also referred to herein as the “active compounds”), are described in Li, C. J. et al., J Biol. Chem., 1993. Unlike prior art β-lapachone syntheses as illustrated in Scheme 1, the synthesis of β-lapachone, in accordance with the present invention and generally illustrated in Scheme 2, commences with the reaction of 2-hydroxy-1,4-naphthoquinone with 1-bromo-3-methyl-2-butene in the presence of sodium iodide and triethylamine (a weak base) in dimethylsulfoxide (DMSO) to produce lapachol in up to 40% yield, after purification (20 g, up to 40% overall yield). Lapachol is then quantitatively converted to β-lapachone by treatment with sulfuric acid. The β-lapachone is purified by recrystallization from ethanol.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:13][N:14](CCN(C)C)C>CN(C=O)C.[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[O:12]=[C:8]1[CH2:9][C:10]2[CH:11]=[C:2]([C:13]#[N:14])[CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7]1
Reactant: CN(C)CCN(C)C
Reactant: O=C1CCc2ccc(Br)cc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)CC(=O)CC2
Temperature: 160 °C
Yield: 186.4 %

Procedure:
A solution of 7-bromo-3,4-dihydronaphthalen-2(1H)-one (500 mg, 2.2 mmol) in 5 mL of anhydrous DMF in a 10 mL CEM microwave tube was added Zn(CN)2 (515 mg, 4.4 mmol), Pd2(dba)3 (55 mg, 0.034 mmol), TMEDA (55 mg, 0.47 mmol) and Xantphos (29 mg, 0.05 mmol) sucessively. The reaction tube was sealed and heated to 160° C. under microwave irradiation with a 5 min hold time and 300 W maxium power input. After cooling under a stream of compressed air, the reaction mixture was washed with EtOAc through a Celite® with a thin layer of silica gel in the middle size. The filtrate was washed with saturated bine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to afford 7-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (150 mg, yield 40%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(Cl)Cl.[C:12]([O:16][C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[Na+].[Na+]>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].O1CCOCC1>[C:12]([O:16][C:17](=[O:18])[NH:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:2]2[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=2)=[CH:25][CH:26]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2ncc(Cl)cn2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 70.4 %

Procedure:
To a 10 mL microwave vial were added 2,5-dichloropyrimidine (285 mg, 1.8 mmol), Pd(dppf)Cl2.DCM (45 mg, 0.05 mmol), (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (419 mg, 1.67 mmol), Na2CO3 (2 mL, 2M) and 1,4-dioxane (7 mL). The vial was flushed with N2 then capped and placed in a heating block and heated at 80° Celsius. After 6 h, the resulting mixture cooled to RT and transferred to a round-bottomed flask and concentrated to dryness. The residue was purified using FCC to provide 376 mg of the title compound. MS (ESI): mass calcd. for C16H18ClN3O2, 319.11; m/z found 320.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].O>CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:3][CH:4]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(C=O)cc1
Yield: 42 %

Procedure:
24.42 g (200 mmol) of 4-hydroxybenzaldehyde are dissolved in 250 ml of N,N-dimethylformamide and treated with 27.64 g (200 mmol) of potassium carbonate. At 100° C., 53.55 g (240 mmol) of tert-butyl α-bromoisobutyrate are added dropwise. The mixture is stirred for another hour, a further 200 mmol of potassium carbonate and 240 mmol of tert-butyl α-bromoisobutyrate are added and, after 4 hours at 100° C., 1 l of water is added. Following extraction with diethyl ether, washing with 1 N aqeuous sodium hydroxide solution and saturated sodium chloride solution and drying over magnesium sulphate, the solvent is distilled off and the residue is purified by flash chromatography on silica gel (cyclohexane→cyclohexane/ethyl acetate 20:1→10:1→5:1) and dried under reduced pressure. The target compound is obtained in the form of colourless crystals in a yield of 42%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH2:18][O:19][P:20]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:15])[C:5]2=[O:38].[CH2:39]([NH:41][C:42](=[O:62])[NH:43][C:44]1[N:49]=[CH:48][C:47](B(O)O)=[C:46]([C:53]2[S:54][CH:55]=[C:56]([C:58]([F:61])([F:60])[F:59])[N:57]=2)[CH:45]=1)[CH3:40].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([C:47]3[CH:48]=[N:49][C:44]([NH:43][C:42](=[O:62])[NH:41][CH2:39][CH3:40])=[CH:45][C:46]=3[C:53]3[S:54][CH:55]=[C:56]([C:58]([F:61])([F:59])[F:60])[N:57]=3)=[CH:11][N:10]=2)[C:5](=[O:38])[C:6]([C:14]([O:16][CH2:17][CH2:18][O:19][P:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])=[O:15])=[CH:7]1)[CH3:13]
Reactant: CCn1cc(C(=O)OCCOP(=O)(OCc2ccccc2)OCc2ccccc2)c(=O)c2cc(Br)cnc21
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCCOP(=O)(OCc2ccccc2)OCc2ccccc2)cn3CC)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.9 %

Procedure:
2-{[Bis(benzyloxy)phosphoryl]oxy}ethyl 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 25, 80 mg, 0.133 mmol) was dissolved in dimethylformamide (15 mL), and the solution was purged with argon. Tetrakis (triphenylphosphine) palladium (15 mg, 0.013 mmol) and 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 9, 71 mg, 0.16 mmol) were added and the mixture was stirred for 20 min at room temperature. Sodium carbonate solution (57 mg, 0.53 mmol) (dissolved in minimum amount of water) was added, and the reaction mixture was heated to 90° C. for 3 h. The reaction mixture was passed through celite and the celite was washed with dimethylformamide. The dimethylformamide layer was poured into water (100 mL) and a precipitate formed. The solid was filtered and dried then purified by flash column chromatography over silica gel (0-8% MeOH/CHCl3) to afford 70 mg (63%) of 2-{[bis(benzyloxy)phosphoryl]oxy}ethyl 1-ethyl-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate as white solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][CH2:15]Br)=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=1>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:14][CH2:15][CH2:11][C:10](=[O:12])[C:8]=2[CH:9]=1
Reactant: CC(=O)c1cc(Br)ccc1OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCOc2ccc(Br)cc21
Reaction time: 20 h
Yield: 69.7 %

Procedure:
To a slurry of NaH (60% dispersion in mineral oil) (1.48 g, 37.1 mmol) in THF (50 mL) at room temperature was added [5-bromo-2-(2-bromo-ethoxy)-phenyl]-ethanone (8.07 g, 25.1 mmol). The reaction mixture was slowly heated to reflux and allowed to stir for 20 h. The solvent was removed in vacuo and the residue subjected to flash chromatography (SiO2, 4:1 ethyl acetate/petroleum ether) to give 7-Bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one as a yellow oil (4.22 g, 70%). 1H NMR (CDCl3) δ 2.15-2.29 (2H, m), 2.89 (2H, t, J=7.0 Hz), 4.24 (2H, t, J=6.6 Hz), 6.97 (1H, d, J=8.8 Hz), 7.50 (1H, dd, J=2.6, 8.1 Hz), 7.87 (1H, d, J=2.6 Hz).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[C@H:22]2[C@@H:17]([CH2:18][C:19]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:20]=3[CH2:21]2)[CH2:16][C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([N:14]1[C@H:22]2[C@@H:17]([CH2:18][C:19]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:20]=3[CH2:21]2)[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1cccc2c1C[C@@H]1[C@H](CC(=O)N1Cc1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cccc2c1C[C@@H]1[C@H](CCN1Cc1ccccc1)C2

Procedure:
0.21 g (5.5 mmol) of LiAlH4 and 0.5 g (1.6 mmol) of trans-(±)-1-benzyl-8-methoxy-2, 3,3a,4,9,9a-hexahydro-1H-benz[f]indol-2-one (8a) are used. Yield: 0.4 g (85%).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[N:10]=1.[OH-].[Na+]>CO>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:11]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=3[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])=[N:10]2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: COC(=O)CCCCCc1nn(-c2ccc([N+](=O)[O-])cc2)c2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCc1nn(-c2ccc([N+](=O)[O-])cc2)c2c1CCCC2
Yield: 77.9 %

Procedure:
A solution of the compound of Example 63 (0.20 g) in methanol (20 ml) was treated with N sodium hydroxide (7.5 ml) and heated at reflux temperature for 30 minutes. The cooled solution was acidified and the precipitate was crystallized from acetonitrile to yield pure title compound (0.15 g), m.p. 119°-121° C.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:68][N:69]1[CH2:74][CH2:73][N:72]([CH2:75][C:76]2[CH:77]=[C:78]([CH:81]=[CH:82][CH:83]=2)[CH:79]=O)[CH2:71][CH2:70]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:79]([C:78]3[CH:81]=[CH:82][CH:83]=[C:76]([CH2:75][N:72]4[CH2:73][CH2:74][N:69]([CH3:68])[CH2:70][CH2:71]4)[CH:77]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CC(c1ccncc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: CN1CCN(Cc2cccc(C=O)c2)CC1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(c1ccncc1)N1CCN(c2c(Br)cnc3[nH]c(-c4cccc(CN5CCN(C)CC5)c4)nc23)CC1
Reaction time: 6 h
Yield: 27.5 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)pyridin-2-amine (50 mg, 0.12 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.37 mmol, 0.37 mL) and 3-[(4-methylpiperazin-1-yl)methyl]benzaldehyde (1.1 eq, 0.14 mmol, 29 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (19 mg, 27%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.37 (d, J=6.7 Hz, 3H, CHCH3), 2.17 (s, br, 4H, piperazine N(CH2)2), 2.37-2.48 (m, br, 4H, piperazine N(CH2)2), 2.55-2.58 (m, br, 4H, piperazine N(CH2)2), 2.64-2.67 (m, br, 4H, piperazine N(CH2)2), 3.56 (s, 2H, NCH2Ar), 3.60 (q, J=6.5 Hz, 1H, CHCH3), 3.68 (s, br, 4H, piperazine N(CH2)2), 7.41 (d, J=5.9 Hz, 2H, pyridine H-3 & H-5), 7.43 (d, J=7.7 Hz, 1H, phenyl H-6), 7.50 (t, J=7.7 Hz, 1H, phenyl H-5), 8.06 (d, J=7.7 Hz, 1H, phenyl H-4), 8.14 (s, br, 1H, phenyl H-2), 8.24 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.56 (d, J=5.9 Hz, 1H, pyridine H-2 & H-6), 13.52 (s, br, 1H, imidazo[4,5-b]pyridine NH);