Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][OH:7].F[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[C:22]([CH3:34])[CH:21]=1)=[N:12][CH:13]=[N:14]2.C(O)(C(F)(F)F)=O>CC(N(C)C)=O>[CH3:3][NH:4][CH2:5][CH2:6][O:7][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[C:22]([CH3:34])[CH:21]=1)=[N:12][CH:13]=[N:14]2
Reactant: CNCCO
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(F)c34)cc2C)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNCCOc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 28 mg, 0.69 mmol) was suspended in DMA (10 ml) and N-methylethanolamine (56 μl, 0.69 mmol) was added under an atmosphere of nitrogen. The mixture was stirred for 20 minutes at ambient temperature, and 5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (obtained as described in Example 103, preparation of starting materials, 100 mg, 0.28 mmol) was added. The mixture was heated under an atmosphere of nitrogen at 110° C. for 1 hour, then at 125° C. for 14 hours. The mixture was cooled to ambient temperature, and acidified with TFA. The mixture was concentrated in vacuo, and the residue purified by reverse-phase HPLC, eluting with 5 to 50% acetonitrile in H2O. The appropriate fractions were evaporated to a volume such that all of the acetonitrile had been removed. The resulting aqueous solution was basified with concentrated aqueous ammonia, and extracted with DCM (4×20 ml). The combined extracts were filtered through a silicone-treated filter paper, and concentrated in vacuo to give 5-[2-(methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine as a yellow solid (40 mg, 34%); NMR Spectrum (CDCl3, 400 MHz) 2.20 (s, 3H), 2.44 (s, 3H), 2.49 (s, 3H), 3.12 (t, 2H), 4.25 (t, 2H), 6.80 (d, 1H), 6.83 (d, 1H), 7.00 (d, 1H), 7.04 (dd, 1H), 7.39 (d, 1H), 7.55 (dd, 1H), 7.61 (dd, 1H), 7.68 (d, 1H), 8.19 (d, 1H), 8.56 (s, 1H), 10.26 (s, 1H); Mass spectrum MH+ 416.0
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([NH:14][CH2:15][CH2:16][OH:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([N:14]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:15][CH2:16][O:17][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: OCCNCCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCN(CCc1ccccc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
Methanesulfonyl chloride (4.3 g, 0.037 mol) was added dropwise at 0° C. to a well stirred solution of 2-phenethylamino-ethanol (2.5 g, 0.015 mol, from step (i) above) and triethylamine (4.6 g, 0.045 mol) in dry dichloromethane (50 ml). The reaction mixture was stirred at room temperature for 3 h and quenched with water. The reaction mixture was extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography over silica gel using 3% methanol in dichloromethane as eluent to yield (3 g) of compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([C:16]#[N:17])[C:3]=1[Br:18].[C:19]1([Cl:25])[C:23](Cl)=[S+:22][S:21][N:20]=1.[Cl-]>ClCCl>[C:11]([O:10][C:9](=[O:15])[NH:8][C:5]1[CH:6]=[CH:7][C:2](/[N:1]=[C:23]2/[C:19]([Cl:25])=[N:20][S:21][S:22]/2)=[C:3]([Br:18])[C:4]=1[C:16]#[N:17])([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(Br)c1C#N
Reactant: Clc1ns[s+]c1Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(/N=c2\ssnc2Cl)c(Br)c1C#N

Procedure:
The thiazolo[5,4-f]quinazoline-2-carbonitriles VIIIaa-ib were prepared following scheme 1: N-Boc Protection of 2-amino-5-nitrobenzonitrile using di-tert-butyl dicarbonate in a suitable solvent, such as dichloromethane, in presence of suitable bases such as triethylamine and 4-(dimethylamino)pyridine and preferably at room temperature, provides tert-butyl (2-cyano-4-nitrophenyl)carbamate I in high yield. Reduction of the nitro intermediate I, for example by treatment with ammonium formate and a catalytic amount of 10% palladium charcoal preferably in ethanol under microwave irradiation for preferably 30 min at 600 W, provides tert-butyl 4-amino-2-cyanophenylcarbamate II in high yield. Treatment of intermediate II by a solution of bromine in dichloromethane in a suitable solvent, such as acetic acid, preferably at room temperature provides tert-butyl 4-amino-3-bromo-2-cyanophenylcarbamate III in a quantitative yield. Intermediate III is reacted with Appel's salt (4,5-dichloro-1,2,3-dithiazolium chloride) (Appel, R. et al., Chem. Ber., 1985, 118, 1632) preferably in dichloromethane at room temperature to afford (Z)-tert-butyl-3-bromo-4-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)-2-cyanophenylcarbamate IV. N-Boc deprotection of intermediate IV using di-tert-butyl dicarbonate in a suitable solvent, such acetic acid, preferably under microwave irradiation at 118° C. provides (Z)-6-amino-2-bromo-3-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)benzonitrile V in a quantitative yield. Cyclization of intermediate V may be accomplished by treatment with copper iodide in a suitable solvent, such as pyridine, preferably under microwave irradiation at 400 W at 130° C. for 20 min to obtain 6-aminobenzo[d]thiazole-2,7-dicarbonitrile VI in good yield (Besson, T. et al., J. Chem. Soc., Perkin Trans. 1, 1998, 3925). Treatment of intermediate VI in a suitable solvent, such as dimethylformamide dimethylacetal, preferably under microwave irradiation at 70° C. (600 W) gives (E)-N′-(2,7-dicyanobenzo[d]thiazol-6-yl)-N,N-dimethylformimidamide VII in good yield. Cyclization of intermediate VII in thiazolo[5,4-f]quinazoline-2-carbonitriles VIIIaa-ib may be accomplished by a Dimroth rearrangement using the appropriate aniline or primary amine R3NH2 (preferably 1.5 equivalent) in a suitable solvent, such acetic acid and preferably under microwave irradiation at 118° C. (600 W) (Foucourt, A. et al., Tetrahedron, 2010, 66, 4495).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cc2Br)cc1
Temperature: 90 °C
Yield: 100 %

Procedure:
A mixture of 2-bromo-1-fluoro-4-nitrobenzene (2.20 g, 10 mmol), 4-hydroxybenzonitrile (1.31 g, 11 mmol), and cesium carbonate (3.58 g, 11 mmol) in DMSO (20 mL) was heated at 90° C. for 2 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 3.19 g (110%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:26]([F:27])=[CH:25][N:24]=[C:23](Cl)[N:22]=2)[CH:16]=1)[CH2:12][CH3:13])(C)(C)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[C:26]([F:27])=[CH:25][N:24]=[C:23]([NH:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:22]=2)[CH:18]=[CH:19][CH:20]=1)[CH2:12][CH3:13]
Reactant: NCCc1ccc(O)cc1
Reactant: CCN(CCCNC(=O)OC(C)(C)C)Cc1cccc(-c2nc(Cl)ncc2F)c1
Product: CCN(CCCN)Cc1cccc(-c2nc(NCCc3ccc(O)cc3)ncc2F)c1

Procedure:
Intermediate 78 was coupled with tyramine following procedure Q. The resulting product was deprotected following procedure R. LC-MS showed the product had the expected M+H+ of 424. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.29 (d, 1H), 8.19 (s, 2H), 7.66 (m, 2H), 7.05 (d, 2H), 6.68 (d, 2H), 4.49 (s, 2H), 3.58 (t, 2H), 3.24 (m, 4H), 2.98 (t, 2H), 2.80 (t, 2H), 2.07 (m, 2H), 1.36 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Br.[Cl:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:29][C:27](=[O:28])[CH2:26][O:25][C:24]1[CH:30]=[CH:31][C:21]([Cl:20])=[CH:22][CH:23]=1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Reactant: O=C(O)COc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1ccc(Cl)cc1)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
In a reaction vessel were placed 0.20 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.11 g of 4-chlorophenoxyacetic acid, 0.08 g of potassium carbonate and 5 ml of N,N-dimethylformamide, followed by stirring at room temperature for 12 hours. The reaction mixture was poured into water, and extracted twice with 30 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.23 g of 3,5-dichloro-4-(3-(4-chlorophenoxyacetyloxy)propyloxy)-1-(3,3-dichloro-2-propenyloxy) benzene (91% yield), nD22.0 1.5709.
Reaction SMILES: [Si]([O:18][C:19]1[CH:54]=[CH:53][C:22]([O:23][CH2:24][C@@H:25]([OH:52])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:51]=[CH:50][C:33]([NH:34][C:35]3[C:40]([NH:41][C:42](=[O:49])[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:52][C@H:25]([CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:54][CH:53]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:51]=[CH:50][C:33]([NH:34][C:35]2[C:40]([NH:41][C:42](=[O:49])[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(Nc3ncccc3NC(=O)c3ccccc3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(Nc1cccnc1Nc1ccc(CCNC[C@H](O)COc2ccc(O)cc2)cc1)c1ccccc1
Yield: 89.7 %

Procedure:
N-{2-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-3-pyridinyl}benzamide (0.064 g, 0.087 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.039 g, 0.078 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([C:22]3[CH2:26][CH2:25][CH2:24][C:23]=3[C:27]([OH:29])=[O:28])[C:14]2=[O:30])=[CH:3]1>CO.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([CH:22]3[CH2:26][CH2:25][CH2:24][CH:23]3[C:27]([OH:29])=[O:28])[C:14]2=[O:30])=[CH:3]1
Reactant: Cc1cccc2c1c(Cn1c(=O)n(C3=C(C(=O)O)CCC3)c3ccccc31)cn2C
Agent: [Pd]
Solvent: CO
Product: Cc1cccc2c1c(Cn1c(=O)n(C3CCCC3C(=O)O)c3ccccc31)cn2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
A mixture of 65 mg (0.16 mmol) of 2-{3-[(1,4-dimethyl-1H-indol-3-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}cyclopent-1-ene-1-carboxylic acid and 30 mg of 10% Pd/C in 3 mL of methanol was stirred at room temperature under hydrogen gas atmosphere (1 atom) for 16 h. The resulting mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by combiflash to give 20 mg (31%) of 2-[3-(1,4-dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-cyclopentanecarboxylic acid as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][C:11]=3[CH:20]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH2:21]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][C:11]=3[CH:20]=2)[CH2:6][CH2:5]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc2cc(N3CCNCC3)ccc2o1
Reactant: ClCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(N3CCN(Cc4ccccc4)CC3)ccc2o1
Reaction time: 2 h

Procedure:
A solution of 1 g of ethyl 5-(1-piperazinyl)-benzofuran-2-carboxylate in 50 ml of dichloromethane is treated with 1 g of benzyl chloride and stirred for 2 hours. After customary working up, ethyl 5-(4-benzyl-1-piperazinyl)benzofuran-2-carboxylate, m.p. 219-222°, is obtained.
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Br:1][CH2:2][CH:3]1[CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:13]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: BrC/C=C/c1ccccc1
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1C(CBr)C1c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 7.4 %

Procedure:
To a solution of [(E)-3-bromo-1-propenyl]benzene (705 mg, 3.58 mmol) in dichloromethane (1 ml) was added rhodium (II) acetate dimer (20 mg, 0.05 mmol). To the mixture was added dropwise at room temperature over 4 h a solution of ethyl diazoacetate (0.43 ml, 0.47 g, 4.15 mmol) in dichloromethane (2.5 ml). The mixture was stirred at room temperature for 60 h. The mixture was purified by silica column (40 g) chromatography eluting with 1:1 hexane:dichloromethane then dichloromethane. Product-containing fractions were purified further by silica column (10 g) chromatography eluting with 9:1 hexane:dichloromethane then dichloromethane. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil (75 mg, 8%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[S:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([F:29])[CH:28]=1>>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=3)[CH2:35][CH2:34]2)=[S:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Reactant: Cc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Product: Cc1nc2ccccc2cc1NC(=S)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 74 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)thiocarbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 125 to obtain the titled compound.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([NH:8][C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[O:10])=[N:5][CH:4]=1)#[N:2].CC(C)([O-])C.[K+].[CH3:27][O:28][CH2:29][CH2:30]Br>CN(C)C=O.O1CCCC1>[C:1]([C:3]1[S:7]/[C:6](=[N:8]\[C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[O:10])/[N:5]([CH2:30][CH2:29][O:28][CH3:27])[CH:4]=1)#[N:2]
Reactant: COCCBr
Reactant: N#Cc1cnc(NC(=O)C23CC4CC(CC(C4)C2)C3)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCn1cc(C#N)s/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of Example 183B (240 mg, 0.84 mmol) in N,N-dimethylformamide/tetrahydrofuran (1:4, 10 mL) were added a solution of potassium tert-butoxide (Aldrich, 133 mg, 1.2 mmol) and commercially available, 2-bromoethyl methyl ether (Aldrich, 104 μL, 1.2 mmol). The reaction mixture was stirred at 80° C. for 16 hours, cooled to room temperature, quenched with saturated aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.59-1.77 (m, 6H), 1.84-1.91 (m, 6H), 1.95-2.04 (m, 3H), 3.26 (s, 3H), 3.71 (t, J=5.3 Hz, 2H), 4.36 (t, J=5.1 Hz, 2H), 8.54 (s, 1H); MS (ESI+) m/z 346 (M+H)+; Anal. Calculated for C18H23N3O2S: C, 62.58; H, 6.71; N, 12.16. Found: C, 62.15; H, 6.89; N, 11.95.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:7][C:8]([N:10]1[C:18]2[CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][C:13]=2[C:12]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[F:28])=[N:11]1)=[O:9])[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.C(OC(Cl)=O)C(C)C.[NH2:48][C@H:49]([C:54]([NH2:56])=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52]>C(Cl)Cl>[NH2:56][C:54](=[O:55])[C@@H:49]([NH:48][C:4](=[O:6])[C@@H:3]([NH:7][C:8]([N:10]1[C:18]2[CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][C:13]=2[C:12]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[F:28])=[N:11]1)=[O:9])[C:2]([CH3:30])([CH3:1])[CH3:29])[CH2:50][CH:51]([CH3:53])[CH3:52]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)O)C(C)(C)C)C1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 71 (40 mg) in DCM was added DIEA (45 uL) followed by isobutylchloroformate (26 uL). After stirring at room temperature for 30 min, leucine amide (18 mg) and DIEA (25 uL) was added and stirred for 1 h. The reaction mixture was evaporated and dissolved in MeOH, and purified with a preparative LC-MS to give compound 72. LCMS (+ESI) m/z=537.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([CH3:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH3:15]N>>[CH3:15][NH:13][S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C:2](=[O:1])[CH3:14])=[CH:9][CH:8]=1)(=[O:11])=[O:12]
Reactant: CN
Reactant: CC(=O)Cc1ccc(S(N)(=O)=O)cc1
Product: CNS(=O)(=O)c1ccc(CC(C)=O)cc1

Procedure:
4-(2-Oxo-propyl)-benzenesulfonyl chloride (prepared as described in European patent specification EP 91749 A2) (0.087 g, 4.1 mmol) was treated with methylamine to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16](O)=[O:17]>C1COCC1>[Br:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:16][OH:17]
Reactant: O=C(O)c1cccc2c(Br)c3ccccc3cc12
Solvent: C1CCOC1
Product: OCc1cccc2c(Br)c3ccccc3cc12

Procedure:
10-Bromo-1-anthracenecarboxylic acid made from example 2B by the procedure of E. Barnett, J. W. Cook, and H. H. Grainger, Ber. 57 B, 1775 (1924), was reduced with BH3 in THF by the procedure outlined in 2C to give (10-bromo-1-anthryl)methanol mp 125°-127°, (EtOAc/hexane), (C,H,Br).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[CH3:13]OC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCOCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([OH:5])[CH3:13])[N:7]=1
Reactant: CON(C)C(=O)c1cccnn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(O)c1cccnn1
Temperature: 150 °C
Reaction time: 0.58 h
Yield: 328.8 %

Procedure:
A suspension of compound 2 (20 mg, 0.049 mmol) and Lawesson's Reagent (20 mg, 0.049 mmol) in anhydrous dioxane (1 mL) was stirred at 150° C. for 35 min in a CEM microware reactor. The mixture was concentrated in vacuo, and the residue was purified by prep-TLC to give compound 3 (20 mg, 96%) as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:42][C:23]4=[N:24][CH:25]=[C:26]([Br:41])[C:27]([N:28]5[CH2:33][CH2:32][N:31]([CH2:34][C:35]6[N:36]=[C:37]([CH3:40])[S:38][CH:39]=6)[CH2:30][CH2:29]5)=[C:22]4[N:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:41][C:26]1[C:27]([N:28]2[CH2:29][CH2:30][N:31]([CH2:34][C:35]3[N:36]=[C:37]([CH3:40])[S:38][CH:39]=3)[CH2:32][CH2:33]2)=[C:22]2[N:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][CH:16]=3)[NH:42][C:23]2=[N:24][CH:25]=1
Reactant: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(N6CCN(C(=O)OC(C)(C)C)CC6)cc5)nc34)CC2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(N6CCNCC6)cc5)nc34)CC2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
tert-Butyl-4-(4-(6-bromo-7-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)piperazine-1-carboxylate (0.022 g, 0.033 mmol) was suspended in DCM (2.0 mL) and the mixture cooled in an ice bath. TFA (0.5 mL) was added and the resulting solution was allowed to warm up to room temperature and stirred for 2 h. The mixture was passed through an SCX column (5 g), the filtrate collected and the solvent removed in vacuo to give the title compound as a solid (0.016 g, 86%); 1H-NMR (500 Mz, DMSO-d6): δ 2.61-2.70 (m, 7H), 2.81-2.89 (m, 4H), 3.15-3.22 (m, 4H), 3.60-3.68 (m, 6H), 7.03 (d, J=9.0 Hz, 2H, ArH, C6H4), 7.32 (s, 1H, thiazole 5-H), 8.02 (d, J=9.0 Hz, 2H, ArH, C6H4), 8.17 (s, 1H, imidazo[4,5-b]pyridine 5-H); LC (Method B)-MS (ESI, m/z) 2.23 min—553/555 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 553.1522, calculated for C25H30BrN8S (M+H)+: 553.1498.
Reaction SMILES: [Cl-].[NH4+].O.[CH2:4]([N:11]([C:16]1[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[C:18]([Br:25])[N:17]=1)[CH2:12][C@H:13]([OH:15])[CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C.[Fe]>[NH2:22][C:21]1[C:16]([N:11]([CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:12][C@H:13]([OH:15])[CH3:14])=[N:17][C:18]([Br:25])=[CH:19][CH:20]=1
Reactant: C[C@@H](O)CN(Cc1ccccc1)c1nc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C[C@@H](O)CN(Cc1ccccc1)c1nc(Br)ccc1N
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 80.5 %

Procedure:
A 100-mL round bottomed flask equipped with a magnetic stir bar was charged with ammonium chloride (0.044 g, 0.820 mmol), water (8.2 mL), iron powder (4.58 g, 82 mmol), and ethanol (21.8 mL). The mixture was heated to 80° C., and a solution of (R)-1-(benzyl(6-bromo-3-nitropyridin-2-yl)amino)propan-2-ol (3.00 g, 8.2 mmol) in ethanol (8.20 mL) was slowly added over 2 min. The reaction mixture was stirred at 80° C. After 90 min, heating was discontinued and the reaction mixture filtered through a pad of Celite. The flask and Celite pad were rinsed with ethanol. The filtrate was concentrated. The residue was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution (20 mL). The ethyl acetate layer was washed with 5% aqueous sodium chloride solution (20 mL) and concentrated under reduced pressure to afford crude (R)-1-((3-amino-6-bromopyridin-2-yl)(benzyl)amino)propan-2-ol (2.22 g) as a dark syrup. MS (ESI, pos. ion) m/z 336, 338 [M+1]+.