Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:9][C:10]1([CH3:20])[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:12]=2[O:11]1.B([O-])([O-])O[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1>Cl[Ni](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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:9][C:10]1([CH3:20])[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[C:18]([CH3:19])[C:12]=2[O:11]1
Reactant: Cc1ccc(OB([O-])[O-])cc1
Reactant: Cc1cccc2c1OC(C)(C)C2
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc3c(c2C)OC(C)(C)C3)cc1
Temperature: 25 °C
Yield: 943.9 %

Procedure:
Tripotassium phosphate (28.1 g, 132 mmol) was added to a solution of toluene (200 mL) containing 2,2,7-trimethyl-2,3-dihydro-1-benzofuran (10.0 g, 5.08 mmol) synthesized in Reference Example 155, bis(triphenylphosphine)nickel (II) dichloride (0.998 g, 1.53 mmol), triphenylphosphine (0.800 g, 3.05 mmol) and 4-methylphenyl borate (8.99 g, 66.1 mmol), and the mixture was stirred under heated reflux for 2 hours. After cooled to room temperature, the reaction solution was filtered using Celite. Water was added to the obtained filtrate, and it was subjected to extraction using ethyl acetate. The extract was dried using anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. After that, the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 20:1) to give 12.1 g of the title compound as a brown solid (yield: 94%).
Reaction SMILES: [CH:1]1([CH:6]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])[CH3:29].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:6]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([NH:34][CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:35])=[O:23])=[CH:25][CH:26]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCC2)sc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.8 %

Procedure:
To a mixture of 4-{[cyclopentyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}benzoic acid (300 mg) synthesized above, β-alanine ethyl ester hydrochloride (189 mg), 1-hydroxybenzotriazole monohydrate (188 mg), triethylamine (343 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (236 mg), and the mixture was stirred at room temperature for 5 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (331 mg, 87%) as a pale-brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:19][CH2:18][C:9]2[C:10]3[C:15](Cl)=[N:14][CH:13]=[N:12][C:11]=3[S:17][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(O)C.Cl>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:15]2[C:10]3[C:9]4[CH2:18][CH2:19][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][C:8]=4[S:17][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Temperature: 70 °C
Yield: 77.2 %

Procedure:
In a 25 mL round-bottom flask were placed 250 mg (0.84 mmol, 1.1 equiv) of 4-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid ethyl ester and 131 mg (0.77 mmol, 1 equiv) m-bromoaniline in 10 mL of ethanol with one drop conc HCl. The flask was equipped with a reflux condenser and heated at 70° C. for 4 h. The mixture was allowed to cool to rt and ethanol was concentrated in vacuo. The resulting crude residue was re-dissolved in EtOAc (10 mL), poured into a separatory funnel and washed with satd NaHCO3 (1×10 mL). The organic layer was dried (MgSO4), filtered and concentrated to give a crude oil. The crude material was further purified by MPLC (Biotage) using 1/4 EtOAc/Hex to provide 257 mg (77%) of the desired product, 14, as a white powder. 1H-NMR (CDCl3-d) δ 8.44 (s, 1H), 7.92 (s, 1H), 7.55 (m, 1H), 7.23 (m, 2H), 7.08 (s, 1H), 4.22 (q, 2H), 3.14 (m, 4H), 2.91 (m, 1H), 2.39 (m, 1H), 2.14 (m, 1H), 1.30 (t, 3H); LCMS RT=3.48 min; [M+H]+=432.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[S:14][CH2:13][C:12]([C:18]([O:20]CC)=[O:19])=[CH:11]3)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.C(#N)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[S:14][CH2:13][C:12]([C:18]([OH:20])=[O:19])=[CH:11]3)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(C)cc3)ccc2SC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CS3)cc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 94.8 %

Procedure:
To a solution of ethyl 6-(4-methylphenyl)-2H-thiochromene-3-carboxylate (2.12 g, 6.84 mmol) in tetrahydrofuran (20 ml) and acetonitrile (20 ml) was added dropwise 1N sodium hydroxide (7 ml), and the mixture was stirred at 60° C. for 2.5 hours. The solvent was evaporated, and the residue was dissolved in diethylether. The mixture was extracted with water. The organic layer was extracted with 0.5N sodium hydroxide, and both of the aqueous layers were made pH 3 with 6N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated to give 6-(4-methylphenyl)-2H-thiochromene-3-carboxylic acid (1.83 g, 95%) as yellow powder.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:14]([CH3:19])([CH3:18])[CH2:13][CH2:12][C:11]([CH3:21])([CH3:20])[C:10]=2[CH:9]=1)=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>CCOCC.O>[CH2:1]([O:3][CH2:4][CH2:5][NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:14]([CH3:19])([CH3:18])[CH2:13][CH2:12][C:11]([CH3:20])([CH3:21])[C:10]=2[CH:9]=1)[CH3:2]
Reactant: CCOCC(=O)Nc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CCOCCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Yield: 75.4 %

Procedure:
A solution of 2-ethoxy-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide (35) (674 mg, 2.33 mmole) in 20 mL ether was treated with 400 mg of lithium aluminium hydride and heated at reflux for 3.5 hours. The reaction mixture was cooled to 0° C., treated successively with 0.4 mL water, 0.4 mL 15% aqueous sodium hydroxide solution, 1.2 mL water and stirred at room temperature until a white precipitate formed. MgSO4 was added and the mixture was filtered and concentrated in vacuo to give a pale brown oil. The product was purified by flash chromatography (SiO2, 10% ethyl acetate/hexanes), to yield 484 mg (75%) of (2-ethoxy-ethyl)-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (37), as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O.O>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: CN1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: CC[C@@H]1C(=O)N(C)c2cnc(N3CCN(C)CC3)nc2N1C1CCCC1

Procedure:
Intermediate B (114 mg, 0.39 mmol) and N-methylpiperazine (2 mmol, 6 eq, 204 mg, 0.22 mL) in 1 mL of DMSO was heated at 120° C. in a microwave for 2 h. The reaction was diluted with water and extracted with EtOAc. The organic extracts were washed 5× with water, then dried with MgSO4 and evaporated. The residue was purified by reverse-phase HPLC (eluting with 10-30% acetonitrile in water with 0.1% TFA over 20 min; Phenomenex Luna C-18 column, 25×2 cm) to give the title compound after lyophylization. LCMS: 359.2 m/z (M+H)+; ret. Time: 6.72 min (Analytical Method A); 1H NMR (400 MHz, CDCl3) δ: 7.6 (s, 1H), 4.3 (ddd, 1H), 4.1 (dd, 1H), 4.8 (broad s, 4H), 3.3 (s, 3H), 2.5 (broad s, 4H), 2.3 (s, 3H), 2.1-1.6 (m, 10H) and 0.9 ppm (dd, 3H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C:14]([C:23](=[O:33])[N:24]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:25])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[CH2:26]([N:24]([CH3:25])[C:23]([C:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CN(Cc1ccccc1)C(=O)C1(c2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(Cc1ccccc1)C(=O)C1(c2ccccc2)CCNCC1
Reaction time: 3 h

Procedure:
A mixture of 4-(benzyl-methyl-carbamoyl)-4-phenyl-piperidine-1-carboxylic acid benzyl ester (4.4 g, 10 mmol) and Pd—C (10%, 400 mg) in MeOH (200 mL) is hydrogenated at r.t. and atmospheric pressure for 3 h. The mixture is filtered and evaporated. The residue is purified by reversed phase MPLC to provide the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.S[C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:21][CH2:20]1
Reactant: Cc1ccc2nc(S)oc2c1
Reactant: CN1CCNCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc2nc(N3CCN(C)CC3)oc2c1
Temperature: 100 °C

Procedure:
Phosphorus pentachloride (302 mg) was dissolved in anhydrous toluene (4 ml), the resulting solution was mixed with 2-mercapto-6-methylbenzoxazole (200 mg) which has been obtained in the same manner as described in Reference Example 1, and the mixture was then stirred with heating at 100° C. for 2 hours. With cooling in an ice bath, to this was added dropwise N-methylpiperazine (1.34 ml). After 20 minutes of stirring, the thus obtained mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order. After drying with magnesium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 2-(4-methyl-1-piperazinyl)-6-methylbenzoxazole (166 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:19]=3)=[N:11][C:12]([C:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[K+].Cl.C(Cl)Cl.CO>CCO.O>[Cl:1][C:2]1[C:3]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])[CH:19]=3)=[N:11][C:12]([C:15]([OH:17])=[O:16])=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN(C)CCCOc1cc(-c2nc(C(=O)[O-])ccc2-c2ncc(Cl)cc2Cl)ccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCO
Product: CN(C)CCCOc1cc(-c2nc(C(=O)O)ccc2-c2ncc(Cl)cc2Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a solution of 1.82 g (3.9 mmol) of 3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylate in 50 mL of EtOH and 10 ml of water is added 0.34 g (6.06 mmol) of KOH. The reaction medium is stirred for 18 hours at room temperature, and then concentrated under reduced pressure. The residue obtained is taken up in 6.1 mL of aqueous 1N HCl solution (6.1 mmol) and 100 ml of a 9/1 DCM/MeOH mixture. The organic phase is dried over Na2SO4 and then concentrated under reduced pressure, to give 1.8 g of 3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylic acid in the form of a gum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:10]=2)=[CH:4][CH:3]=1.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>>[CH3:37][C:34]1[CH:35]=[CH:36][N:23]2[C:24]=1[C:25](=[O:33])[N:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]([C@@H:19]([NH:18][C:16]1[C:17]3[C:9]([S:8][C:5]4[CH:6]=[CH:7][C:2]([NH:1][S:47]([CH3:46])(=[O:49])=[O:48])=[CH:3][CH:4]=4)=[CH:10][N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[C:12]=3[N:13]=[CH:14][N:15]=1)[CH3:20])=[N:22]2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Sc3ccc(N)cc3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Sc3ccc(NS(C)(=O)=O)cc3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12

Procedure:
(S)-2-(1-((5-((4-Aminophenyl)thio)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with methanesulfonyl chloride (10 μl, 0.14 mmol) according to the method described in Preparation 15b. The residue (15 mg, 85% purity) was used in the next synthetic step without further purification.
Reaction SMILES: S([O-])(=O)(=O)C.[I-:6].[Na+].[CH3:8][C:9]([CH2:11][CH3:12])=O>>[I:6][CH2:8][C@H:9]1[CH2:12][CH2:11][C@H:9]([CH2:8][I:6])[CH2:12][CH2:11]1
Reactant: [I-]
Reactant: CCC(C)=O
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Product: IC[C@H]1CC[C@H](CI)CC1

Procedure:
Add 30 gms. of the mesylate prepared in step (a) to 300 ml. methylethyl ketone (MEK), then add 90 gm. sodium iodide and reflux for about 30 minutes. Remove the solvent and extract with methylene chloride to yield trans 1,4-bis iodomethyl cyclohexane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16]2)[CH:12]=[CH:11][C:10]=1[NH:22][N:23]=[C:24]([C:29](=[O:33])[CH2:30][O:31][CH3:32])[C:25]([O:27][CH3:28])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34]OC(OC)N(C)C>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16]2)[CH:12]=[CH:11][C:10]=1[N:22]1[CH:34]=[C:30]([O:31][CH3:32])[C:29](=[O:33])[C:24]([C:25]([O:27][CH3:28])=[O:26])=[N:23]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)C(=NNc1ccc(-n2cc(F)c(F)c2)cc1OCc1ccccc1)C(=O)OC
Reactant: COC(OC)N(C)C
Product: COC(=O)c1nn(-c2ccc(-n3cc(F)c(F)c3)cc2OCc2ccccc2)cc(OC)c1=O
Temperature: 25 °C

Procedure:
A mixture of methyl 2-{[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]hydrazono}-4-methoxy-3-oxobutanoate (4.85 g) and N,N-dimethylformamide dimethyl acetal (100 mL) was heated under reflux for 3 hr. The mixture was allowed to be cooled to room temperature, and the precipitate was collected by filtration, and recrystallized from methanol to give the title compound (4.57 g).
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]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[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+].[CH3:67][N:68]1[CH2:73][CH2:72][N:71]([CH2:74][C:75]2[CH:76]=[C:77]([CH:80]=[CH:81][CH:82]=2)[CH:78]=O)[CH2:70][CH2:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:78]([C:77]3[CH:80]=[CH:81][CH:82]=[C:75]([CH2:74][N:71]4[CH2:72][CH2:73][N:68]([CH3:67])[CH2:69][CH2:70]4)[CH:76]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
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: CN1CCN(Cc2cccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)c2)CC1
Reaction time: 6 h
Yield: 17.8 %

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-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (75 mg, 0.19 mmol), DMF (0.85 mL), ethanol (0.15 mL), 1M Na2S2O4 (3 eq, 0.57 mmol, 0.57 mL) and 3-[(4-methylpiperazin-1-yl)methyl]benzaldehyde (1.1 eq, 0.21 mmol, 46 mg). After 6 h, concentration in vacuo and preparation by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (19 mg, 18%) as a colourless solid; 1H-NMR (500 MHz, DMSO-d6) 2.15 (s, 3H, NCH3), 2.50 (hidden by DMSO peak, 4H, piperazine N(CH2)2), 2.64 (br, 4H, piperazine N(CH2)2), 3.30 (hidden by watert-in-DMSO peak, 4H, piperazine N(CH2)2), 3.56 (s, 2H, CH2), 3.63 (s, 2H, CH2), 3.68 (t, J=4.8 Hz, 4H, piperazine N(CH2)2), 7.40 (dd, J=7.8, 4.8 Hz, 1H, pyridine H-5), 7.43 (d, J=7.8 Hz, 1H, phenyl H-4 or H-6), 7.50 (t, J=7.8 Hz, 1H, phenyl H-5), 7.79 (d, br, J=7.7 Hz, 1H, pyridine H-4), 8.07 (d, br, J=8.5 Hz, 1H, phenyl H-4 or H-6), 8.14 (s, br, 1H, phenyl H-2), 8.25 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.50 (dd, J=4.8, 1.5 Hz, 1H, pyridine H-6), 8.57 (d, J=1.6 Hz, 1H, pyridine H-2), 13.52 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([NH2:30])[CH3:29]>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:30][CH2:28][CH3:29])=[O:24])=[CH:21][CH:20]=3)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)cc1
Reactant: CCN
Product: CCNC(=O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)cc1
Yield: 15 %

Procedure:
4-(1-Benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (43 mg) was coupled with ethylamine as in General Procedure 8 to give the title compound as a tan solid (15% yield). M.p.=195° C., LCMS: m/z=387.31 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.24 (3H, t, J=7.3 Hz), 3.44 (2H, quartet, J=7.3 Hz), 4.51 (2H, s), 5.26 (2H, s), 7.33 (8H, m), 7.76 (1H, d, J=8.6 Hz), 7.81 (2H, d, J=8.1 Hz), 8.05 (1H, d, J=8.3 Hz).
Reaction SMILES: Cl.Cl.[Cl:3]C1C=C([CH:10]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH2:11][C:12]2([OH:22])[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15][CH2:14][CH2:13]2)C=CC=1.Cl.Cl.[Cl:32][C:33]1[CH:34]=[C:35](C(C2(O)C3C(CCCC3)CCC2)CN2CCNCC2)[CH:36]=[CH:37][CH:38]=1>>[ClH:3].[ClH:32].[Cl:32][C:33]1[CH:38]=[C:37]([CH:11]([C:12]2([OH:22])[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15][CH2:14][CH2:13]2)[CH2:10][N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)[CH:36]=[CH:35][CH:34]=1
Reactant: CN1CCN(C(CC2(O)CCCC3CCCCC32)c2cccc(Cl)c2)CC1
Reactant: OC1(C(CN2CCNCC2)c2cccc(Cl)c2)CCCC2CCCCC21
Agent: Cl
Product: CN1CCN(CC(c2cccc(Cl)c2)C2(O)CCCC3CCCCC32)CC1

Procedure:
In an analogous manner to Example 24 1-[1-(3-chlorophenyl-2-(4-methylpiperazin-1-yl)ethyl]decahydronaphthalen-1-ol dihydrochloride was prepared from 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]decahydronaphthalen-1-ol (see Example 72). MS (ES) m/z 391.3; RMS: calcd for C23H35ClN2O+H, 391.25161; found (ESI, [M+H]+), 391.2528.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[Cl:12][CH2:11][CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)=[CH:3][CH:4]=1
Reactant: ClCCCOc1ccc(Br)cc1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: ClCCCOc1ccc(-c2ccncc2)cc1
Yield: 85 %

Procedure:
Following the procedure described in example 24, but starting from 1-bromo-4-(3-chloropropoxy)benzene (2.5 g), potassium carbonate (4.14 g), 4-pyridylboronic acid (1.47 g) and palladium tetrakistriphenylphosphine (116 mg) in toluene (24 mL) affords 2.11 g of 4-[4-(3-chloropropoxy)phenyl]pyridine as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:24]1([C:36](O)=[O:37])[C:25]([C:33](O)=[O:34])=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[CH:28][CH:29]=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:14][C:12]=3[N:13]=2)=[CH:3][C:2]=1[N:1]1[C:33](=[O:34])[C:25]2[C:24](=[CH:29][CH:28]=[C:27]([C:30]([OH:32])=[O:31])[CH:26]=2)[C:36]1=[O:37]
Reactant: O=C(O)c1ccc(C(=O)O)c(C(=O)O)c1
Reactant: Nc1cc(-c2nc3cc(-c4ccccc4)ccc3o2)ccc1Cl
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cc(-c3nc4cc(-c5ccccc5)ccc4o3)ccc1Cl)C2=O

Procedure:
Prepared by the method of Example 15e), from 2-(3-amino-4-chlorophenyl)-5-phenylbenzoxazole (43 mg, 0.13 mmol) and 1,2,4-benzenetricarboxylic acid (26 mg, 0.13 mmol) the title compound was obtained (10 mg, 15%). 1H NMR (DMSO) δ 8.58(d, 1H), 8.48(dd, 1H), 8.38(m, 2H), 8.17(d, 1H), 8.08(d, 1H), 7.99(d, 1H), 7.88(d, 1H), 7.76(m, 3H), 7.50(m, 2H), 7.39(t, 1H). MS 492.8 m/z (M−H)−.
Reaction SMILES: Cl[Si](C)(C)C.[CH:6]1([NH:13][CH2:14][CH2:15][N:16]([CH2:27][CH2:28][C:29]2[C:37]3[S:36][C:35](=[O:38])[NH:34][C:33]=3[C:32]([OH:39])=[CH:31][CH:30]=2)[C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C.Cl[C:48](=[O:70])[CH2:49][CH2:50][N:51]([CH2:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:52](=[O:61])[O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>ClCCl.C(OCC)(=O)C>[CH2:19]([O:18][C:17]([N:16]([CH2:27][CH2:28][C:29]1[C:37]2[S:36][C:35](=[O:38])[NH:34][C:33]=2[C:32]([OH:39])=[CH:31][CH:30]=1)[CH2:15][CH2:14][N:13]([CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[C:48](=[O:70])[CH2:49][CH2:50][N:51]([CH2:62][CH2:63][C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:52](=[O:61])[O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)CCN(CCc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)N(CCNC1CCCCCC1)CCc1ccc(O)c2[nH]c(=O)sc12
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N(CCC(=O)N(CCN(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1)C1CCCCCC1)CCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chlorotrimethylsilane (1.323 mL) was added to a cooled (0° C.) solution of benzyl 2-(cycloheptylamino)ethyl(2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)carbamate, prepared as in Example 23 step i) (1.260 g) and triethylamine (1.81 mL) in dichloromethane (35 mL). The reaction mixture was stirred at room temperature for 2 h then a solution of benzyl 3-chloro-3-oxopropyl(phenethyl)carbamate, prepared as in Example 5 step ii) (0.991 g) in dichloromethane (10 mL) was added. The reaction mixture was stirred at room temperature for 4 h then diluted with ethyl acetate and washed with 2M hydrochloric acid (×2) and saturated sodium hydrogen carbonate. The organic layer was separated, washed with water and saturated brine, dried over sodium sulphate, filtered and evaporated. The crude product was purified by flash silica chromatography (Biotage), elution gradient 1 to 6% methanol in dichloromethane. Fractions containing product were evaporated to dryness to afford the product as a yellow foam (1.416 g). The material was used in the next step directly.