Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:5]([N+:22]([O-])=O)=[C:4]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1>C1(C)C=CC=CC=1.C(O)(C)C.[Pd]>[NH2:22][C:5]1[C:4]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:3][C:2]([CH3:1])=[C:7]([CH3:8])[C:6]=1[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCNC(=O)OC(C)(C)C)c1C
Agent: [Pd]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCCCNC(=O)OC(C)(C)C)c1C
Yield: 90.6 %

Procedure:
A solution of tert-butyl 4-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]butylcarbamate (7.32 g, 17.00 mmol) in a mixture of toluene (150 mL) and isopropanol (10 mL) was combined with a slurry of 10% palladium on carbon in toluene. The mixture was place under hydrogen pressure on a Parr apparatus for 24 hours. Additional catalyst was added at 1.5 hours (2.2 g) and 3 hours (3 g). The reaction mixture was filtered through a layer of Celite® filter agent to remove the catalyst. The layer of filter agent was washed with ethanol (1 L), ethanol/methanol (1 L), and methanol (1 L). The filtrate was concentrated under reduced pressure. The residue was combined with dichloromethane and heptane and then concentrated under reduced pressure to provide 6.17 g of tert-butyl 4-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]butylcarbamate as a sludgy brown yellow oil.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH2:7]1[C:9]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)[CH2:8]1.COC(C)(C)C.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]=[C:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:9]21[CH2:7][CH2:8]2
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCCCCCC12CC2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCCCCCC12CC2
Yield: 75.9 %

Procedure:
64.3 g (180 mmol) of methyltriphenylphosphonium bromide was added while stirring under nitrogen to a solution of 19.1 g (170 mmol) of potassium tert-butylate in 350 ml of dry tetrahydrofuran and the mixture was heated to reflux. Then, a solution of 22.8 g (150 mmol) of spiro[2.7]decan-4-one in 50 ml of dry tetrahydrofuran was added dropwise to the boiling reaction mixture. The mixture was heated under reflux for a further 2 hours. After cooling, the reaction mixture was poured into 11 of tert-butyl methyl ether/water (1:1). The organic phase was separated and the aqueous phase was extracted twice with 500 ml of tert-butyl methyl ether. The organic extracts were combined, dried over sodium sulfate and concentrated on a rotary evaporator. After flash chromatography (n-pentane, Rf=0.97) on silica gel, there was obtained 17.1 g (76%) of 4-methylenespiro[2.7]decane (V, n=2) as a colorless liquid with the following properties:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:31]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: CCCCCNCCCCC
Solvent: CN(C)C=O
Product: CCCCCN(CCCCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Yield: 67.7 %

Procedure:
1.13 g (3 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature overnight with 2 g (12.7 mmol) of dipentylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.01 g (68%) of (S)-8-chloro-1-(5-dipentylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH:9]([NH:20][CH3:21])[C:10]3[C:15]([C:16]=2[C:17]=1[O:18]C)=[CH:14][CH:13]=[CH:12][CH:11]=3>Br>[OH:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH:9]([NH:20][CH3:21])[C:10]3[C:15]([C:16]=2[C:17]=1[OH:18])=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CNC1Cc2ccc(OC)c(OC)c2-c2ccccc21
Agent: Br
Agent: Cl
Product: CNC1Cc2ccc(O)c(O)c2-c2ccccc21

Procedure:
3.4 g of 3,4-dimethoxy-9-methylamino-9,10-dihydrophenanthrene hydrochloride obtained in Example 2 in 25 cm3 of 66% hydrobromic acid is heated under reflux for one hour under nitrogen.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:6]#[N:7].[OH-].[NH4+:13]>C1COCC1>[NH2:13][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:6]#[N:7]
Reactant: N#Cc1cc(F)cc(CBr)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1cc(F)cc(CN)c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To 3-(bromomethyl)-5-fluorobenzonitrile (Intermediate 14, step 1, 10 g, 0.47 mol) in THF (50 mL) was added ammonium hydroxide solution 25% (2.0 L). The resulting mixture was stirred for 2 h at 85° C. It was then cooled down to RT and extracted with dichloromethane. The organic layer was washed with water, brine, dried and concentrated, affording the title compound as a slight yellow liquid (5 g, 71%). 1H NMR (DMSO-d6, 400 MHz): δ 7.6 (d, J=6.6 Hz, 1H), 7.57 (t, J=0.6 Hz, 1H), 7.55 (s, 1H), 3.74 (d, 2H), 1.97 (s, 2H). LC/MS (Method A) 151.0 (M+H)+. HPLC (Method A) Rt: 0.88 min (Purity 98%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17][CH3:18])[CH:12]=2)[N:3]=1.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]2[C:5]([CH:6]=[C:28]([CH2:27][CH2:26][CH2:25][C:22]3[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=3)[C:29](=[O:30])[N:10]2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17][CH3:18])[CH:12]=2)=[CH:8][CH:9]=1
Reactant: CSc1cccc(Nc2nc(C)ccc2C=O)c1
Reactant: CCOC(=O)CCCCc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CSc1cccc(-n2c(=O)c(CCCc3ccncc3)cc3ccc(C)nc32)c1

Procedure:
The procedure of Example 1 was repeated using 6-methyl-2-(3-methylthiophenylamino)nicotinaldehyde (1.0 eq., prepared in Synthetic Example 2), ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq.) and LDA (1.5 eq.) to obtain 7-methyl-1-(3-methylthiophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 158 to 159° C./AcOEt, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24]([C:28](Cl)=[O:29])[CH:23]=1>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:28](=[O:29])[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:31])[CH:23]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
Teiethylamine (0.5 g, 5.2 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and m-toluoyl chloride (0.5 g, 2.9 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (20 mL). The mixture was filtered, and the solid was slurried with hot methanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-methyl-benzamide (0.7 g, 86%) as a white solid: mp 253-255° C.; 1H NMR (DMSO-d6) δ 2.01-2.05 (m, 1H), 2.35 (s, 3H, CH3), 2.35-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.40-4.61 (m, 4H, 2CH2), 5.12-5.19 (dd, J=5.0 and 13.2 Hz, 1H, CH), 7.34-7.70 (m, 7H, Ar), 9.05 (t, J=5.6 Hz, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.90, 22.59, 31.17, 46.28, 51.58, 121.62, 124.36, 127.76, 128.20, 128.30, 130.66, 131.60, 131.86, 134.07, 134.75, 137.59, 140.11, 166.45, 168.06, 170.99, 172.82; Anal. calcd. for C22H21N3O4: C, 67.51; H, 5.41; N, 10.74. Found: C, 67.52; H, 5.35; N, 10.71.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([C:11]2([C:15]2[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=2)[CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH:12]([C:11]2([C:15]2[CH:16]=[C:17]([NH:21][S:23]([CH3:22])(=[O:25])=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH3:14])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cccc(N)c2)C2CN(Cc3ccccc3)CC21
Solvent: c1ccncc1
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(Cc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 14 h
Yield: 49.4 %

Procedure:
To a solution of 3-(3-benzyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 30, 1.58 g, 5.68 mmol) in pyridine (10 ml) under nitrogen at 0° C. was added methanesulphonyl chloride (0.66 ml, 8.52 mmol) dropwise to the solution, and the mixture was stirred for 14 hours at room temperature. The pyridine was evaporated in vacuo and the residue was partitioned between dichloromethane (50 ml) and dilute aqueous sodium hydrogen carbonate solution (1 M, 50 ml). The layers were separated and the organic extract was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica (60 g) column chromatography eluting with ethyl acetate:hexane (5:95) then ethyl iacetate:hexane:triethylamine (5:95:0.1 increasing to 80:20:0.1). Appropriate fractions were combined and concentrated in vacuo to give the title compound as an off-white solid (1 g, 50%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[C:6]([CH2:14][CH:15]=[CH2:16])[C:5]=1[OH:17])(=[O:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[C:6]([CH2:14][CH2:15][CH3:16])[C:5]=1[OH:17])(=[O:3])[CH3:2]
Reactant: C=CCc1c(O)c(C(C)=O)cc2c1CCCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(O)c(C(C)=O)cc2c1CCCC2
Yield: 82.8 %

Procedure:
5% Palladium/carbon catalyst (9 g) was added to a solution of the product of step (b) (115 g) in ethanol (500 ml). The mixture was shaken with hydrogen at an overpressure of 4 to 5 psi at room temperature for 1 hour. The catalyst was removed by filtration and the filtrate concentrated and cooled. The precipitated solid was filtered off and dried to give 7-acetyl-6-hydroxy-5-propyl-1,2,3,4-tetrahydronaphthalene (96 g), mp 52°-53°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:19])([F:18])[F:17])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([Br:21])[C:3]=1[NH2:22].C(N(CC)CC)C.[N+:30]([C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[N:42]1[CH:46]=[N:45][CH:44]=[N:43]1)[C:36](O)=[O:37])([O-:32])=[O:31].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>ClCCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:17])([F:18])[F:19])[C:9]([F:14])([F:15])[C:10]([F:11])([F:13])[F:12])[CH:5]=[C:4]([Br:21])[C:3]=1[NH:22][C:36](=[O:37])[C:35]1[CH:39]=[CH:40][C:41]([N:42]2[CH:46]=[N:45][CH:44]=[N:43]2)=[C:33]([N+:30]([O-:32])=[O:31])[CH:34]=1
Reactant: O=C(O)c1ccc(-n2cncn2)c([N+](=O)[O-])c1
Reactant: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br)c1ccc(-n2cncn2)c([N+](=O)[O-])c1
Yield: 65 %

Procedure:
To a suspension of 2,6-dibromo-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-phenylamine (Example I1) (635 mg, 1.35 mmol) in 1,2-dichloroethane (6.5 ml) was added triethylamine (0.57 ml, 4.06 mmol), followed by 3-nitro-4-(1H-1,2,4-triazol-1-yl)benzoic acid (634 mg, 2.7 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP—Cl”) (689 mg, 2.7 mmol). The reaction mixture was stirred at reflux for 16 hours. The progress of the reaction was followed by thin layer chromatography and, because it was necessary in this case, further doses of 3-nitro-4-(1H-1,2,4-triazol-1-yl)benzoic acid (4×0.675 mmol), bis(2-oxo-3-oxazolidinyl)phosphonic chloride (4×1.35 mmol) and triethylamine (4×1.35 mmol) were added over the course of 48 hours. The reaction was quenched by addition of aqueous hydrochloric acid (1M) and the phases were separated. The organic phase was washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:2) to give Compound No. A4 of Table A (605 mg, 65% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30]([OH:32])=O)[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.[C:41]1([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30]([N:50]3[CH2:51][CH2:52][CH:47]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH2:48][CH2:49]3)=[O:32])[CH2:28][CH2:27][S:26]2(=[O:33])=[O:34])[C@H:10]([CH2:16][N:17]([CH3:18])[CH3:19])[CH2:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Reactant: c1ccc(C2CCNCC2)cc1
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)N4CCC(c5ccccc5)CC4)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 22.5 %

Procedure:
2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7, 0.065 g, 0.108 mmol) was reacted with 4-phenylpiperidine (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 0.023 g, 0.140 mmol) to form [2-(3-{[(6-chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidin-3-yl]-(4-phenyl-piperidin-1-yl)-methanone (0.018 g, 23%). m/z=741 (M+1); HRMS: calcd for C40H55ClFN4O4S. Calc [M+H+] 741.3611. found 741.3611.
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:7])=[CH:4][N:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[CH:39]=[CH:38][S:37][CH:36]=2)=[O:34])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[C:5]2[CH:23]=[CH:24][C:2]([C:27]3[CH:28]=[C:29]([NH:32][C:33]([C:35]4[CH:39]=[CH:38][S:37][CH:36]=4)=[O:34])[CH:30]=[CH:31][C:26]=3[CH3:25])=[N:3][CH:4]=2)[CH2:17][CH2:18]1
Reactant: CN1CCN(Cc2ccccc2NC(=O)c2ccc(Cl)nc2)CC1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cn1

Procedure:
N-[2-(4-Methylpiperazin-1-ylmethyl)phenyl]-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 14) using General Method B. LCMS: retention time 2.58 min, MH+ 526. NMR: δH [2H6]-DMSO 11.64, (1H, b), 10.14, (1H, s), 9.23, (1H, s), 8.38, (2H, m), 8.31, (1H, d), 7.91, (1H, s), 7.79-7.75, (2H, m), 7.65, (2H, m), 7.38-7.29, (3H, m), 7.11, (1H, t), 3.77, (2H, s), 2.67-2.24, (11H, m), 2.16, (3H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([C:38]1[C:39]([C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-])=O)=[CH:46][CH:45]=2)=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:37])[C:6]([N:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24])[CH3:9])=[O:7].[H][H].[ClH:55]>CO.C(O)C.[OH-].[Pd+2].[OH-]>[ClH:55].[ClH:55].[NH2:50][C:47]1[CH:48]=[CH:49][C:44]([C:39]2[C:38]([C:36]([NH:35][C:34]3[CH:33]=[CH:32][C:5]([C:6]([N:8]([C:10]4[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=4[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[O:24])[CH3:9])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])=[O:37])=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:45][CH:46]=1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1ccccc1-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1ccccc1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 3-methoxy-4-(4′-nitrobiphenyl-2-carboxamido)-N-[4-methyl-2-[5-(4-methylpiperazin-1-ylcarbonyl)pent-1-yloxy]phenyl]-N-methylbenzamide (910 mg), 20% palladium hydroxide (200 mg) in methanol (30 ml) was stirred under atmospheric pressure of hydrogen at ambient temperature. After 5 hours, the reaction mixture was filtered through a bed of Celite, and the solvent was removed by evaporation and the crude product was purified by silica gel column chromatography (SiO2; 30 g, 5% methanol in chloroform) to give free product. To a solution of this product (810 mg) in ethanol (20 ml) was added 1N hydrochloric acid (2.39 ml) and stirred at ambient temperature for 10 minutes. The solvent was removed to give 4-(4′-aminobiphenyl-2-carboxamido)-3-methoxy-N-[4-methyl-2-[5-(4-methylpiperazin-1-ylcarbonyl)pent-1-yloxy]phenyl]-N-methylbenzamide dihydrochloride as amorphous.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=3)[C:9]3[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:8]=3[N:7]=2)[CH2:2]1.C(N(CC)CC)C.Br[CH2:31][CH2:32][OH:33]>>[NH2:17][C:13]1[N:12]=[C:11]([N:10]2[C:9]3[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:8]=3[N:7]=[C:6]2[O:5][CH:3]2[CH2:2][N:1]([CH2:31][CH2:32][OH:33])[CH2:4]2)[CH:16]=[CH:15][N:14]=1
Reactant: Nc1nccc(-n2c(OC3CNC3)nc3ccc(Br)cc32)n1
Reactant: OCCBr
Solvent: CCN(CC)CC
Product: Nc1nccc(-n2c(OC3CN(CCO)C3)nc3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
A mixture of 4-[2-(azetidin-3-yloxy)-6-bromo-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (2 g, 0.44 mmol, 8% purity) and triethylamine (1.5 mL) in 2-bromoethan-1-ol (1.5 mL) was stirred at room temperature for 12 h. The reaction mixture was purified on a C18 column (water/acetonitrile, 5:95-80:20) to yield 100 mg (50%) of 2-(3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-ol as a yellow solid: LC-MS: m/z=+405 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]=O)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C(NCCCC)CCC.C1(=O)OC(=O)C2=CC=CC=C12.[N+:33]([CH:36](O)[CH3:37])([O-:35])=[O:34]>C(Cl)Cl>[CH2:8]1[O:7][C:6]2[CH:10]=[C:2]3[C:3]([CH:11]=[C:36]([N+:33]([O-:35])=[O:34])[CH2:37][O:1]3)=[CH:4][C:5]=2[O:9]1
Reactant: CC(O)[N+](=O)[O-]
Reactant: O=Cc1cc2c(cc1O)OCO2
Agent: O=C1OC(=O)c2ccccc21
Solvent: CCCCNCCCC
Solvent: ClCCl
Product: O=[N+]([O-])C1=Cc2cc3c(cc2OC1)OCO3
Temperature: 25 °C
Yield: 61.2 %

Procedure:
Aldehyde (2a) (6 g, 36.14 mmol) was dissolved in 300 ml of CH2Cl2 along with 3.1 ml of dibutylamine (18.16 mmol) and 10.72 g of phthalic anhydride in a two necked flask equipped with a Dean-Stark trap, a condenser and a dropping funnel. Nitroethanol (7 ml 97.69 mmol) was added dropwise over a period of 18 hours, while the solution was stirred at reflux. After addition, the reaction was stirred for an additional 24 hrs. The flask was then cooled to room temperature, filtered and the solution extracted with 2 M NaOH (300 ml×3) and brine (100 ml), then dried over MgSO4. The solvent was then evaporated to leave a concentrated solution which was passed through a short column of silica to remove dark polar impurities. The isolated material was recrystallized from methanol to give 4.89 g (61% yield) of the title compounds as red needles: mp 139° C.; 1H-NMR (CDCl3) δ 5.20 (s, 2, ArOCH2), 6.02 (s, 2, OCH2O), 6.49 (s, 1, ArH), 6.69 (s, 1, ArH), 7.75 (s, 1, ArCH).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][CH2:11][C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:25])=[CH:18][CH:19]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNC(=O)OCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC(=O)OCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-carbamic acid benzyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:49])[N:32]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:33]1[S:34][C:35]([CH:39]=[O:40])=[C:36]([Cl:38])[N:37]=1)([CH3:29])([CH3:28])[CH3:27].O>O1CCCC1>[C:26]([O:30][C:31](=[O:49])[N:32]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:33]1[S:34][C:35]([CH:39]([OH:40])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)=[C:36]([Cl:38])[N:37]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1nc(Cl)c(C=O)s1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2sc(N(Cc3ccc(Cl)cc3)C(=O)OC(C)(C)C)nc2Cl)c2cccnc21
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 57.4 %

Procedure:
To a solution of 3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 99 mg, 0.25 mmol) in tetrahydrofuran (5 ml) at −20° C. under nitrogen was added 2.0 M solution isopropylmagnesium chloride in tetrahydrofuran (0.2 ml, 0.31 mmol). The reaction mixture was stirred for 1.5 hours, then allowed to warm to 5° C. After the reaction mixture was cooled down to −20° C., a solution of (4-Chloro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (95, 80 mg, 0.2 mmol) in tetrahydrofuran (5 mL) was slowly added. The reaction mixture was stirred for 2.5 hrs, then allowed to warm to 5° C. The reaction mixture was poured into iced water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as an off-white solid (97, 76 mg, 50%). MS (ESI) [M+H+]=661.32, 663.32.