Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[N:13]1([C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: C1COCCN1
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCOCC1

Procedure:
Using 3-nitro-benzoic acid (334 mg) and morpholine (209 μl) instead of 1-ethyl-piperazine, in the same manner as Step A in Example 1-D-101, the desired compound was obtained (340 mg, 72%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19](=[CH2:21])[CH3:20].[I-].[K+]>CS(C)=O.O>[CH3:20][C:19]([CH2:21][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N+:9]([O-:11])=[O:10])=[CH2:18]
Reactant: C=C(C)CCl
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=C(C)COc1cccc(C)c1[N+](=O)[O-]
Yield: 100.2 %

Procedure:
A mixture of 20.0 grams (0.130 mole) of 3-methyl-2-nitrophenol and 22.5 grams (0.163 mole) of potassium carbonate in 200 mL of dimethyl sulfoxide was stirred, and 15.3 mL (0.156 mole) of methallyl chloride was added dropwise during a five minute period. Upon completion of addition, 5.4 grams (0.033 mole) of potassium iodide was added in one portion. The reaction mixture was then stirred at ambient temperature for about 18 hours. After this time the reaction mixture was poured into 500 mL of water. The mixture was then extracted with two 200 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 27.0 grams of 2-methyl-3-(3-methyl-2-nitrophenoxy)-1-propene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: B.CSC.[CH3:5][C:6]([NH:9][C:10](=O)[CH:11]([OH:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)([CH3:8])[CH3:7].CO.Cl>O1CCCC1>[ClH:18].[Cl:18][C:14]1[CH:13]=[C:12]([CH:11]([CH2:10][NH:9][C:6]([CH3:8])([CH3:7])[CH3:5])[OH:19])[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)NC(=O)C(O)c1cccc(Cl)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: CC(C)(C)NCC(O)c1cccc(Cl)c1

Procedure:
Borane-methyl sulphide (2.15 g, 2.7 ml, 4 equivs.) was added dropwise, under nitrogen, to a stirred solution of N-[1,1-dimethylethyl]-3-chloro-α-hydroxybenzene acetamide (1.71 g) in dry tetrahydrofuran. The resulting solution was stirred and heated under reflux for 2 h., cooled, and treated with methanol (1 ml). The reaction mixture was heated under reflux for 1 h., cooled, treated with methanolic hydrogen chloride, and the solvent evaporated to give 3-chloro-α-[[[1,1-dimethylethyl]amino]methyl]benzenemethanol hydrochloride salt, 1.5 g, m.p. 165°-175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4][NH2:5].[C:11](=[S:13])=[S:12].I[CH3:15]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4][NH:5][C:11](=[S:13])[S:12][CH3:15]
Reactant: NCc1c(Cl)cccc1Cl
Reactant: S=C=S
Reactant: CI
Product: CSC(=S)NCc1c(Cl)cccc1Cl
Yield: 29.7 %

Procedure:
2,6-Dichlorobenzylamine (0.020 mol) was reacted with carbon disulfide (0.020 mol) and iodomethane (0.019 mol) substantially as described in Example 1B above to obtain 1.5 g (32%) white crystals: mp 47°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([C:16](O)=[O:17])=[CH:14][N:13]=[C:12]2[N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[N:20]=[CH:21][C:11]=12.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:53][O:54][C:55]([CH3:59])([CH3:58])[CH2:56][OH:57].CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:57][CH2:56][C:55]([CH3:59])([CH3:58])[O:54][NH:53][C:16]([C:15]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[C:11]2[CH:21]=[N:20][N:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[C:12]2=[N:13][CH:14]=1)=[O:17]
Reactant: COc1ccc(Cn2ncc3c(Nc4ccc(I)cc4F)c(C(=O)O)cnc32)cc1
Reactant: CC(C)(CO)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3c(Nc4ccc(I)cc4F)c(C(=O)NOC(C)(C)CO)cnc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.6 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (737 mg, 1.4 mmol), HOBt (231 mg, 1.7 mmol), and EDCI (327 mg, 1.7 mmol) in DMF (15 mL) was added a solution of 2-aminooxy-2-methyl-propan-1-ol hydrochloride (280 mg, 2.0 mmol), and DIPEA (603 μL, 3.6 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 3 days then diluted with water (30 mL) and the aqueous layer extracted with dichloromethane (3×20 mL). The combined organic fractions were filtered through a hydrophobic frit and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (420 mg, 49%). LCMS (Method B): RT=3.47 min, [M+H]+=606.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:45](=[O:46])[N:13]3[C:14]([C:29]([O:31][CH:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])=[C:15]([CH2:19][S:20][C:21]4[N:22]=[N:23][N:24]([CH2:26][C:27]#[CH:28])[N:25]=4)[CH2:16][S:17](=O)[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.P(Cl)(Cl)Cl>O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:45](=[O:46])[N:13]3[C:14]([C:29]([O:31][CH:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])=[C:15]([CH2:19][S:20][C:21]4[N:22]=[N:23][N:24]([CH2:26][C:27]#[CH:28])[N:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCn1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3S(=O)C2)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: C#CCn1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3SC2)n1
Temperature: -30 °C
Reaction time: 0.83 h
Yield: 91.8 %

Procedure:
A mixture of benzhydryl 7-(2-phenylacetamido)-3-[2-(2-propynyl)-2H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate-1-oxide (16.0 g) and dry N,N-dimethylformamide (160 ml) was cooled to -30° C. and thereto was added phosphorus trichloride (6.7 g). The resulting solution was stirred for 50 minutes at -30° C. The reaction mixture was allowed to warm to ambient temperature, added to water (200 ml) and then extracted with ethyl acetate (×3). The extracts were combined, washed successively with a saturated aqueous solution of sodium bicarbonate (×3) and water (×3), dried over magnesium sulfate, treated with activated charcoal and then evaporated. The residue was pulverized in a mixture of isopropyl ether and n-hexane, collected by filtration, washed with n-hexane and then dried to give benzhydryl 7-(2-phenylacetamido)-3-[2-(2-propynyl)-2H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (14.33 g).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](=[O:18])[CH2:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]=[CH:7][CH:8]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25].Cl.CN>CO>[CH3:23][N:24]1[CH:26]=[C:11]([C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[C:10](=[O:18])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:20])[F:1])[CH:4]=2)=[CH:25]1
Reactant: CCCCC(=O)CC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: COC(OC)N(C)C
Agent: CN
Agent: Cl
Solvent: CO
Product: CCCCC(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
To a 6 g. portion of crude 1-(3-trifluoromethylphenyl)-2,4-octanedione was added 40 ml. of N,N-dimethylformamide dimethyl acetal and a few milliliters of methanol. The mixture was stirred under reflux overnight, and was then evaporated under vacuum to obtain 8.9 g. of a thick dark oil. The oil was taken up in 50 ml. of methanol, 9 g. of methylamine hydrochloride was added, and the mixture was stirred under reflux for 3 hours. It was then evaporated to a semi-solid under vacuum, and the residue was partitioned between diethyl ether and water. The organic layer was dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on a 300 g. silica gel column with 2:3 ethyl acetate:dichloromethane, and the product-containing fractions were combined and evaporated under vacuum to obtain 0.17 g. of the desired product in impure form. Nmr analysis in DMSOd6 showed peaks at δ7.6-8.3 (m, 6H, aromatic); 3.8 (s, 3H, N--CH3); 3.0-3.3 (t, 2H, COCH2); 0.7-1.8 (m, 7H, CH2CH2CH3).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH:5]1[CH3:25])#[N:2].[C:26]([CH2:28][C:29](O)=[O:30])#[N:27]>>[C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:29](=[O:30])[CH2:28][C:26]#[N:27])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH:5]1[CH3:25])#[N:2]
Reactant: CC1CN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CCC1=CC#N
Reactant: N#CCC(=O)O
Product: CC1CN(c2ccc(N3C[C@H](CNC(=O)CC#N)OC3=O)cc2F)CCC1=CC#N
Yield: 81 %

Procedure:
The title compound was prepared as per Example-29 by using (S)-N-{3-[4-(4-cyanomethylidene-3-methylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine and cyanoacetic acid in 81% yield.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5](Br)=[CH:4][CH:3]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1cccs1
Reactant: Brc1ccc(Br)c2nsnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: c1csc(-c2ccc(-c3cccs3)c3nsnc23)c1

Procedure:
A solution of 4,7-dibromobenzo[c][1,2,5]thiadiazole (3.0 g, 10.2 mmol) and thiophen-2-ylboronic acid (2.87 g, 22.4 mmol) in 150 mL of 1,2-dimethoxyethane and 50 mL anhydrous ethanol was carefully degassed by bubbling nitrogen through the solution. Next, 7.16 g (67.2 mmol) of sodium carbonate dissolved in 30 mL water was added. The resulting emulsion was degassed, and the catalyst Pd(PPh3)4 (200 mg, 0.17 mmol) was added. Afterwards, the mixture was refluxed under nitrogen overnight. After removal of the organic solvent by reduced pressure, the mixture was poured into water (300 mL) and was extracted with chloroform (3×40 mL). The organic phase was washed with water (30 mL), dried over magnesium sulphate, and the solvent was removed in vacuo. Purification by flash silica gel column chromatography [hexane:chloroform=1:1 (v/v)] followed by recrystallization from hexane/dichloromethane (DCM) yielded orange crystals of TBT (2.6 g, 84.9%).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH:29]([C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)([CH3:31])[CH3:30]>N.CO>[CH:29]([C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:40])=[O:39])=[CH:34][CH:33]=1)([CH3:31])[CH3:30]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)c1ccc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.7 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 4-Isopropylbenzenesulfonyl chloride (22 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (2.9 mg). MS m/z 371 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=[O:5].CC1(C)C(C)(C)OB([C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26])=[N:23][CH:24]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:4]([C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[C:19]1[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26])=[N:23][CH:24]=1)=[O:5]
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cccc(Cl)c1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cccc(C)c2C=O)cn1
Temperature: 100 °C

Procedure:
2-chloro-6-methylbenzaldehyde (156 mg, 1.01 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (434 mg, 1.25 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), and 2M K3PO4 (aq) (1.0 mL, 2.00 mmol) were dissolved in 1,4-dioxane (3.0 mL) and heated to 100° C. After 4 h the resulting mixture was cooled to room temperature, diluted with DCM, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]2[N:13]([CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:12]3[CH:21]=[C:22]([N+:25]([O-])=O)[CH:23]=[CH:24][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2].I.CS[C:33]([C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)=[NH:34]>C(O)C.[Pd]>[CH2:17]([N:16]([CH2:19][CH3:20])[CH2:15][CH2:14][N:13]1[C:12]2[CH:21]=[C:22]([NH:25][C:33]([C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)=[NH:34])[CH:23]=[CH:24][C:11]=2[N:10]=[C:9]1[CH2:8][C:7]1[CH:28]=[CH:29][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: CCOc1ccc(Cc2nc3ccc([N+](=O)[O-])cc3n2CCN(CC)CC)cc1
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCO
Product: CCOc1ccc(Cc2nc3ccc(NC(=N)c4cccs4)cc3n2CCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
{2-[2-(4-Ethoxy-benzyl)-6-nitro-benzoimidazol-1-yl]-ethyl}-diethyl-amine 43 (90 mg, 0.227 mmol) was dissolved in anhydrous ethanol (7 mL) in a dry argon purged flask. Palladium, 10 wt % on activated carbon (24 mg, 0.0227 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 3 hours, thin layer chromatography in a solvent system of (5% 2M NH3 in methanol/95% dichloromethane) shows complete conversion to 44 3-(2-Diethylamino-ethyl)-2-(4-ethoxy-benzyl)-3H-benzoimidazol-5-ylamine, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol (7 mL) and the ethanolic solution of the amine 44 is charged to a small, argon purged flask fitted with a magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide 9a (129.5 mg, 0.454 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 44 hours. The solvent was evaporated and residue partitioned between H2O and ethyl acetate and 1M sodium hydroxide solution added to adjust pH to 8. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford crude. The product was purified using silica gel column chromatography eluting with 3% methanol/97% dichloromethane to 5% methanol/95% dichloromethane to afford a yellow solid 45 N-[3-(2-Diethylamino-ethyl)-2-(4-ethoxy-benzyl)-3H-benzoimidazol-5-yl]-thiophene-2-carboxamidine. Yield: 38 mg (35.2%). 1H NMR (DMSO) δ: 0.81 (t, 6H, J=7.0), 1.28 (t, 3H, J=7.0), 2.35-2.50 (2×m, 6H), 3.97 (q, 2H, J=7.0), 4.07 (t, 2H, J=6.7), 4.21 (s, 2H), 6.42 (br s, 2H), 6.67-6.70 (m, 1H), 6.85-6.88 (m, 1H), 6.88 (d, 2H, J=8.6), 7.08-7.11 (m, 1H), 7.17 (d, 2H, J=8.7), 7.46 (d, 1H, J=8.5), 7.60 (d, 1H, J=5.2), 7.73 (d, 1H, J=3.6); MS (ESI): 476 (MH+, 100%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:15]3[C:14]4[CH:16]=[C:17]([C:20]#[N:21])[N:18]=[CH:19][C:13]=4[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:11]=3[N:10]=[CH:9][CH:8]=2)[CH2:3]1.[Cl:30]N1C(=O)CCC1=O>C(#N)C.C(O)(C)C>[Cl:30][C:8]1[CH:9]=[N:10][C:11]2[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]3[CH:19]=[N:18][C:17]([C:20]#[N:21])=[CH:16][C:14]=3[C:15]=2[C:7]=1[N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](O)C3)ccnc21
Solvent: CC#N
Solvent: CC(C)O
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](O)C3)c(Cl)cnc21
Temperature: 35 °C
Reaction time: 5 h

Procedure:
A mixture of (S)-4-(3-hydroxypyrrolidin-1-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (140 mg, 0.34 mmol) and N-chlorosuccinimide (137 mg, 1.02 mmol) in acetonitrile (1.3 mL) and isopropyl alcohol (0.4 mL) was stirred at 35° C. for 5 hours. The cooled reaction mixture was quenched with saturated aqueous sodium thiosulfate (1 mL), diluted with ethyl acetate (50 mL), and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow solid, which was used in the next step without any further purification (100 mg).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:22][C:23]1(C)[C:27](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:15]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=1[C:23]([CH3:27])=[CH2:22])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)c(Oc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1ccc(C(=O)OC(C)(C)C)cc1Oc1ccccc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of tert-butyl 4-bromo-3-phenoxybenzoate (400 mg, 1.15 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (193 mg, 1.15 mmol) and sodium carbonate (366 mg, 3.45 mmol), tetrakis(triphenylphosphine)palladium (40 mg, 0.035 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was stirred at 90° C. overnight under nitrogen atmosphere. After being cooled to room temperature, the reaction was concentrated. The residue was purified by pre-HPLC to get tert-butyl 3-phenoxy-4-(prop-1-en-2-yl)benzoate (309 mg, 87%) as a yellow solid LRMS (M+H+) m/z: calcd 311.16. found 311.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(NC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.BrC1C(N2CCN([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)CC2)=C([N+]([O-])=O)C(N)=NC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CN(C1C=CC(C=O)=CC=1)C>CN(C=O)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(c3ccccc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2nc3c(N4CCN(c5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 18 h
Yield: 36 %

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-phenylpiperazin-1-yl)pyridin-2-amine (75 mg, 0.20 mmol), DMF (1.5 mL), 1M Na2S2O4 (3 eq, 0.60 mmol, 0.60 mL) and 4-(N,N-dimethylamino)benzaldehyde (1.05 eq, 0.21 mmol, 31 mg). After 18 h, filtration of the precipitate and trituration with Et2O gave the product (34 mg, 36%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 3.00 (s, 6H, N(CH3)2), 3.36-3.38 (m, 4H, piperazine N(CH2)2), 3.78-3.80 (m, 4H, piperazine N(CH2)2), 6.80-6.83 (m, 1H, phenyl H-4), 6.82 (d, J=8.7 Hz, 2H, N,N-dimethylaminophenyl), 7.03 (d, J=8.0 Hz, 2H, phenyl H-2 & H-6), 7.25 (t, br, J=8.0 Hz, 2H, phenyl H-3 & H-5), 8.02 (d, J=8.8 Hz, 2H, N,N-dimethylaminophenyl), 8.19 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.14 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(Cl)Cl>[N:12]1([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: NS(=O)(=O)c1ccc(F)cc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(N2CCOCC2)cc1
Yield: 73.5 %

Procedure:
4-Fluorobenzenesulfonamide (5.50 g, 31.4 mmoles) was dissolved in 100 ml of morpholine (99.6 g, 1.14 moles) and was refluxed for 3 days. The solvent was removed by evaporation, yielding an orange oil. Methylene chloride (100 ml) was added, causing the oil to solidify. The solid was collected by filtration, then heated in 100 ml of ethanol. After cooling, the solid was collected by filtration, yielding 5.59 g (73%) of 4-(4-morpholinyl)benzenesulfonamide as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[NH2:16][CH2:17][CH:18]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20]>>[CH2:31]([O:30][C:28]([NH:27][CH:18]([C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:17][NH:16][C:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)=[O:14])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: NCC(NC(=O)OCc1ccccc1)C(=O)N1CCCCC1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: O=C(NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1)OCc1ccccc1
Yield: 44 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-[3-amino-2-(benzyloxycarbonylamino)propionyl]piperidine to give N-[2-(benzyloxycarbonylamino)-2-(piperidinocarbonyl)ethyl]-1-(4-pyridyl)piperidine-4-carboxamide in 44% yield;