Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[C:5]=2[C:4](=[O:20])[O:3]1.[CH3:22][O:23][C:24]1[N:29]=[C:28]([Sn](CCCC)(CCCC)CCCC)[CH:27]=[CH:26][CH:25]=1.[Cl-].[Li+]>O1CCOCC1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[N:29]=3)[C:5]=2[C:4](=[O:20])[O:3]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Reactant: CC1(C)OC(=O)c2c(cccc2OS(=O)(=O)C(F)(F)F)O1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1cccc(-c2cccc3c2C(=O)OC(C)(C)O3)n1
Temperature: 140 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
10.9 g of 2,2-dimethyl-5-trifluoromethylsulfonyloxy-4H-(1,3)-benzodioxin-4-one, 16.0 g of 6-methoxy-2-tributylstannylpyridine, 4.25 g of lithium chloride, 0.78 g of tetrakistriphenylphosphine-palladium0 and 40 mg of 2,6-di-t-butyl-4-methylphenol are dissolved in 120 ml of dioxane and the mixture is stirred for 4 h at 140° C. in an autoclave. It is concentrated under reduced pressure and the product is chromatographed on silica gel 60 using ethyl acetate/toluene. 9.1 g (95%) of a solid of m.p. 130-132° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:20][CH2:19]1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)[CH2:20][CH2:19]2)=[CH:3][C:2]([C:35]2[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1)C1CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1)C1CC1
Temperature: 80 °C

Procedure:
To a suspension of (6-bromo-4-((trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)amino)quinolin-3-yl)(cyclopropyl)methanone (46 mg, 0.10 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) and Pd(dppf)Cl2 (11 mg, 0.015 mmol) in dioxane (4 mL) was added Cs2CO3 (1.0 M in H2O, 0.4 mL, 0.4 mmol). N2 gas was bubbled through the reaction mixture and the mixture was then heated at 80° C. for 2 h. The solution was allowed to cool to room temperature, then directly subjected to column chromatography (silica, 0-20% methanol/dichloromethane). The resultant residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to afford the desired product (22.1 mg, 41%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.09 (s, 1H), 8.28 (d, J=2.1 Hz, 1H), 7.97-7.91 (m, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.55 (s, 2H), 4.19-4.10 (m, 1H), 3.14-3.07 (m, 4H), 2.89-2.78 (m, 3H), 2.31 (d, J=12.6 Hz, 5H), 2.04-1.97 (m, 4H), 1.83-1.79 (m, 1H), 1.57 (q, J=12.3 Hz, 4H), 1.32-1.04 (m, 6H). ESI MS m/z 538 [C30H33O2N3O2+H]+; HPLC>99% (AUC), tR=11.29 min.
Reaction SMILES: O1C2C(=CC=CC=2)/C(=[N:11]/[OH:12])/CC1.[CH2:13]([CH:15]1[C:23](=O)[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[CH2:16]1)[CH3:14]>>[CH2:13]([CH:15]1[CH2:16][C:17]2[C:18](/[C:23]/1=[N:11]\[OH:12])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH3:14]
Reactant: CCC1Cc2cccnc2C1=O
Reactant: O/N=C1\CCOc2ccccc21
Product: CCC1Cc2cccnc2/C1=N\O

Procedure:
Following the procedure for the preparation of (4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting 6-ethyl-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, DMSO-d6) δ) 11.21, 8.45, 7.74, 7.29, 3.27, 3.11, 2.65, 1.84, 1.46, 0.85; HRMS (FAB) calcd for C10H12N2O+H 177.1028, found 177.1029.
Reaction SMILES: Br.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](SCC1C=CC=CC=1)=[NH:8].[NH2:17][C:18]1[CH:19]=[CH:20][C:21]2[N:26]([CH2:27][CH2:28][N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24][S:23][C:22]=2[CH:38]=1>CCO>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[NH:8])[NH:17][C:18]1[CH:19]=[CH:20][C:21]2[N:26]([CH2:27][CH2:28][N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:25][CH2:24][S:23][C:22]=2[CH:38]=1
Reactant: N=C(SCc1ccccc1)c1ccco1
Reactant: CN(CCN1CCSc2cc(N)ccc21)C(=O)OC(C)(C)C
Agent: Br
Solvent: CCO
Product: CN(CCN1CCSc2cc(NC(=N)c3ccco3)ccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
Benzyl furan-2-carbimidothioate hydrobromide (1.199 g, 4.02 mmol) was added to a mixture of tert-butyl 2-(7-amino-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl(methyl)carbamate (0.763 g, 2.361 mmol) in EtOH (20 mL). The mixture was stirred under room temperature overnight. The mixture was quenched with saturated sodium bicarbonate solution (50 mL), diluted with water (50 mL), and extracted with CH2Cl2 (2×50 mL). The organic phase was washed with brine (50 mL) and dried (Na2SO4). The crude material was subject to flash chromatography on silica gel (2.5-5% (2M NH3 in MeOH):CH2Cl2). The collected fractions were concentrated to give a white foam (0.88 g, 90%). 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.44 (s, 1H), 6.74-6.69 (m, 1H), 6.62 (d, J=7.5 Hz, 1H), 4.72 (brs, 2H), 3.64-3.60 (m, 2H), 3.41 (s, 4H), 3.04-3.01 (m, 2H), 2.92 (s, 3H), 1.45 (s, 9H); ESI-MS (m/z, %): 419, 417 (MH+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[Na+].Cl>O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[CH:16][N+:13]([O-:15])=[O:14]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C=C[N+](=O)[O-])cc(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 34.5 g. (0.208 mole) 3,5-dimethoxybenzaldehyde and 12.68 g. (0.208 mole) nitromethane in 40 ml. methanol was cooled to 0° C. under a nitrogen atmosphere. To this was added dropwise a cold solution of 8.43 g. (0.211 mole) sodium hydroxide in 30 ml. water and stirring continued at 0° C. for 15 minutes after the addition was completed. The mixture was diluted with ice-water and added slowly to a solution of 40 ml. concentrated hydrochloric acid in 60 ml. water. The precipitated product (44 g.) was collected by filtration and recrystallized from methanol to give 28.6 g., M.P. 132° C. J. Org. Chem., 27, 376 (1976) reported M.P. 133.5°-134.5° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[C:12]2[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:29]=1>>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][NH:18][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH2:5][CH2:4][NH:3][S:34]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)(=[O:36])=[O:35])[CH:8]=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCN)c2n1
Agent: Cl
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCNS(=O)(=O)c3cccnc3)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [8-(2-aminoethoxy)-2-methylquinolin-4-yl]-(3,4-dichlorobenzyl)-amine dihydrochloride and pyridine-3-sulfonyl chloride.
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[N:5]=[C:4]([CH3:13])[N:3]=1.[CH2:14]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])[CH3:15].C(=O)=O>C(O)CCC>[CH2:14]([O:16][C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:2]2[C:7]3[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=3[N:5]=[C:4]([CH3:13])[N:3]=2)[CH2:23][CH2:24]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)N1CCNCC1
Reactant: Cc1nc(Cl)c2c(n1)NC(=O)CO2
Agent: O=C=O
Solvent: CCCCO
Product: CCOC(=O)N1CCN(c2nc(C)nc3c2OCC(=O)N3)CC1
Yield: 87 %

Procedure:
A mixture containing 1 g of 4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one (Khim. Geterotsikl. Soed. 1976, 681), 10 ml of n-butanol and 1.58 g of 1-ethoxycarbonylpiperazine is refluxed under protection against moisture and carbon dioxide, then evaporated. The residue is triturated with water and the product precipitated at 0° to 4° C. is filtered, washed with water and ether and dried to give 1.4 g (87%) of product, m.p.: 197°-198° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][CH:28](OC=C)[C:27]=1[CH3:34].Cl([O-])(=O)(=O)=O.[Li+].[CH:41]([O:43]CC)=[CH2:42]>CCOCC.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][CH:28]([CH2:42][CH:41]=[O:43])[C:27]=1[CH3:34]
Reactant: C=COC1CCC(Cc2c(OC)c(C)c3c(c2OS(=O)(=O)c2ccc(C)cc2)C(=O)OC3)=C1C
Reactant: C=COCC
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CCOCC
Product: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=C(C)C(CC=O)CC1)C(=O)OC2
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a solution of 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofurnylmethyl)-2-methylcyclopent-2-en-1-ol (0.157 g) in ethyl vinyl ether (10 mL) was added mercuric acetate (0.052 g). After stirring for 30 hours at ambient temperature, the reaction was diluted with ether and passed quickly through a fritted funnel half filled with celite and capped with silica. To this ethereal solution [containing 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-2-methyl-1-vinyloxycyclopent-2-ene, which was not isolated or characterized] was then added lithium perchlorate (10 mL, 0.5M solution in ether). After 0.5 hours, the reaction was diluted with aqueous sodium bicarbonate and washed with brine. Drying over magnesium sulfate was followed by filtration and solvent removal. The product 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-ylacetaldehyde (0.050 g) was finally obtained after chromatography (hexanes/ethyl acetate, 2/1).
Reaction SMILES: I[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]1[N:33]=[C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:31]=[CH:30][CH:29]=1)CCC>CN(C=O)C.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>[CH2:15]([NH:14][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]([N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)[N:33]=3)=[CH:3][C:4]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:5][C:6]=2[N:7]=1)=[O:13])[CH3:16]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(I)c2s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(N2CCOCC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cccc(N4CCOCC4)n3)c2s1
Temperature: 120 °C
Yield: 6.2 %

Procedure:
To a solution of 1-(7-iodo-5-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea (0.15 g, 0.35 mmol) in DMF (5 mL) was added 4-(6-tributylstannanyl-pyridin-2-yl)-morpholine (0.30 g, 0.70 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was then degassed for half an hour followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.018 mmol). The reaction mixture was then again degassed for half an hour and heated at 120° C. for 15 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), DMF was distilled off; water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude residue was purified by prep HPLC to get the title compound (0.01 g, 6.0%) as white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:21]1>>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:20]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=5)[CH2:21]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: c1cc(C2CCNC2)ccn1
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCC(c4ccncc4)C3)c(F)cc2c1=O
Yield: 67 %

Procedure:
Starting from 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.85 g, 3.0 mmol) and 4-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound (0.79 g, 67%), mp 223°-225° C.
Reaction SMILES: [Na].[O:2]=[C:3]1[NH:7][C:6](=[O:8])[CH:5](P(OCC)(=O)OCC)[NH:4]1.[N+:17]([C:20]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])=[CH:24][C:21]=1[CH:22]=O)([O-:19])=[O:18].C(OCC)C>C(O)C.C(Cl)(Cl)Cl>[N+:17]([C:20]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])=[CH:24][C:21]=1[CH:22]=[C:5]1[NH:4][C:3](=[O:2])[NH:7][C:6]1=[O:8])([O-:19])=[O:18]
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Reactant: O=Cc1cc(OCCCCS(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cc(OCCCCS(=O)(=O)c3ccccc3)ccc2[N+](=O)[O-])N1
Reaction time: 1 h
Yield: 8.6 %

Procedure:
Sodium (0.386 g, 0.017 g, atom) was dissolved in ethanol (70 mL) and diethyl 2,4-dioxoimidazolidine-5-phosphonate (3.96 g, 17 mmol) added. After 1 hour, a solution of 2-nitro-5-[4-(phenylsulfonyl)butoxy]benzaldehyde (4.70 g, 13 mmol) (prepared by alkylating 5-hydroxy-2-nitrobenzaldehyde with 4-phenylsulfonylbutyl bromide) in ethanol and chloroform was added. After 20 minutes, the solvent was evaporated and the residue extracted with chloroform to give a foamy solid which was dissolved in acetontirile. Diethyl ether was added to the point of precipitate nd the mixture allowed to stand overnight. A solid (0.86 g) was collected and further purified gy crystallication from acetonitrile-diethyl ether to give 5-[[2-nitro-5-[4-(phenylsulfonyl)butoxy]phenyl]methylene]-2,4-imidazolidinedione (0.5 g). Concentration of the combined mother liquors afforded 4.1 g of material that was used without further purification. Yield (4.6 g, 61%). Crystallized material had m.p. 150°-152° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.C[Si](C)(C)[C:19]([F:22])([F:21])[F:20].Cl>COCCOC.CCOC(C)=O.[F-].[Cs+]>[F:20][C:19]([F:22])([F:21])[CH:11]([C:10]1[CH:13]=[CH:14][C:7]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=1)[OH:12]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(OCCCC(F)(F)F)cc1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: OC(c1ccc(OCCCC(F)(F)F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 123.4 %

Procedure:
To the solution of Intermediate 2A (26.7 g, 114 mmol) and trimethyl(trifluoromethyl)silane (16.9 g, 119 mmol) in anhydrous DME (112 mL) was added CsF (500 mg, 3.29 mmol). The reaction was stirred at rt for 16 h. To the mixture was added 4 N aq HCl (114 mL) and the reaction was stirred at rt for 2.5 h. The reaction was diluted with EtOAc (300 mL) and washed with water, sat'd aq NaHCO3, sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated to provide Intermediate 2B (42.5 g, 122%) as an oil. The crude product was used without further purification. LCMS Anal. Calc'd for C12H12F6O2 302.21, found [M−H] 301.2.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].[CH2:19](Br)[CH:20]([CH3:22])[CH3:21].[NH4+].[Cl-]>CN(C=O)C>[CH2:19]([N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]1=[O:1])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1=O
Reactant: CC(C)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)CN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Reaction time: 0.08 h
Yield: 48.4 %

Procedure:
To a solution of (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (116 mg, 0.510 mmol) in DMF (2 mL) at 0° C. was added sodium hydride (60% in oil, 23 mg, 0.57 mmol) in 2 portions. After stirring for 5 min, isobutyl bromide (175 mg, 1.28 mmol) was added to the reaction mixture and the mixture was stirred at rt for 20 h. Saturated aqueous NH4Cl (2 mL) was added to the mixture and crude product was extracted with methylene chloride (3 mL) and the combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified using silica gel chromatography to afford (S)-tert-Butyl 1-isobutyl-2-oxoazepan-3-ylcarbamate (46.4 mg, 0.247 mmol, 49% yield). Anal. Calcd. for C15H28N2O3 m/z 284.2. found: 285.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.44 (d, J=6.64 Hz, 1H), 4.26 (t, J=9 Hz, 1H), 3.57-3.50 (m, 1H), 3.26-3.17 (m, 2H), 3.10-3.05 (m, 1H), 1.84-1.62 (m, 5H), 1.37 (s, 9H), 1.34-1.24 (m, 2H), 0.84-0.80 (m, 6H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:24]4[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccc(OC(F)(F)F)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (82 mg, 88%), MS (ISP) m/z=372.4 [(M+H)+], mp 311.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:31]1[C:44]2[C:35](=[N:36][C:37]3[C:42]([C:43]=2[NH:45][C:46]2[CH:47]=[C:48]([NH:54][C:55](=[O:59])[CH:56]([NH2:58])[CH3:57])[CH:49]=[C:50]([CH2:52][OH:53])[CH:51]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][CH:32]=1>>[CH:41]1[C:42]2[C:37](=[N:36][C:35]3[C:44]([C:43]=2[NH:45][C:46]2[CH:47]=[C:48]([NH:54][C:55]([CH:56]([NH:58][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:22][CH2:21][N:20]([C:23]6[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=6)[CH2:19][CH2:18]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH3:57])=[O:59])[CH:49]=[C:50]([CH2:52][OH:53])[CH:51]=2)=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:38]=[CH:39][CH:40]=1
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(F)cc(F)c3)CC2)cc1C(=O)O
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(F)cc(F)c3)CC2)cc1C(=O)NC(C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 48.7 %

Procedure:
The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3,5-difluorophenyl)-piperazine-1-carbonyl]-amino}-6-methoxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15](F)[C:14]=3[Cl:21])[OH:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(Cl)C=1C=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:21])[OH:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: OC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Agent: O=Cc1c(Cl)cccc1Cl
Product: OC(c1c(Cl)cccc1Cl)c1c[nH]c2ncc(Br)cc12

Procedure:
Prepared according to the method described above for synthesis of (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,6-dichloro-3-fluorophenyl)methanol, using 2,6-dichloro-benzaldehyde. MS (ES+): m/z 370.85, 372.85, 374.83 [MH+]; HPLC: tR=3.25 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:3][CH:2]=1.C(Cl)(Cl)Cl>CO.O.O1CCOCC1>[CH3:20][C:1]1[CH:2]=[C:3]2[C:4]([NH:7][C:8]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][C:9]=3[C:10]2=[O:12])=[CH:5][CH:6]=1
Reactant: Cc1ccc(Nc2cc(C(=O)O)ccc2C(=O)O)cc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc2[nH]c3cc(C(=O)O)ccc3c(=O)c2c1
Temperature: 100 °C
Yield: 107.1 %

Procedure:
To a round bottom flask equipped with a condenser was added compound 138A (2.0 g), polyphosphoric acid (15 g) and CHCl3 (50 mL), and the mixture was heated to 100° C. for 18 h. LC/MS indicated that the reaction was complete. The reaction mixture was cooled to room temperature, diluted with MeOH (25 mL), and H2O (50 mL) was added. The resulting mixture was filtered through a medium porosity fritted funnel, washed with MeOH:1% Et3N in H2O (1:1, 30 mL) two times, and dried in air to give a yellow paste which was then dispersed in dioxane (10 mL) with sonication and dried over lyophlyzer to give compound 138B as a yellow solid (2.0 g). HPLC retention time: 2.76 min., condition A. M+: 254.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([O-:22])=[CH:9][CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc2ncccc2c1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc2c(ccc[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.9 %

Procedure:
Commercially available 6-nitroquinoline (1.0 g, 5.6 mmol) was dissolved in CHCl3 (30 mL) and mCPBA (1.76 g, 7.8 mmol) was added portionwise and the reactions stirred at rt for 48 h. The mixture was then washed with saturated aqueous NaHCO3, 1 N aqueous NaOH, and 5% aqueous NaHSO3, dried (Na2SO4), filtered and concentrated under reduced pressure to give compound 45A (1.0 g, 93%) as a light yellow solid. LC/MS m/z 191 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH3:12])=[N:6][CH:5]=1.C1C(=O)N([Br:21])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH2:10][Br:21])[C:7]([O:11][CH3:12])=[N:6][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cnc(OC)c(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cnc(OC)c(CBr)c1
Reaction time: 5 h
Yield: 53.9 %

Procedure:
A solution containing 6-methoxy-5-methyl-nicotinic acid methyl ester (4.00 g, 22.1 mmol), NBS (5.11 g, 28.7 mmol), and AIBN (0.90 g, 5.5 mmol) in CCl4 (100 mL) is warmed to reflux. After 5 h, the reaction mixture is cooled and then concentrated in vacuo. The residue is dissolved in EtOAc (500 mL) and washed successively with aqueous Na2S2O3 (300 mL), water (100 mL), brine then dried over anhydrous Na2SO4, filtered and concentrated. The crude product is purified by silica gel flash column chromatography (hexane/diethyl ether, 9:1) to provide 3.10 g (54%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ3.90 (s, 3H), 4.07 (s, 3H), 4.46 (s, 2H), 8.19 (d, J=2.2 Hz, 1H), 8.79 (d, J=2.2 Hz, 1H) ppm; MS (EI): m/z 259 (M+).