Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=2)=[CH:5][CH:4]=1.Cl[CH2:28][C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCCCCCC>CC1CCCO1.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:28][C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:23][CH2:22]3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=2)=[CH:7][CH:8]=1
Reactant: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCNCC2)n1
Reactant: ClCc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCCCCCC
Solvent: CC1CCCO1
Product: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(Cc3ncccn3)CC2)n1
Reaction time: 0.17 h

Procedure:
A slurry of 4-[4-(4-fluorophenyl)-1-piperidin-4-yl-1H-imidazol-5-yl]pyrimidin-2-amine, hydrochloride salt (C9, which can be prepared by the method of J. Sisko, U.S. Pat. No. 6,239,279 B1, May 29, 2001) (200 mg, 0.534 mmol), 2-(chloromethyl)pyrimidine (110 mg, 0.667 mmol) and cesium carbonate (365 mg, 1.12 mmol) in 2-methyltetrahydrofuran (3 mL) and water (1 mL) was heated overnight at 70° C. The resulting solution was cooled, and the organic layer was concentrated in vacuo. Addition of dichloromethane produced a solid; heptane (10 mL) was added, and the resulting mixture was stirred for 10 minutes. Filtration provided the title product as a solid. Yield: 205 mg, 0.476 mmol, 89%. APCI m/z 431.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.08-2.14 (m, 4H), 2.30-2.36 (m, 2H), 3.09 (br d, J=12 Hz, 2H), 3.84 (s, 2H), 4.62 (m, 1H), 6.40 (d, J=5.2 Hz, 1H), 7.07 (dd, J=8.8, 8.8 Hz, 2H), 7.39-7.43 (m, 3H), 8.04 (s, 1H), 8.13 (d, J=5.2 Hz, 1H), 8.80 (d, J=5.0 Hz, 2H).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[ClH:17]>O1C=COC=C1>[ClH:17].[ClH:17].[CH:1]1([N:4]2[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CC2)CC1
Agent: C1=COC=CO1
Agent: Cl
Product: C1CN(C2CC2)CCN1
Temperature: 45 °C

Procedure:
A solution of tert-butyl 4-cyclopropylpiperazine-1-carboxylate (92 g) in 1,4-dioxin (200 mL) was treated with HCl (4 M in 1,4-dioxin, 500 mL) over 10 min while maintaining the temperature below 40° C. After the addition was complete, the mixture was heated at 45° C. for 9 h and then was cooled to room temperature. The thick suspension was diluted with hexanes (400 mL) and was cooled to 10° C. The resulting solid was collected by filtration, washed with hexanes, and dried to yield the title compound as a white solid.
Reaction SMILES: O[C@@H](C1C=CC=CC=1)CNC1C=CNC(=O)C=1C1NC2C(C(O)=O)=CC=CC=2N=1.C(N)C1C=CC=CC=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.F[C:72]1[CH:73]=[C:74]([CH:105]=[CH:106][CH:107]=1)[CH2:75][NH:76][C:77]([C:79]1[C:87]2[NH:86][C:85]([C:88]3[C:89](=[O:104])[NH:90][CH:91]=[CH:92][C:93]=3[NH:94][CH2:95][C@@H:96]([OH:103])[C:97]3[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=3)=[N:84][C:83]=2[CH:82]=[CH:81][CH:80]=1)=[O:78]>CN(C=O)C>[CH2:75]([NH:76][C:77]([C:79]1[C:87]2[NH:86][C:85]([C:88]3[C:89](=[O:104])[NH:90][CH:91]=[CH:92][C:93]=3[NH:94][CH2:95][C@@H:96]([OH:103])[C:97]3[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=3)=[N:84][C:83]=2[CH:82]=[CH:81][CH:80]=1)=[O:78])[C:74]1[CH:105]=[CH:106][CH:107]=[CH:72][CH:73]=1
Reactant: O=C(NCc1cccc(F)c1)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Solvent: NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12

Procedure:
2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid benzylamide was synthesized from 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid, benzylamine, DIEA, HATU and DMF using a similar procedure as 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid 3-fluoro-benzylamide yielding 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid benzylamide. LC/MS calcd for C28H25N5O3 (m/e) 479.0, obsd 480 (M+H). 1H NMR (tautomers 1:2; DMSO-d6) δ: 13.38-13.52 (m, 1H), 11.14-11.38 (m, 1H), 10.33-11.02 (m, 1H), 9.18-9.43 (m, 1H), 7.69-7.99 (m, 2H), 7.15-7.61 (m, 12H), 6.12-6.30 (m, 1H), 5.74-5.99 (m, 1H), 4.52-4.96 (m, 3H), 3.49-3.30 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][CH2:36][CH2:37][NH:38][CH2:39][CH3:40]>>[CH2:39]([N:38]([CH2:37][CH2:36][O:35][CH3:34])[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1)[CH3:40]
Reactant: CCNCCOC
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCN(CCOC)c1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cn1

Procedure:
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with cesium carbonate and N-(2-methoxyethyl)ethylamine. ES-MS m/e (%): 472 (M+H+, 100).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][OH:10].[O:11]=[S:12]1(=[O:35])[C:17]2[CH:18]=[C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30]#[N:31])=[CH:25][CH:24]=3)[CH:20]=[CH:21][C:16]=2[N:15]2[CH2:32][CH2:33][CH2:34][CH:14]2[NH:13]1>CS(C)=O>[O:35]=[S:12]1(=[O:11])[C:17]2[CH:18]=[C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30](=[N:9][OH:10])[NH2:31])=[CH:25][CH:24]=3)[CH:20]=[CH:21][C:16]=2[N:15]2[CH2:32][CH2:33][CH2:34][C:14]2=[N:13]1
Reactant: NO
Reactant: N#CCc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: NC(Cc1ccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)cc1)=NO
Reaction time: 0.17 h

Procedure:
2.51 ml (18.0 mmol) of triethylamine are added to a solution of 1.25 g (18.0 mmol) of hydroxylamine hydrochloride in 4 ml of DMSO and the suspension is stirred for 10 minutes. The precipitate is filtered off and the filtrate is concentrated. 992 mg (3.00 mmol) of the product of Step A of Example 27 are added to the filtrate and the solution is stirred at 75° C. for 1 hour 30 minutes. The solution is allowed to return to ambient temperature, and precipitation of the reaction mixture is brought about using water. The precipitate is filtered off to yield the title product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:13][CH3:14])[CH:7]=[C:8]([N+]([O-])=O)[CH:9]=1)([O-:3])=[O:2].[CH3:15][S:16][Si](C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O.C(OCC)(=O)C>[CH3:14][O:13][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[C:8]([S:16][CH3:15])[CH:7]=1
Reactant: COc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CS[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(SC)cc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 28.6 %

Procedure:
To a solution of 3,5-dinitroanisole (5.0 g, 25.23 mmol) in dimethylsulfoxide (50 mL) were added methylthiotrimethylsilane (4.86 g, 40.37 mmol) and cesium carbonate (16.61 g, 50.46 mmol) at room temperature. The resulting dark green solution was stirred for 15 h at this temperature. Then, the reaction mixture was heated to 90° C. and the resulting brown mixture was stirred for another 5 h at which time TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was cooled to room temperature and diluted with water (100 mL) and ethyl acetate (100 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined extracts were washed with brine solution (150 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and the concentration of the solution under vacuum gave the crude residue which was purified by using an ISCO 120 column chromatography, eluting with 0-20% ethyl acetate in hexanes to obtain 1-methoxy-3-methylsulfanyl-5-nitro-benzene (1.44 g, 28.6%) as an yellow solid: EI(+)-HRMS m/e calcd for C8H9NO3S (M)+ 199.0303, found 199.0294.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])=[CH:4][CH:3]=1.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(N(CC)CC)C>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:37]([NH:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:38])=[CH:7][CH:6]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)cc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1ccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)cc1

Procedure:
The title compound was prepared from [4-(4-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and phenyl isocyanate in substantially the same manner as described in Example 61 with one change: no triethylamine was used; off-white solid: MS (ES) m/z 510.2.
Reaction SMILES: BrC1C=CC(C([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH3:22])=[CH:13][CH:12]=2)=O)=CC=1.O>Cl>[CH3:22][N:18]1[CH2:19][CH2:20][CH2:21][CH:17]1[C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH2:8])=[CH:12][CH:13]=1
Reactant: CN1CCCC1c1ccc(CCNC(=O)c2ccc(Br)cc2)cc1
Agent: Cl
Solvent: O
Product: CN1CCCC1c1ccc(CCN)cc1
Yield: 51.7 %

Procedure:
A solution of 4-bromo-N-{2-[4-(1-methyl-2-pyrrolidinyl)phenyl]ethyl}benzamide (1.12 g, 2.89 mmol) obtained in Example 136 in concentrated hydrochloric acid (14 ml) was stirred at 100° C. for one day. Water was added to the reaction mixture, and the mixture was washed with diethyl ether and basified with potassium carbonate. This was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by alumina column chromatography (developing solvent; ethyl acetate:methanol=1:1) to give the title compound (305 mg).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])[CH3:10].C(N(C(C)C)CC)(C)C.Cl>C(Cl)Cl>[Br:1][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:9][CH3:10])[C:12]=1[OH:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccccc1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
N-Bromosuccinimide (29.1 g, 163.7 mmol) was added as a suspension in CH2Cl2 (200 mL) over 2 h to a solution of 2-ethylphenol (20.0 gm, 163.7 mmol), diisopropylethylamine (2.3 mL, 16.4 mmol), and CH2Cl2 (300 mL). The resulting solution was maintained at room temperature for 2 h. One normal HCl (100 mL) was added and the mixture was stirred vigorously for 0.5 h. The layers were separated, and the organic phase was washed with 1 N HCl (2×100 mL). The combined aqueous layers were extracted with CH2Cl2 (1×100 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (SiO2, gradient elution 5 to 10% CH2Cl2/hexanes) to yield 26.5 g (80%) of 2-bromo-6-ethylphenol 1 as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[NH2:13][C:14]1[CH:28]=[C:27]([Cl:29])[C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:16]([Cl:30])[CH:15]=1>C(#N)C>[Cl:29][C:27]1[CH:28]=[C:14]([NH:13][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[Cl:1])=[O:8])[CH:15]=[C:16]([Cl:30])[C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: Nc1cc(Cl)c(OCCCCCC(=O)O)c(Cl)c1
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: CC#N
Product: O=C(O)CCCCCOc1c(Cl)cc(NC(=O)NC(=O)c2ccccc2Cl)cc1Cl
Temperature: 25 °C
Yield: 84.5 %

Procedure:
A solution of 7.5 g (41.1 mmol) of 2-chlorobenzoyl isocyanate in 300 ml of acetonitrile was added to a suspension of 10.0 g (34.2 mmol) of 6-(4-amino-2,6-dichlorophenoxy)hexanoic acid in 700 ml of dry acetonitrile under a protective gas atmosphere at room temperature. The mixture was boiled under reflux for 2 hours and cooled to room temperature. The resulting precipitate was filtered off with suction and washed with 50 ml of acetonitrile. The residue was stirred with 100 ml of methanol, filtered off with suction, washed with a little methanol and dried at 40° C. under vacuum overnight. 13.7 g (28.9 mmol, 85%) of the required product were obtained. Melting point: about 171-173° C.
Reaction SMILES: [CH3:1][C:2]1[S:16][C:5]2=[N:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([OH:10])=[C:4]2[CH:3]=1.[H-].[Na+].[CH2:19](I)[CH3:20]>CN(C)C=O>[CH2:19]([N:6]1[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9](=[O:10])[C:4]2[CH:3]=[C:2]([CH3:1])[S:16][C:5]1=2)[CH3:20]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2sc(C)cc2c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2sc(C)cc2c1=O
Temperature: 70 °C

Procedure:
A mixture of 0.237 part of ethyl 2-methyl-4-hydroxythieno-(2,3-b)pyridine-5-carboxylate, 5 parts by volume of dry dimethylformamide and 0.048 part of 50% sodium hydride in mineral oil is heated at 70° C for 30 minutes, and 0.12 part by volume of ethyl iodide is added thereto. The mixture is heated at 70° C for 2 hours and the solvent is evaporated under reduced pressure. The residue is extracted with chloroform, and the extract is washed with saturated aqueous sodium chloride and dried over sodium sulfate. Evaporation of the solvent gives ethyl 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno(2,3-b)pyridine-5-carboxylate as crystals. Recrystallization from ethyl acetate yields colorless plates melting at 140°-142° C. This product is identical with the product in Example 24.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([CH3:8])[CH2:4][C:5](O)=[O:6].Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][N:31]([C:5](=[O:6])[CH2:4][CH:3]([CH3:8])[C:2]([F:10])([F:9])[F:1])[CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:17][CH2:18]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: CC(CC(=O)O)C(F)(F)F
Agent: Cl
Product: CC(CC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1)C(F)(F)F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from 4,4,4-trifluoro-3-methylbutanoic acid (Lancaster, Cat. #L12160) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=463.2.
Reaction SMILES: I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.[OH-].[NH4+].[Cu]I>[CH3:27][O:26][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH2:9][N:6]1[C:5]2[CH:28]=[CH:29][C:2]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: C1COCCN1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(N5CCOCC5)ccc43)cc2OC)cn1
Temperature: 120 °C
Reaction time: 16 h
Yield: 25.8 %

Procedure:
To a suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.32 g, 0.64 mmol) in dimethyl sulfoxide (4 mL) was added morpholine (0.067 g, 0.77 mmol), copper(I) iodide (0.015 g, 0.076 mmol), potassium carbonate (0.22 g, 1.54 mmol), and L-proline (0.018 g, 0.15 mmol). The light yellow reaction mixture was heated to 120° C. After 16 h, the reaction mixture was allowed to cool to room temperature and was diluted with 3 N ammonium hydroxide solution (20 mL). The mixture was extracted with dichloromethane (×3). The combined organic phases were washed with water (×2), brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (CombiFlash, 40 g SiO2 column, 1-5% methanol/dichloromethane elute) afforded 0.076 g (26%) of the product as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=1.9 Hz, 1H), 7.85 (s, 1H), 7.66 (dd, J=8.5, 2.5 Hz, 1H), 7.35-7.13 (m, 2H), 6.98 (dd, J=8.8, 2.2 Hz, 1H), 6.90-6.82 (m, 1H), 6.78-6.67 (m, 3H), 5.23 (s, 2H), 5.02 (s, 2H), 3.93 (s, 3H), 3.95-3.85 (m, 4H), 3.76 (s, 3H), 3.18-3.12 (m, 4H) ppm; (M+1)=461.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][CH:16]=[C:17]2[C:22](=[O:23])OC(C)(C)OC2=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClC1C=CC=CC=1Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([C:22]([OH:23])=[CH:17][CH:16]=[N:15]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(=CNc2cccc(OCc3ccccc3)c2)C(=O)O1
Solvent: Clc1ccccc1Cl
Product: Oc1ccnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 0 %

Procedure:
A solution of 5-((3-(Benzyloxy)phenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (300 g, 849.8 mol) in 1,2-dichlorobenzene (3 L, Aladdin) was heated to reflux for 5 hours. The reaction mixture was cooled to room temperature, followed by further cooling in an ice bath for 2 hours. The solid was collected through filtration, stirred with MeOH (300 mL) at room temperature for 2 hours. The solid was collected through filtration and dried in vacuo at 45° C. to afford the title compound as a pale solid (103 g, 48.5%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:13][NH:12][CH2:11]2)[S:6][CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:45]=[C:46]1[NH:55][C:54]2[N:53]=[CH:52][C:51](/[CH:56]=[CH:57]/[C:58](O)=[O:59])=[CH:50][C:49]=2[CH2:48][CH2:47]1>CN(C)C=O.O.C(OCC)(=O)C>[Br:2][C:3]1[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:11][N:12]([C:58](=[O:59])/[CH:57]=[CH:56]/[C:51]3[CH:50]=[C:49]4[C:54](=[N:53][CH:52]=3)[NH:55][C:46](=[O:45])[CH2:47][CH2:48]4)[CH2:13]2)[S:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: Brc1csc(COC2CNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCc4cc(Br)cs4)C3)cnc2N1
Reaction time: 8 h
Yield: 62.3 %

Procedure:
3-((4-Bromothiophen-2-yl)methoxy)-azetidine hydrochloride (168 mg, 0.59 mmol), EDCI (113 mg, 0.59 mmol), HOBt (82 mg, 0.59 mmol) and diisopropylethylamine (171 μL, 1.00 mmol) were successively added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (100 mg, 0.39 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred overnight then diluted by addition of ethyl acetate (40 mL) and water (40 mL). The aqueous phase was separated and extracted with ethyl acetate (2×40 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was triturated in diethyl ether to afford a pale yellow solid (109 mg, 62%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](N)=[N:6][C:7]=1[CH3:8].N([O-])=O.[Na+].[OH-].[Na+].[ClH:16]>>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([Cl:16])=[CH:4][CH:3]=1
Reactant: Cc1nc(N)ccc1Br
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(Cl)ccc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a solution of 5-bromo-6-methyl-pyridin-2-ylamine (2.0 g, 10.6 mmol) in concentrated HCl (10 mL) was added NaNO2 (1.1 g, 15.9 mmol) at room temperature. The reaction was stirred for 2 hours, then cooled to 0° C., made basic with NaOH and extracted with Et2O. The Et2O layer was dried (MgSO4) and concentrated in vacuo to give 55A (0.63 g, 28%). HPLC Rt=2.29 min.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].N(C(C)(C)C#N)=NC(C)(C)C#N.C(Br)(=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@H](C(=O)O)C1(C)C
Agent: CC(=O)Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
5.0 g of cis-chrysanthemic acid and 0.2 g of azobisisobutyronitrile were dissolved in 50 ml of toluene and thereto was added dropwise a solution of acetyl bromide (55 mg) in toluene with stirring at 80° C. over a period of 20 minutes. Then, the same treatment as in Example 1 was effected to obtain 4.6 g of chrysanthemic acid. The IR spectrum thereof was identical with that of chrysanthemic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1COCCN1
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Yield: 88.6 %

Procedure:
To a solution of 1.67 g (19.14 mmol) of morpholine in 50 ml of dry pyridine was added 3.26 g (12.76 mmol) of 4-bromobenzenesulfonyl chloride in an atmosphere of argon, and the mixture was allowed to react at 0° C for 3 hours. To the solution was added water followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane yielded 3.45 g (11.3 mmol) of N-(4-bromobenzenesulfonyl)morpholine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Br:15])=[O:6].C([C:29]1[C:30]([N:36]=[CH:37][N:38]([CH3:40])C)=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=1)#N.NC1C=C(C=CC=1SC1C=CC(O)=CC=1)C(NC1C=CC(Br)=CC=1)=O>>[Br:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:16]=[CH:17][C:18]([S:19][C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[C:2]([NH:1][C:40]2[C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[N:31][C:30]=3[N:36]=[CH:37][N:38]=2)[CH:3]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2Br)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(C(=O)NCc4ccccc4Br)ccc3Sc3ccc(O)cc3)ncnc2n1
Yield: 71 %

Procedure:
The product of Example 31A was reacted with the product of Example 9B using the procedure of Example 22C substituting the product of Example 31A for the product of Example 22B and substituting the product of Example 9B for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (60 mg, 71%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.68 (s, 3 H) 4.48 (d, J=5.52 Hz, 2 H) 6.84 (d, J=8.82 Hz, 2 H) 6.87-6.96 (m, 1 H) 7.16-7.25 (m, 1 H) 7.25-7.40 (m, 4 H) 7.56 (d, J=8.09 Hz, 1 H) 7.61 (d, J=8.82 Hz, 1 H) 7.76 (d, J=8.82 Hz, 1 H) 7.93 (s, 1 H) 8.58 (s, 1 H) 8.74-8.85 (m, 1 H) 8.94-9.21 (m, 1 H) 9.94 (s, 1 H) 10.16 (s, 1 H); MS (ESI+) m/z 572/574 (M+H)+.