Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[O:7][CH2:8][C:9]([O-:11])=[O:10])([O-])=O.[CH2:18]1COC[CH2:19]1.[H][H].[ClH:25]>[Ni].CO.O1CCOCC1.CCO>[ClH:25].[ClH:25].[NH2:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[NH2:15])[O:7][CH2:8][C:9]([O:11][CH2:18][CH3:19])=[O:10]
Reactant: O=C([O-])COc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: [H][H]
Reactant: C1CCOC1
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)COc1ccc(N)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a Parr hydrogenation bottle was added 13.0 g of 2-(3,4-dinitrophenoxy)acetate, Raney Nickel (2.0 g, wet), THF (100 mL) and EtOH (150 mL). The atmosphere of the vessel was replaced by hydrogen gas. The reaction was shaken on a Parr hydrogenator at 40 psi at room temperature, overnight. The catalyst was filtered through a plug of Celite and the filtrate was concentrated under reduced pressure to give a residue, which was dissolved in methanol, acidified with 4 N hydrogen chloride in 1,4-dioxane and filtered. The resulting filtrate was concentrated under reduced pressure to give ethyl 2-(3,4-diaminophenoxy)acetate dihydrochloride (8.5 g, 83%), and was used directly in the next step without any further purification. MS (EI): 276 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[Br-].[N:15]1C=CC=C[C:16]=1[Zn+]>C1COCC1>[C:16]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1)#[N:15]
Reactant: Brc1cncc(-c2ccccn2)c1
Reactant: [Zn+]c1ccccn1
Agent: [Br-]
Solvent: C1CCOC1
Product: N#Cc1cncc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
2-(3-Bromopyridin-5-yl)pyridine (2 g, 10.9 mmol) in THF (10 ml) was added dropwise to a solution of 2-pyridylzincbromide (22 ml of a 0.5M solution in THF, 11 mmol) in THF (10 ml) under a nitrogen atmosphere. Tetrakis (triphenylphosphine)palladium(0) (630 mg, 0.54 mmol) was added and the reaction stirred at ambient temperature for 18 hours. The reaction was quenched with saturated aqueous ammonium chloride solution then the volatiles were removed by evaporation. The residue was suspended in water then extracted with DCM. The organic extracts were combined, washed with water then filtered through phase separating paper and the volatiles removed by evaporation. The residue was purified by column chromatography on silica gel eluting with hexane:EtOAc (2:1). The purified product was triturated with diethyl ether to give the title compound (0.98 g, 50%) as a white solid. NMR (DMSO): 7.47 (t, 1H), 7.97 (t, 1H), 8.15 (d, 1H), 8.75 (d, 1H), 8.90 (d, 1H), 9.07 (s, 1H), 9.53 (s, 1H); m/z 182 (MH)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].N1C=CC=CC=1.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>O1CCCC1>[C:22]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:25])[CH:23]=[CH2:24]
Reactant: O=C(O)CCCCCCCCCCCO
Reactant: C=CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC(=O)OCCCCCCCCCCCC(=O)O
Temperature: 0 °C
Reaction time: 5 h
Yield: 40.2 %

Procedure:
12-Hydroxydodecanoic acid (5.0 g, 0.023 mol) dissolved in tetrahydrofuran (100 ml) and pyridine (2.16 g, 0.027 mol) was cooled to 0° C. Acryloyl chloride (3.15 g, 0.023 mol) in tetrahydrofuran (75 ml) was then added dropwise to the solution. The mixture was stirred for 5 hours at 0° C. then stirred overnight at room temperature. The precipitated pyridinium salt was filtered off and the solvent removed under vacuum. The resulting liquid was purified by flash chromatography (silica gel/chloroform) to give 2.5 g (40%) of the title compound. 1H NMR (60 MHz, CDCl3): δ 1.20 (s, 18H, CH2), 2.15 (m, 2H, CH2COOH), 4.0 (m, 2H, COOCH2), 5.7-6.0 (m, 3H, CH2 = and =CH).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17](I)[CH:18]([CH3:20])[CH3:19]>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(Cl)nc2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
To a solution of 2-chloro-benzoimidazole (1.0 eq.) in DMF was added K2CO3 (2.0 eq.) and isobutyl iodide (1.5 eq.). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was poured into ice-water. The mixture was extracted with ethyl acetate (3×100 mL), washed with brine, dried over Na2SO4, concentrated to get a residue, which was purified by column chromatography to afford 4 g (96%) of 2-chloro-1-isobutyl-benzoimidazole.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH:24]([C:30]2[CH:35]=[C:34]([CH:36]=O)[CH:33]=[C:32]([O:38][CH2:39][CH3:40])[CH:31]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1)#[N:16].[C:41]1([NH2:48])[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH2:47].O>C(#N)C>[NH:47]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:48]=[C:36]1[C:34]1[CH:35]=[C:30]([CH:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([C:15]#[N:16])=[CH:22][CH:21]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:31]=[C:32]([O:38][CH2:39][CH3:40])[CH:33]=1
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(C=O)cc(OCC)c1
Reactant: Nc1ccccc1N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(-c2nc3ccccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in acetonitrile (1.5 ml) was added dropwise very slowly (2 h.) to a solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-formyl-phenyl)-acetate (460 mg, 1.305 mmol) obtained in Example 244.1 and 1,2-phenylenediamine in acetonitrile (2 ml). The reaction mixture was stirred for 4 h. at room temperature. Water/saturated Na2CO3 solution (1:1) was added and the mixture was extracted with CH2Cl2. The organic phase was washed with H2O, dried, filtered and concentrated. The residue was purified by chromatography (SiO2, hexane/EtOAc 3:2). There were obtained 173 mg (30%) of ethyl (RS)-[3-(1H-benzoimidazol-2-yl)-5-ethoxy-phenyl]-(4-cyano-phenylamino)-acetate as a colorless solid; MS: 441 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:21]=[C:22]([C:23](OC)=[O:24])[C:4]=2[N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[CH:21]=[C:22]([CH2:23][OH:24])[C:4]=2[N:3]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc(C(F)(F)F)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cn2c(C)nc3c(CO)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of methyl 2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylate, prepared as described in Example 30 (0.37 g, 0.827 mmol) in Tetrahydrofuran (THF) (10 mL) was cooled to 0° C. LiAlH4 (0.038 g, 1 mmol) in THF (3 mL) was added in and the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched with water (0.04 mL), NaOH (15%, 0.04 mL) then water (0.12 mL). Anhydrous MgSO4 was added and the reaction mixture was filtered through celite and washed with EtOAc. Evaporation of the solvent gave the crude product. The crude product was purified on a silica column (1˜4% MeOH/DCM) to give the solid (0.32 g, 88%).
Reaction SMILES: [BrH:1].[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[C:11]2[NH:12][C:13]([CH3:33])=[C:14]([C:31]#[N:32])[CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C(O)(=O)C.C(Cl)(Cl)Cl>[C:2]1([CH:8]([Br:1])[CH2:10][CH2:9][C:11]2[NH:12][C:13]([CH3:33])=[C:14]([C:31]#[N:32])[CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=C([C@@H]2C[C@H]2c2ccccc2)NC(C)=C(C#N)C1c1cccc([N+](=O)[O-])c1
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(CCC(Br)c2ccccc2)NC(C)=C(C#N)C1c1cccc([N+](=O)[O-])c1

Procedure:
5 ml of a solution of hydrobromic acid in 30% acetic acid are added at 25° C. and under inert atmosphere to a solution of the less polar diastereoisomer of trans-2-(2-phenyl-1-cyclopropyl)-3-carboethoxy-5-cyano-6-methyl-4-(m-nitrophenyl)-1,4-dihydropyridine (0.5 g) in chloroform (5 ml). After 1 1/5 hours the mixture is poured into water (50 ml) and extracted with diethyl ether (25 ml). The phases are separated and the organic one is washed with a 5% NaHCO3 aqueous solution (3×50 ml) and water (2×50 ml), dried on sodium sulphate, filtered and the solvent is evaporated under reduced pressure. 500 mg of the more polar diastereoisomer of 2-(3-phenyl-3-bromopropyl)-3-carboethoxy-5-cyano-6-methyl -4-(m-nitrophenyl)-1,4-dihydropyridine are obtained as an amorphous solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>>[CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[CH2:17][CH2:18]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: N#Cc1ccc(Br)cc1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Product: Cc1c(C)c(N2CCN(c3ccc(C#N)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 39.3 %

Procedure:
By using 1-(2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (130 mg, 0.50 mmol) synthesized in Reference example 56 and 4-bromobenzonitrile (182 mg, 1.0 mmol), the reaction was carried out in the same manner as Example 23 to obtain the title compound 71 mg (yield 39%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13]([O:19][CH3:20])=[CH:12][C:11]=1[CH3:21])[C:6]([NH:8][NH2:9])=O.[N:22]#[C:23][NH2:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(O)C>[CH:16]([C:14]1[C:13]([O:19][CH3:20])=[CH:12][C:11]([CH3:21])=[C:10]([CH:5]2[CH2:4][CH2:3][CH2:2][N:8]3[N:9]=[C:23]([NH2:24])[N:22]=[C:6]23)[CH:15]=1)([CH3:18])[CH3:17]
Reactant: N#CN
Reactant: COc1cc(C)c(C(CCCCl)C(=O)NN)cc1C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: COc1cc(C)c(C2CCCn3nc(N)nc32)cc1C(C)C
Temperature: 80 °C
Yield: 56.8 %

Procedure:
5-Chloro-2-(5-isopropyl-4-methoxy-2-methylphenyl)pentanoic acid hydrazide (4.4 g) and cyanamide (3.6 g) were dissolved in ethanol (150 mL). p-Toluenesulfonic acid monohydrate (4 g) was added and the mixture was heated under reflux at 80° C. for two hours. After cooling to room temperature, triethylamine (9.8 mL) was added and the mixture was further heated under reflux at 80° C. for three days. The reaction solution was concentrated under reduced pressure. A sodium bicarbonate solution and ethyl acetate were added and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.4 g). The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:15][C:16]2[C:17]([NH2:22])=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1.O>ClCCl>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([N:15]2[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22][C:28]2=[O:29])([CH3:14])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(Nc2ccccc2N)CCN(Cc2ccccc2)CC1
Solvent: O
Solvent: ClCCl
Product: CC1(n2c(=O)[nH]c3ccccc32)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.4 %

Procedure:
A mixture of 121 mg N-(1-benzyl-4-methyl-piperidin-4-yl)-benzene-1,2-diamine and 79 mg CDI in 5 mL dichlormethane was stirred 24 h at RT. Water was added and the mixture was extracted with ethylacetate. The organic layer was concentrated to give 119 mg of the desired product. (M+H)+:322
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([O:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[N:3]=1.O=P(Cl)(Cl)Cl.N1C=CC=CC=1.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]#[N:8])=[C:4]([O:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: CC(C)OCCOc1nc(Cl)c(C(F)(F)F)cc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)OCCOc1nc(Cl)c(C(F)(F)F)cc1C#N
Reaction time: 1 h

Procedure:
A mixture of 6-chloro-2-(2-isopropoxyethoxy)-5-(trifluoromethyl)nicotinamide (0.2 g, 0.61 mmol) in acetonitrile (20 mL) was added POCl3 (0.28 g, 1.84 mmol) and pyridine (0.29 g, 3.68 mmol). After stirred at r.t for 1 hr, the mixture was diluted by 0.2 M NaOH solution, extracted by EtOAc and the organic layer was concentrated in vacuo to afford 6-chloro-2-(2-isopropoxyethoxy)-5-(trifluoromethyl)nicotinonitrile. (180 mg, 95.7%). 1H-NMR (400 MHz, CDCl3) δ (ppm) 8.14 (s, 1H), 4.64-4.61 (t, 2H), 3.83-3.81 (t, 2H), 3.72-3.66 (m, 1H), 1.19-1.17 (d, 6H).
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[NH2:21][C:22]1[C:23]([N:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[CH3:53])[CH2:43][CH2:42]2)=[CH:24][C:25]([Cl:40])=[C:26]([CH:39]=1)[C:27]([NH:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][C:34]1=[O:38])=[O:28].[Cl-].[Li+]>CN(C=O)C>[Cl:40][C:25]1[C:26]([C:27](=[O:28])[NH:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][C:34]2=[O:38])=[CH:39][C:22]([NH:21][C:9]([C:7]2[N:8]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[O:5][CH:6]=2)=[O:11])=[C:23]([N:41]2[CH2:42][CH2:43][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[CH3:53])[CH2:45][CH2:46]2)[CH:24]=1
Reactant: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Reactant: O=C(O)c1coc(C2CC2)n1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2coc(C3CC3)n2)CC1
Reaction time: 0.05 h

Procedure:
To a solution of 2-cyclopropyl-oxazole-4-carboxylic acid 1h (122.2 mg, 0.79 mmol) in DMF (5.0 mL) HATU (404.4 mg, 1.06 mmol) was added and stirred for 3 min. N,N-diisopropylethylamine (0.46 mL, 2.66 mmol) was added to this followed by 5-amino-2-chloro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 1g (250.0 mg, 0.53 mmol) in DMF (5.0 mL) and the reaction was stirred at 25° C. for 16 h. LCMS indicated the completion of reaction. Saturated solution of lithium chloride was added to this and the contents were extracted with ethyl acetate, organic layer was dried on anhydrous sodium sulfate, concentrated and the crude ii was purified on preparative HPLC using water/methanol (0.1% TFA) (42.0 mg, 13%).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[CH:15]2[N:12]([C:13](=[O:17])[C:14]2=O)[CH:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].[CH:23]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:24]>C1C=CC=CC=1>[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])/[C:14]/2=[CH:25]\[CH:23]=[O:24])[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])/[C:14]/2=[CH:2]/[CH:1]=[O:6])[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=S1C2C(=O)C(=O)N2C(C(=O)O)C1(C)C
Agent: CC(C)(C)C(=O)O
Solvent: c1ccccc1
Product: C=S1[C@@H]2/C(=C/C=O)C(=O)N2[C@@H](C(=O)O)C1(C)C
Product: C=S1[C@@H]2/C(=C\C=O)C(=O)N2[C@@H](C(=O)O)C1(C)C
Reaction time: 0.17 h

Procedure:
A solution of 3.8 g of methylene-6,7-dioxo-3,3-dimethyl-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate in 100 ml of benzene is treated at 20° with 3.5 g of formylmethylenetriphenylphosphorane. After 10 minutes, the reaction mixture is evaporated. The residue is chromatographed on silica gel while eluting with n-hexane/ethyl acetate (8:2). There are obtained methylene-(2S,5R)-6-[(E)-formylmethylene]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate [Rf: 0.27; cyclohexane/ethyl acetate (8:2); NMR (CDCl3), δ (ppm): 5.68 (1H3); 5.9 (1H5); 6.24 (1H); 10.3 (1H)] and methylene-(2S,5R)-6-[(Z)-formylmethylene]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate [Rf: 0.2; cyclohexane/ethyl acetate (8:2); NMR (CDCl3), δ (ppm): 5.68 (1H3); 6.12 (1H 5); 6.55 (1H); 9.86 (1H)].
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].N1C=C(C#C[C:23]2[CH:24]=[C:25]([CH:47]=[CH:48][C:49]=2[CH3:50])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:31]([C:43]([F:46])([F:45])[F:44])[CH:30]=2)=[O:27])N2C=CN=CC=12.N#N.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:48]2[CH:47]=[C:25]([CH:24]=[CH:23][C:49]=2[CH3:50])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:31]([C:43]([F:46])([F:45])[F:44])[CH:30]=2)=[O:27])[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Reactant: C#Cc1cnc2ccccn12
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2ccccn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
3-Ethynylimidazo[1,2-a]pyridine (37 mg, 0.26 mmol), 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (103.4 mg, 0.2 mmol), (prepared as in Example 2), Pd[(PPh3)4] (11.6 mg, 5mol %), and Cul (2.9 mg, 7.5 mmol %) was placed in a vial with rubber septum. The mixture underwent 3 cycles of vacuum/filling with N2, and DMF (1.5 ml) and N,N-diisopropylethylamine (53 mL, 0.3 mmol) was added. The mixture was stirred at rt for 16 h, and the reaction was quenched with H2O. EtOAc and more water were added for extraction. The combined organic layer was dried (Na2SO4), filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluent: 5% MeOH in methylene chloride, MeOH was pre-saturated with ammonia gas), giving the titled compound as an off-white solid (53%, 56 mg): MS (M+H)+ 532.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([O:11][CH2:12][CH3:13])=[O:10].S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28].[Cl-].[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:21][O:20][CH2:19][CH2:18][O:17][C:16]1[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([N+:27]([O-:29])=[O:28])[CH:15]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(OCCOC)c(OCCOC)c1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 100 %

Procedure:
In a 20 L-volume glass reaction vessel equipped with a stirrer, a thermometer and a reflux condenser, the acetic acid solution containing 2,023 g (6.78 moles) of ethyl 3,4-bis(2-methoxyethoxy)benzoate prepared in the Synthesis Example 1 was placed. To the solution, 318 g (3.18 moles) of concentrated sulfuric acid was gently added while stirring the solution at room temperature. The mixture was heated to 60 to 70° C. To the mixture, 1,857 g (20.34 moles) of 69 wt. % nitric acid was gently added while stirring the mixture. The resulting mixture was allowed to react for 2 hours while maintaining the temperature. After the reaction was complete, the reaction solution was cooled to room temperature. To the reaction solution, 5,200 mL of a 20 wt. % aqueous sodium chloride solution and 5,200 mL of toluene were added. The separated organic layer (toluene layer) was washed twice with 7,800 mL of a 1 mole per L aqueous sodium hydroxide solution, and further washed twice with 7,800 mL of a 20 wt. % aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure to obtain 2,328 g of ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate as an orange liquid (isolation yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[F:21][C:22]([F:35])([F:34])[O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:34])[F:35])=[CH:29][CH:28]=2)(=[O:32])=[O:31])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Product: O=S(=O)(Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1)c1ccc(OC(F)(F)F)cc1

Procedure:
N-[3,5-Dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethoxy-benzenesulfonamide was synthesized (83%) from 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (420) and 4-trifluoromethoxybenzenesulfonyl chloride (Maybridge) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.15 (d, J=2.2 Hz, 1H), 8.03-7.98 (m, 2H), 7.68 (d, J=8.7 Hz, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.46 (dd, J=8.7, 2.2 Hz, 1H), 7.31 (s, 2H). MS (EI): m/z 567 (M−H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][C:9]([CH3:11])=[CH:8][C:6]=2[N:7]=1.[CH2:13]([NH2:17])[CH2:14][CH2:15][NH2:16].[O:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][NH:21][CH2:20][CH2:19]1>>[O:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][N:21]([C:2]2[N:3]=[C:4]([NH:16][CH2:15][CH2:14][CH2:13][NH2:17])[C:5]3[S:10][C:9]([CH3:11])=[CH:8][C:6]=3[N:7]=2)[CH2:20][CH2:19]1
Reactant: NCCCN
Reactant: c1ccc2c(c1)CNCCO2
Reactant: Cc1cc2nc(Cl)nc(Cl)c2s1
Product: Cc1cc2nc(N3CCOc4ccccc4C3)nc(NCCCN)c2s1

Procedure:
The title compound was prepared in analogy to Example 1-1 in Scheme 1 by using 2,4-dichloro-6-methylthieno[3,2-d]pyrimidine and propane-1,3-diamine, followed by reaction with 2,3,4,5-tetrahydro-1,4-benzoxazepine. MS obsd. (ESI+) [(M+H)+] 370; 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.43 (d, J=6.6 Hz, 1H), 7.10-7.19 (m, 1H), 6.94-7.05 (m, 2H), 6.80 (s, 1H), 4.92 (s, 2H), 4.25-4.32 (m, 2H), 4.14-4.21 (m, 2H), 3.74 (br. s., 2H), 2.96 (t, J=6.3 Hz, 2H), 2.49-2.57 (m, 3H), 1.88 (m, 2H).