Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[C:45]([C:48]1[C:49]([Cl:56])=[C:50]([C:53](O)=[O:54])[NH:51][CH:52]=1)(=[O:47])[CH3:46].CCN(C(C)C)C(C)C>CN(C=O)C>[C:45]([C:48]1[C:49]([Cl:56])=[C:50]([C:53]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]3[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=3)[C:28]=2[F:44])=[O:54])[NH:51][CH:52]=1)(=[O:47])[CH3:46]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(=O)c1c[nH]c(C(=O)O)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1c[nH]c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)c1Cl
Reaction time: 8 h
Yield: 8.4 %

Procedure:
HATU (0.092 g, 0.241 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), 4-acetyl-3-chloro-1H-pyrrole-2-carboxylic acid (0.030 g, 0.161 mmol) and DIPEA (0.042 mL, 0.241 mmol) in DMF (2 mL). The resulting solution was stirred overnight. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4 and evaporated to a residue. Purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.0065 g, 7%) as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm ppm 11.46 (br. s., 1H), 7.88 (br. s., 1H), 7.79 (s, 1H), 7.63 (s, 1H), 7.36-7.50 (m, 4H), 4.73 (d, 2H), 2.41 (s, 3H). LCMS: m/z 480.0 (M+1).
Reaction SMILES: [CH:1]([N:4]([CH:23]([CH3:25])[CH3:24])[C:5](=[O:22])[CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)OC1C=CC(C)=CC=1)([CH3:3])[CH3:2].[OH-:26].[Na+]>C1(C)C=CC=CC=1>[OH:26][C:19]1[CH:20]=[CH:21][C:16]([CH3:7])=[CH:17][C:18]=1[CH:7]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:6][C:5]([N:4]([CH:1]([CH3:2])[CH3:3])[CH:23]([CH3:24])[CH3:25])=[O:22]
Reactant: Cc1ccc(OC(CC(=O)N(C(C)C)C(C)C)c2ccccc2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(C(CC(=O)N(C(C)C)C(C)C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A three-necked round-bottom flask equipped with condenser, mechanical stirrer, thermometer, is loaded with N,N-diisopropyl-3-phenyl-3-p-tolyloxy-propionamide (1.0 g; 0.0029 mol) and polyphosphoric acid (16.5 g). After four hours under stirring at room temperature the reaction is completed. The reaction mixture is poured in ice/water (10 g), alkalinized to pH 9-10 with NaOH 50% w/w and left under stirring for 30 minutes, then diluted with toluene (30 ml). The phases are separated and the aqueous phase is extracted with toluene (2×30 ml). The combined organic phases are dried over sodium sulfate and evaporated to dryness. The resulting oil is purified by flash chromatography (hexane/ethyl acetate 7:3). 0.59 g of product, as a pale yellow oil, are obtained.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].OCC([C@H]([C@@H]([C@@H](C)O)O)O)=O>>[O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: C[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O
Agent: C[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO
Product: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O

Procedure:
6-Deoxy-D-glucose→6-deoxy-D-arabino-hexulose (otherwise 6-deoxy-D-fructose)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:20]=[C:10]3[NH:11][C:12](=[O:19])[C:13]4[C:18]([N:9]3[N:8]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:2]1.I[CH:22]([CH3:24])[CH3:23].[H-].[Na+].O>O1CCOCC1>[CH:22]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:20]=[C:10]3[NH:11][C:12](=[O:19])[C:13]4[C:18]([N:9]3[N:8]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:2]1)([CH3:24])[CH3:23]
Reactant: O=c1[nH]c2cc(C3CCCNC3)nn2c2ccccc12
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N1CCCC(c2cc3[nH]c(=O)c4ccccc4n3n2)C1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 19 (0.07 g, 0.3 mmol) and 2-iodopropane (0.09 mL, 0.9 mmol) in dioxane (2 mL) and was treated with sodium hydride (0.01 g, 0.4 mmol). The mixture was stirred overnight at 65° C., cooled to ambient temperature, treated with water and concentrated. The residue was purified by flash chromatography on silica gel with 10% methanol/dichloromethane to provide the title compound. 1H NMR (CD3OD) δ 8.21 (dd, J=8.0, 1.5 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.81-7.87 (m, 1H), 7.42-7.47 (m, 1H), 5.88 (s, 1H), 3.21 (dt, J=11.3, 1.9, 1H), 2.99-3.10 (m, 2H), 2.92 (dt, J=13.2, 6.6 Hz, 1H), 2.51 (t, J=11.0 Hz, 1H), 2.38 (td, J=11.5, 2.8 Hz, 1H), 2.09 (ddd, J=9.0, 3.8, 3.7 Hz, 1H), 1.83-1.92 (m, 1H), 1.70-1.82 (m, 1H), 1.59 (qd, J=12.3, 4.0 Hz, 1H), 1.14-1.19 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:10].Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[Cl:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH:6][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][C:3]=1[F:10]
Reactant: Nc1cc(F)c(Cl)c(F)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Nc1cc(F)c(Cl)c(F)c1
Temperature: 80 °C
Reaction time: 36 h

Procedure:
A mixture of 4-chloro-3,5-difluoroaniline (1.64 g, 10.0 mmol), 2-chloro-3-nitropyridine (1.56 g, 9.84 mmol) and cesium carbonate (6.56 g, 20.1 mmol) in N,N-dimethylformamide (30 mL) was stirred at 80° C. for 36 hours. The reaction mixture was cooled to room temperature, diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (5×50 mL), dried over sodium sulfate, filtered, concentrated in vacuo and purified by chromatography on silica gel (Gradient: 0% to 5% ethyl acetate in petroleum ether) to provide the product as a yellow solid. Yield: 200 mg, 0.70 mmol, 7%. 1H NMR (400 MHz, CDCl3) δ 10.23 (br s, 1H), 8.55-8.61 (m, 2H), 7.52 (br d, J=9 Hz, 2H), 6.96-7.01 (m, 1H).
Reaction SMILES: C[Mg]I.[Cl:4][C:5]1[CH:6]=[C:7]([N:12]2[CH:16]=[C:15]([CH:17]=[O:18])[N:14]=[CH:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11].[CH2:19]1COCC1.[Cl-].[NH4+]>CCOCC>[Cl:4][C:5]1[CH:6]=[C:7]([N:12]2[CH:16]=[C:15]([CH:17]([OH:18])[CH3:19])[N:14]=[CH:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: C1CCOC1
Reactant: O=Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)c1cn(-c2ccc(Cl)c(Cl)c2)cn1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of methylmagnesium iodide in ether (3 M, 13.7 ml, 41.1 mmol) and ether (40 ml), 1-(3,4-dichloro-phenyl)-1H-imidazole-4-carbaldehyde (2.58 g, 10.7 mmol) was added in portions. THF (50 ml) was then added slowly and stirring was continued for 1 h at reflux. After the addition of aqueous ammonium chloride (saturated, 30 ml), the mixture was extracted with AcOEt. The organic phase was dried (Na2SO4) and evaporated to give 1-[1-(3,4-dichloro-phenyl)-1H-imidazol-4-yl]-ethanol (2.56 g, 93%) as a light brown solid. MS: m/e=257.0 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]2[C:6]=1[CH2:7][C:8](=[O:15])[NH:9]2.[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][NH:17]1>CS(C)=O>[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][N:17]1[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]2[C:6]=1[CH2:7][C:8](=[O:15])[NH:9]2
Reactant: O=C1Cc2c(OCCCl)ccc(F)c2N1
Reactant: C1=Cc2ccccc2CN1
Solvent: CS(C)=O
Product: O=C1Cc2c(OCCN3CCc4ccccc4C3)ccc(F)c2N1
Yield: 45 %

Procedure:
4-(2-Chloroethoxy)-7-fluoro-1,3-dihydro-indol-2-one was reacted with dihydroisoquinoline in anhydrous dimethyl sulfoxide in the same manner described for intermediate 16 to afford the title compound in 45% yield. The fumarate salt was made in ethanol: mp 230°-235° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:30][C:31]([C:33]1[CH:43]=[CH:42][C:36]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:35][CH:34]=1)=[O:32]>CC(C)=O>[O:32]=[C:31]([C:33]1[CH:43]=[CH:42][C:36]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:35][CH:34]=1)[CH2:30][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Reactant: c1ccc(CNCC2CCc3ccccc3C2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1ccc(C(=O)CN(Cc2ccccc2)CC2CCc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Benzylaminomethyl-1,2,3,4-tetrahydronaphthalene (XXXIV) (2.8 g), N,N-diisopropyl-N-ethylamine (1.44 g) and 4'-(2-bromoacetyl)methanesulfonanilide (Temple, D. L. et al., J. Med. Chem., 19(5), 626-633 (1976)) (3.27 g) were dissolved in acetone (40 ml) and stirred 18 hours at ambient temperature. The solvent was evaporated and the residue was dissolved in CH2Cl2, which was washed with H2O, dried (MgSO4) and evaporated. The HCl salt was made by dissolving the residue in MeOH/concentrated HCl, concentrating, and triturating the residue with 2-PrOH and ether. The solid product, 4'-[1-oxo-2-(N-benzyl-N-((1,2,3,4-tetrahydro-2-naphthyl)methyl)-amino)ethyl]methanesulfonanilide.HCl (XXXIII.HCl), 3 g, had NMR and mass spectra consistent with the structure indicated. It was used without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C[Si]([C:14]#[CH:15])(C)C.C(N(CC)CC)C>CN(C)C=O>[C:14]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9])#[CH:15]
Reactant: COc1ccccc1I
Reactant: C#C[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1ccccc1OC
Yield: 50.9 %

Procedure:
2-Iodoanisole (10.5 g) and trimethylsilylacetylene (10.3 g) were reacted in dimethylformamide (50 ml), in the presence of dichloro-bis-triphenylphosphine palladium (1.0 g), cuprous iodide (0.5 g) and triethylamine (15 ml) in nitrogen atmosphere at 50° C. for 12 hr. The resulting reaction solution was evaporated, and to the resulting residue were added ethyl acetate and water. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was dissolved in methanol (100 ml), a 5N aqueous solution of sodium hydroxide (20 ml) was added thereto, and then reacted at 60° C. for 1 hr. The reaction solution was evaporated, and to the resulting residue were added ether and water. The resulting ether layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a pale yellow oil (3.02 g, yield; 51%).
Reaction SMILES: [K].[CH3:2][C:3](C)([O-:5])[CH3:4].[CH3:7][N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:25][CH3:26])=[CH:13][CH:14]=2)[C:9]1=[O:27]>CS(C)=O>[CH3:7][N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:2][CH:3]3[O:5][CH2:4]3)=[CH:20][CH:19]=2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:25][CH3:26])=[CH:13][CH:14]=2)[C:9]1=[O:27]
Reactant: COc1ccc2cc(-c3ccc(O)cc3)n(C)c(=O)c2c1
Reactant: CC(C)(C)[O-]
Agent: [K]
Solvent: CS(C)=O
Product: COc1ccc2cc(-c3ccc(OCC4CO4)cc3)n(C)c(=O)c2c1

Procedure:
1.35 gm (10 mmols+20%) of potassium-tert.butoxide were added to a solution of 2.8 gm (10 mmols) of 2-methyl-3-(4-hydroxy-phenyl)-7-methoxy-isoquinolin-1(2H)-one in 20 ml of dimethylsulfoxide, while stirring; the potassium salt precipitated out after a short time. 2.8 ml of epibromohydrin were now added, and the mixture was stirred at room temperature until the reaction had gone to completion. The reaction mixture was then poured into ice water, and the cristalline precipitate was collected by suction filtration, washed and dried.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:16])[NH:10][C:11](=[S:15])[NH:12][C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24]>CN(C)C=O>[CH2:1]([C:8]1[C:9](=[O:16])[NH:10][C:11]([S:15][CH2:23][CH3:24])=[N:12][C:13]=1[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Cc1[nH]c(=S)[nH]c(=O)c1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of 5-benzyl-6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.2 g) and potassium carbonate (0.24 g) in N,N-dimethylformamide (4 mL) was added ethyl iodide (0.035 mL), and the mixture was stirred for 4 hr. The insoluble material was filtered off. The filtrate was diluted with ethyl acetate, washed with 1 M hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.22 g, 97%) as a pale-yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH2:11]([O:13][CH2:14][CH2:15]Br)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:13][CH2:14][CH2:15][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:12]
Reactant: CCOCCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCCOc1ccccc1[N+](=O)[O-]
Yield: 42.2 %

Procedure:
2-Nitrophenol (91.0 g. 0.65 mole), 2-bromoethyl ethyl ether (100.0 g. 0.65 mole), anhydrous potassium carbonate (9.0 g, 0.72 mole) and acetone (1 liter) were refluxed for 65 hours. The reaction mixture was filtered, and the acetone removed by rotary evaporation. The residue was partitioned between 200 ml. of dichloromethane and 100 ml water. The organic phase was further washed with 200 ml. of 10% sodium hydroxide followed by 100 cc of water. The product (58.0 g) was obtained in 42% yield by a vacuum distillation (100°-120° C./0.5 mm).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH:15]([CH:16]=[N:17][O:18][CH2:19][CH3:20])[CH:14]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9].CCCCCC>C(Cl)Cl>[ClH:2].[CH2:19]([O:18][N:17]=[CH:16][CH:15]1[C:10]2([C:5]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=3)[CH:14]1[CH2:13][NH:12][CH2:11]2)[CH3:20]
Reactant: CCON=CC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: CCON=CC1C2CNCC12c1ccc(Cl)c(Cl)c1
Yield: 153.4 %

Procedure:
HCl (g) was bubbled through a solution of tert-butyl 1-(3,4-dichlorophenyl)-6-((ethoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (70 mg, 0.17 mmol) obtained in step-2 of example 6 in dry DCM (5 mL). After the completion of the reaction as confirmed by TLC, the reaction mixture was purged with excess of nitrogen. The solvent was removed in vacuo to afford a gummy solid which was titurated with hexane to afford hydrochloric acid salt of 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane-6-carbaldehyde O-ethyl oxime (39 mg, 95%) as a white solid as a mixture of isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:18][CH:19]3[CH2:37][CH:36]4[N:21]([C:22](=[O:42])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([OH:41])=O)([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:20]3)=[CH:8][C:9]([C:13]3[N:14]=[CH:15][S:16][CH:17]=3)=[N:10]2)=[CH:5][CH:4]=1.C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C([NH:84][S:85]([CH:88]6[CH2:90][CH2:89]6)(=[O:87])=[O:86])=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:18][CH:19]3[CH2:37][CH:36]4[N:21]([C:22](=[O:42])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:84][S:85]([CH:88]6[CH2:90][CH2:89]6)(=[O:87])=[O:86])=[O:41])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:20]3)=[CH:8][C:9]([C:13]3[N:14]=[CH:15][S:16][CH:17]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3cscn3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3cscn3)nc2c1

Procedure:
The title compound was prepared from 18-[7-methoxy-2-(thiazol-4-yl)quinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (35) following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide 11: m/z=694 (M+H)+. 1H NMR (CDCl3): 0.80-1.55 (m, 13H), 1.80-1.98 (m, 3H), 2.19-2.28 (m, 1H), 2.30-2.40 (m, 1H), 2.47-2.62 (m, 2H), 2.63-2.75 (m, 2H), 2.88-2.96 (m, 1H), 3.97 (9s, 3H), 4.02 (d, J=11.5 Hz, 1H), 4.11 (dd, J=11.4 Hz, J=3.8 Hz, 1H), 4.60 (t, J=7.9 Hz, 1H), 5.00 (t, J=9.5 Hz, 1H), 5.49 (br s, 1H), 5.70-5.77 (m, 1H), 6.68 (s, 1H), 7.12 (dd, J=2.5 Hz, J=9.1 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.59 (s, 1H), 7.96 (d, J=9.1 Hz, 1H), 8.35 (d, J=2.1 Hz, 1H), 8.94 (d, J=2.1 Hz, 1H), 9.2 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])=[CH:4][C:5](=O)[CH3:6].Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:12]([CH3:13])[C:11]2[C:5]([CH:4]=1)=[CH:6][CH:14]=[CH:15][CH:10]=2
Reactant: COC(C)=CC(C)=O
Reactant: Brc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(C)c2ccccc2c1
Temperature: 42.5 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
A solution of 5-BuOH (44.5 g, 600 mmol) in dry THF (240 mL) was added dropwise to a suspension of NaNH2 (84.4 g, 2.2 mmol) in dry THF (480 mL) under nitrogen. The resulting mixture was heated for 2 h at 40-45° C. After the mixture was cooled, a solution of 4-methoxypent-3-en-2-one (68.5 g, 600 mmol) in dry THF (480 mL) was added dropwise at 30-40° C. The resulting mixture was stirred at 45° C. for 2 h. A solution of bromobenzene (47.1 g, 300 mmol) in dry THF (240 mL) was added and the mixture was stirred at 55° C. for 6 h. The mixture was allowed to cool to room temperature overnight. The mixture was poured into ice, acidified with an aqueous 3 M HCl solution to pH 4-5 and extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure, and the residue was diluted with acetone (480 mL) and stirred with conc. HCl solution (24 mL) for 10 min. The mixture was diluted with EtOAc (200 mL) and washed with saturated brine (200 mL). The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was subjected to flash chromatography (700 g silica gel with dry-loading, eluting by 2% EtOAc in heptanes to give orange oil (19 g, yield: 37%).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.C1N=C[N:23](C(N2C=NC=C2)=O)C=1.C(=O)([O-])[O-].[NH4+].[NH4+].O>CN(C=O)C>[OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:23])=[O:17])=[CH:14][CH:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 40 mL scintillation vial containing 4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid (77 mg, 0.28 mmol, 1.0 eq.) and CDI (101.3 mg, 0.62 mmol), 2.5 eq.) in DMF (3.0 mL) was added Ammonium carbonate (123.3 mg, 1.28 mmol, 4.5 eq.). The mixture was stirred at room temperature overnight. The mixture was treated with H2O (5 mL) and the layers were separated. The aqueous was extracted with EtOAc (2×5 mL), combined organic phase was washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give 4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamide as a white solid. LCMS (m/z) 270 (M+H); 1H NMR (DMSO-d6) δ: 9.14 (s, 1H), 7.87-7.92 (m, 2H), 7.73 (d, J=7.8 Hz, 1H), 7.05 (d, J=8.8 Hz, 4H), 4.93 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[C:17]3[CH:18]=[N:19][CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH:22]=3)[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][C:38](=O)[C:39](O)=[O:40])[CH:32]=1>C(O)C>[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][C:38]2[C:39](=[O:40])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[C:17]4[CH:18]=[N:19][CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]5[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=5)[CH:22]=4)[CH:10]=3)[C:3]3[N:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:32]=1
Reactant: Nc1cccnc1Nc1cccc(/C=C/c2cncc(/C=C/c3ccncc3)c2)c1
Reactant: O=C(O)C(=O)Cc1cccnc1
Solvent: CCO
Product: O=c1c(Cc2cccnc2)nc2cccnc2n1-c1cccc(/C=C/c2cncc(/C=C/c3ccncc3)c2)c1
Yield: 60.2 %

Procedure:
A mixture of 3-amino-2-[3-[(E)-2-[5-[(E)-2-(4-pyridyl)vinyl]pyridin-3-yl]vinyl]phenylamino]pyridine (260 mg) and 3-pyridylpyruvic acid (121 mg) in ethanol (5 ml) was stirred under reflux for 5 hours. After removal of the solvent, the residue was chromatographed on silica gel column (chloroform-methanol, 9:1) and crystallized from methanol to give 2-(3-pyridylmethyl)-3-oxo-4-[3-[(E)-2-[5-[(E)-2-(4-pyridyl)vinyl]pyridin-3-yl]vinyl]phenyl]-3,4-dihydropyrido[2,3-b]pyrazine (208 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C([Li])CCC.[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>O1CCCC1>[Cl:1][C:2]1[C:3]2[C:10]([C:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:26])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)c1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
In a three-neck reactor 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1 g, 3.58 mmol) was dissolved in 36 mL tetrahydrofuran. The mixture was cooled at −78° C. and butyllithium solution (2.5 M in hexane, 3.20 mL, 8 mmol) dissolved in 10 mL was added dropwise over 15 min. The reaction was stirred at −78° C. for 20 min. Then benzyl carbonochloridate (570 μl, 3.99 mmol) was added dropwise. The reaction was stirred overnight. Water was added and the mixture evaporated. The crude was partitioned between ethyl acetate and water, brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified using SP1® Purification System (0% to 20%, hexane-ethyl acetate) to give 490 mg (48% yield) of the title compound. Purity 100%.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[N:16][C:17](S(C)(=O)=O)=[N:18][C:11]=2[NH:10][CH2:9][CH2:8]1.[C:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])[CH3:40]>>[C:39]([N:42]1[CH2:47][CH2:46][N:45]([C:17]2[N:16]=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[C:12]3[C:13](=[O:14])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:1])([F:38])[F:37])[CH:32]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:30]=4)[CH2:8][CH2:9][NH:10][C:11]=3[N:18]=2)[CH2:44][CH2:43]1)(=[O:41])[CH3:40]
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCN2
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2nc3c(c(-c4ccccc4C)n2)C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCN3)CC1
Yield: 48.1 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-2-(methylsulfonyl)-4-(2-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin (Compound of Reference Example 20; 83.8 mg) was reacted with 1-acetylpiperazine (23.1 mg) to obtain 2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-4-(2-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin (43.8 mg, 46%).