Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([C:13]#[N:14])[C:6]1=[O:15])([CH2:3][CH3:4])[CH3:2].[Br:16]N1C(=O)CCC1=O.CN(C)C=O>C(=O)([O-])O.[Na+]>[Br:16][C:9]1[C:8]([O:11][CH3:12])=[C:7]([C:13]#[N:14])[C:6](=[O:15])[N:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH:10]=1
Reactant: CCC(C)n1ccc(OC)c(C#N)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)n1cc(Br)c(OC)c(C#N)c1=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
A mixture of 1-(sec-butyl)-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step A (260 mg), N-bromosuccinimide (269 mg) and N,N-dimethylformamide (3 mL) was stirred at 60° C. for 2 hr 30 min. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted threetimes with ethyl acetate. The extracts were combined, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (260 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:31][C:32]([NH2:34])=[O:33])[CH:5]=[CH:6][C:7]=1/[CH:8]=[CH:9]/[S:10]([N:13]1[CH2:30][CH2:29][C:16]2([N:20]=[C:19]([CH:21]3[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]3)[NH:18][C:17]2=[O:28])[CH2:15][CH2:14]1)(=[O:12])=[O:11].[H][H]>C(#N)C.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:31][C:32]([NH2:34])=[O:33])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][S:10]([N:13]1[CH2:14][CH2:15][C:16]2([N:20]=[C:19]([CH:21]3[CH2:22][CH2:23][CH:24]([CH3:27])[CH2:25][CH2:26]3)[NH:18][C:17]2=[O:28])[CH2:29][CH2:30]1)(=[O:12])=[O:11]
Reactant: Cc1cc(CC(N)=O)ccc1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cc(CC(N)=O)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Yield: 72.3 %

Procedure:
20% palladium hydroxide (7.4 mg) was added to a solution of Compound 737 (14.7 mg, 0.030 mmol) in acetonitrile (1.0 mL), and the mixture was stirred at room temperature for one hour in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give 2-(3-methyl-4-{2-[2-(4-methyl-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-phenyl)-acetamide (Compound 750) as a white powder (10.6 mg, 72%).
Reaction SMILES: [OH:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:7]([CH2:15]CC(O)=O)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.[H-].[Na+].O.[CH3:31]N(C)C=O>C1(C)C=CC=CC=1>[CH3:31][O:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:7]([CH3:15])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: O=C(O)CCC1=C(c2ccccc2)c2ccc(O)cc2Sc2ccccc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)Sc1ccccc1C(C)=C2c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
7-hydroxy-11-[(2-carboxy)ethyl]-10-phenyldibenzo[b,f]thiepin (1.87 g) in dry dimethylformamide (25 ml) was treated with sodium hydride (0.4 g of 75%) and stirred, first at room temperature and then at 50° C. until effervescence ceased. A solution of 1-chloro-2-NN-dimethylamino-ethane in toluene (15 ml of 1 M) was added and the mixture was heated with stirring under argon to 100° C. After 1.5 hours the mixture was allowed to cool, treated with water and extracted three times with ethyl acetate. The ethyl acetate solution was evaporated and the residue dissolved in methanol (10 ml) and 10% aqueous sodium hydroxide (5 ml) and refluxed for 20 minutes. The solvent was mostly removed and the sodium salt was dissolved in 200 ml of boiling water. Carbon dioxide was passed through the boiling solution until the pH fell to 8. This was extracted three times into ethyl acetate with a little methanol. The solution was dried and evaporated.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[C:25]([F:36])[CH:24]=3)[CH:16]=2)=[C:9]([CH3:37])[C:8]=1[CH3:38])[CH3:2].[OH-].[Na+].[ClH:41].Cl.C(OCC)(=O)C>CO.O1CCCC1.C(OCC)(=O)C>[ClH:41].[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([CH3:38])=[C:9]([CH3:37])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[C:25]([F:36])[CH:24]=3)[CH:16]=2)=[C:11]([CH3:14])[C:12]=1[CH3:13])[CH3:2]
Reactant: CCOCCOc1c(C)c(C)c(-c2cccc(CNc3ccc(CCC(=O)OCC)c(F)c3)c2)c(C)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOCCOc1c(C)c(C)c(-c2cccc(CNc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of ethyl 3-[4-({[4′-(2-ethoxyethoxy)-2′,3′,5′,6′-tetramethylbiphenyl-3-yl]methyl}amino)-2-fluorophenyl]propanoate (0.40 g, 0.77 mmol) in a mixture of methanol (4.0 mL) and tetrahydrofuran (8.0 mL) was added 1 N aqueous sodium hydroxide solution (1.53 mL, 1.53 mmol), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was neutralized with 1 N hydrochloric acid, and diluted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=1/2) to give a colorless oil. The obtained oil was dissolved in ethyl acetate, and 4 N hydrogen chloride/ethyl acetate solution was added. The precipitated crystals were collected by filtration, washed with ethyl acetate, and dried to give the title compound (0.28 g, yield 70%) as colorless crystals.
Reaction SMILES: CC([O-])(CC)C.[Na+].Cl[C:9]1[N:14]=[C:13]2[O:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[C:17]([C:18](=[O:21])[NH:19][CH3:20])[C:12]2=[CH:11][C:10]=1[C:29]1[CH:30]=[N:31][C:32]([O:39][CH3:40])=[C:33]([CH:38]=1)[C:34]([O:36]C)=[O:35].[F:41][C:42]([F:46])([F:45])[CH2:43][NH2:44]>O1CCOCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:16]2[O:15][C:13]3=[N:14][C:9]([NH:44][CH2:43][C:42]([F:46])([F:45])[F:41])=[C:10]([C:29]4[CH:30]=[N:31][C:32]([O:39][CH3:40])=[C:33]([CH:38]=4)[C:34]([OH:36])=[O:35])[CH:11]=[C:12]3[C:17]=2[C:18](=[O:21])[NH:19][CH3:20])=[CH:23][CH:24]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(-c3cnc(OC)c(C(=O)OC)c3)cc12
Reactant: NCC(F)(F)F
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NCC(F)(F)F)c(-c3cnc(OC)c(C(=O)O)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
Sodium 2-methylbutan-2-olate (0.281 g, 2.55 mmol) was added to a stirring solution of methyl 5-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-2-methoxynicotinate (0.120 g, 0.255 mmol), 2,2,2-trifluoroethanamine (0.253 g, 2.55 mmol), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (0.020 g, 0.026 mmol), in dioxane (2.55 ml) at 100° C. Immediately, the reaction mixture turned to a dark amber color. LCMS after 1 h shows complete conversion to the desired coupled product with simultaneous deprotection of the tButyl ester. The reaction mixture was cooled to rt and concentrated to a dry solid. The resultant solid was then taken up in EtOAc and diluted with 1 M HCl. The layers were separated and the aq layer was extracted with EtOAc (2×15 mL). The layers were washed with water, brine, dried over Na2SO4, filtered and concentrated to give a yellow solid. This solid was then triturated with DCM (25 mL) for 3 h. The solids were filtered to give the desired 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)-2-methoxynicotinic acid (110 mg, 0.21 mmol, 83% yield) as a yellow solid. LC-MS retention time: 1.68 min; m/z (observed boronic acid M+H): 519. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (500 MHz, METHANOL-d4) δ 8.38 (d, J=2.5 Hz, 1H), 8.29 (d, J=2.5 Hz, 1H), 7.91 (dd, J=8.2, 6.1 Hz, 3H), 7.69 (s, 1H), 7.23-7.19 (m, 3H), 4.18 (d, J=9.3 Hz, 2H), 4.07 (s, 3H), 2.91 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:10])[CH2:7][C:8]#[N:9])[CH3:4].F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21].Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:5][C:6](=[O:10])[CH:7]([C:8]#[N:9])[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21])[CH3:4]
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)c1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.96 g, 60% in mineral oil, 24 mmol) in DMF (6 mL) at 0° C. was added ethylcyanoacetate (2.72 g, 24 mmol) in DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 30 minutes then 4-fluoro-3-nitro-benzonitrile (2.05 g, 22.7 mmol) in DMF (5 mL) was added dropwise. 1M HCl and ethyl acetate were added to the reaction mixture after 1 hour. The organic layer was washed with water and brine, then dried over sodium sulphate and concentrated to give a brown oil which was purified by flash column chromatography to give the title compound. 1H NMR (DMSO-d6) δ 8.79 (1H), 8.38 (1H), 7.95 (1H, d, J=2), 6.38 (1H), 4.21 (2H), 1.19 (3H, t).
Reaction SMILES: Br[CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O>[OH:5][CH2:4][C:3]1([CH2:7][OH:8])[CH2:6][N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2]1
Reactant: NCc1ccccc1
Reactant: OCC1(CBr)COC1
Agent: Cl
Solvent: O
Product: OCC1(CO)CN(Cc2ccccc2)C1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
18.1 g of 1A and 11.7 g of benzylamine were mixed with 5 ml of water and the resulting mixture was stirred at 100° C. After 4 hours the solution was allowed to cool to ambient temperature and 13.8 ml of 36% (w/w) hydrochloric acid was added. The resulting mixture was stirred at 60° C. After 2 hours the solution was again allowed to cool to room temperature and then washed with dichloromethane to remove by-products. The aqueous layer was made alkaline by the addition of a solution of 5.5 g of sodium hydroxide in 10 ml of water and stirred at 100° C. for 1 hour. After cooling to ambient temperature the pH of the mixture was raised by addition of another solution of 5.5 g of sodium hydroxide in 10 ml of water and washed with hexane to remove benzylamine. The water was evaporated under reduced pressure, and the solid residue was taken up in dichloromethane. Inorganic salts, which remained undissolved, were removed by filtration, and the dichloromethane was evaporated in vacuo, leaving 1, as a white crystalline solid.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[F:7][C:8]1[CH:9]=[C:10]([N:20]2[CH2:24][CH:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1.C[OH:32]>O>[F:7][C:8]1[CH:9]=[C:10]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:11]=[CH:12][C:13]=1[N:14]1[CH2:15][CH2:16][S:17](=[O:32])[CH2:18][CH2:19]1
Reactant: CC(=O)NCC1CN(c2ccc(N3CCSCC3)c(F)c2)C(=O)O1
Reactant: CO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCS(=O)CC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Sodium metaperiodate (42 mg, 0.196 mmol) was dissolved in water (1 mL) and then cooled to 0° C. (ice bath). Next, the N-[[3-[3-fluoro-4-(4-thiomorpholinyl) phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (66 mg, 0.187 mmol) was added. Methanol (3 mL) was added to increase solubility. The reaction was stirred at 0° C. for an additional 4 hours under N2 before being stoppered and stored in the freezer (65 hours). The reaction was filtered through a medium-porosity sintered glass funnel, rinsing the flask and filter cake with CHCl3 (5 mL). The filtrate was transferred to a separatory funnel, the layers separated, and the water layer further extracted with more CHCl3 (3×5 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure to yield 80 mg of a gummy solid. The material was chromatographed on silica gel (10 g silica, packed with 10% CH3CN/CHCl3), eluting with a gradient of 1-5% MeOH in 10% CH3CN/CHCl3 to give 49 mg (71%) of the title compound as an off-white solid with a mp of 159°-161° C. and a HRMS (M+) calculated for C16H20N3O4FS 369.1158, found 369.1182.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[C:4]#[N:5].CO.O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: NCc1c(Cl)cc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,4,6-trichlorobenzonitrile (0.69 mmol) in 2 mL THF was added a solution of BH3 (2.77 mmol, 1M in THF). The reaction mixture was heated to 40° C. for 2 h and then cooled to RT. 1 mL MeOH was added and the mixture was stirred at RT for 30 min. Water was added, the mixture was basified with 1M NaOH solution and extracted twice with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as slightly yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[NH:5][CH3:6].Br.Br[CH:14]([C:16]1[CH:17]=[C:18]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH:19]=[C:20]2[C:25]=1[O:24][C:23]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[CH:22][C:21]2=[O:32])[CH3:15]>>[CH3:36][N:35]([CH3:37])[C:33]([C:18]1[CH:19]=[C:20]2[C:25](=[C:16]([CH:14]([N:5]([CH3:6])[C:4]3[CH:7]=[C:8]([F:11])[C:9]([F:10])=[C:2]([F:1])[CH:3]=3)[CH3:15])[CH:17]=1)[O:24][C:23]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[CH:22][C:21]2=[O:32])=[O:34]
Reactant: CNc1cc(F)c(F)c(F)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)c(F)c(F)c1
Yield: 35.6 %

Procedure:
3,4,5-trifluoro-N-methylaniline (197 mg, 1.22 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (150 mg, 0.31 mmol) using an analogous procedure to the one described in Example 3.03 to give N,N-dimethyl-8-(1-(methyl(3,4,5-trifluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (54.0 mg, 36.1%) as a white solid. Mass Spectrum: M+H+ 490. NMR Spectrum (DMSOd6): 1.54 (d, 3H), 2.62 (s, 3H), 2.91 (bs, 3H), 3.00 (bs, 3H), 3.24-3.31 (m partially hidden by H2O, 2H), 3.33-3.42 (m partially hidden by H2O, 2H), 3.45-3.52 (m, 2H), 3.52-3.60 (m, 2H), 5.55 q, 1H), 5.56 (s, 1H), 6.73 (d, 1H), 6.75 (d, 1H), 7.67 (d, 1H), 7.89 (d, 1H).
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.[C:18]1([Si:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)Cl)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C1COCC1.CC(O)C>[C:32]1([Si:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:1][N:2]=[C:3]2[CH:8]=[CH:7][C:6](=[C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:10]#[N:11])[CH:5]=[CH:4]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: N#CC(=C1C=CC(=NO)C=C1)c1ccccc1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CC(=C1C=CC(=NO[Si](c2ccccc2)(c2ccccc2)c2ccccc2)C=C1)c1ccccc1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
7 g (31 mmol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-phenyl-acetonitrile, prepared as described in example 1.1, are dissolved in 80 ml of THF and cooled in an ice bath. After adding 10 g (34 mmol) of triphenylchlorosilane to the solution, 4.7 g (47 mmol) of triethylamine are added dropwise, keeping the temperature below 5° C. While the reaction mixture is stirred at 5° C. for 90 min, a precipitate is formed. The precipitate is filtered off and washed with THF. The filtrate is concentrated by a rotary evaporator to afford a red liquid. The residue is diluted with 2-PrOH and stirred at room temperature for 30 min. After cooling the mixture in an ice bath, the solid is isolated by filtration and washed with 2-PrOH. The product is obtained in the form of a pale yellow solid, mp 161-165° C. (Dec). The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 6.79(Z)/6.94(E) (dd, 1H), 7.04(Z)/7.15(E) (dd, 1H), 7.32-7.71 (m, 22H). 1H-NMR reveals that the product is a 77:23 mixture of Z and E isomers. The signals are tentatively assigned to Z and E isomers.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH3:34])[C:21](=[O:33])[CH2:22][NH:23][C:24](=[O:32])[CH2:25][N:26]4[CH2:31][CH2:30][S:29][CH2:28][CH2:27]4)[C:14]=3[Cl:35])[C:5]2=[N:4][C:3]=1[CH3:36].ClC1C=CC=C(C(OO)=[O:45])C=1>C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH3:34])[C:21](=[O:33])[CH2:22][NH:23][C:24](=[O:32])[CH2:25][N:26]4[CH2:27][CH2:28][S:29](=[O:45])[CH2:30][CH2:31]4)[C:14]=3[Cl:35])[C:5]2=[N:4][C:3]=1[CH3:36]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CN4CCSCC4)c3Cl)cccn2c1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CN4CCS(=O)CC4)c3Cl)cccn2c1Br
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a solution of 3-bromo-8-[2,6-dichloro-3-[N-methyl-N-[(thiomorpholinoacetyl)glycyl]amino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (200 mg) in methylene chloride (2 ml) was added m-chloroperbenzoic acid (80% purity, 76 mg) under ice-bath cooling, and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was washed with water twice and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=5:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-methyl-N-[[(1-oxothiomorpholino)acetyl]glycyl]amino]benzyloxy]-2-methylimidazo[1,2-a]-pyridine (96 mg) as an amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:11]=[CH:10][CH:17]=[CH:16][C:13]=2[CH:14]=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Oc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A heterogeneous mixture of 4-chlorophenol (14.1 g, 0.11 mmol), 4-fluorobenzaldehyde 12.4 g, 0.1 mmol) and Cs2CO3 (65.0 g, 0.20 mmol) in DMF (400 mL) was stirred at 90° C. for 6 h. The reaction mixture was poured into water (1.2 L) and extracted with ethyl acetate (2×200 mL). The organic phase was washed with water (2×100 mL), dried and concentrated to give essentially pure 4-chlorophenoxybenzaldehyde, which was used directly for the next step.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].S(C1C=CC(C)=CC=1)(O[CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)(=O)=O>CS(C)=O>[CH:27]1([N:12]2[C:13]3[C:9](=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=3)[C:10]([C:15]3[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=3)=[CH:11]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: N#Cc1ccc(-c2c[nH]c3cc([N+](=O)[O-])ccc23)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2cn(C3CCCC3)c3cc([N+](=O)[O-])ccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Method M Add KOH pellets (200 mg, 3.42 mmol) to a solution of 4-(6-nitro-1H-indol-3-yl)-benzonitrile, 9, (150 mg, 0.57 mmol) in DMSO (10 mL). After the KOH pellets dissolve, add cyclopenyl tosylate (210 mg, 0.85 mmol) in DMSO (3 mL). Allow the reaction mixture to stir overnight at ambient temperature. Add additional cyclopentyl tosylate (210 mg, 0.85) and allow the reaction mixture to stir for another 6 h. Add still more cyclopentyl tosylate (210 mg, 0.85 mmol) and allow the reaction mixture to stir overnight at ambient temperature. Quench the resulting reaction mixture with 5N HCl/ice. Extract the quenched reaction mixture with EtOAc. Wash the EtOAc extracts with brine. Dry the organic layer over MgSO4, filter, and remove the solvent from the filtrate to provide a solid. Purify by silica gel column chromatography (0-100% EtOAc/hexanes gradient) and collect the fractions and remove the solvent to afford 110 mg (58%) of the title compound. LRMS (API ES+)=332.2 (M+H).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19].C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)=[N:23][CH2:22][CH2:21][O:17][N+:18]([O-:20])=[O:19])#[N:2]
Reactant: NCCO[N+](=O)[O-]
Reactant: COC(=NC#N)c1cnccn1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O=[N+]([O-])O
Product: N#CNC(=NCCO[N+](=O)[O-])c1cnccn1
Temperature: 25 °C
Reaction time: 46 h
Yield: 26 %

Procedure:
Methyl N-cyanopyrazinecarboximidate (0.49 g, 3.0 mmol) was dissolved in methanol (6 ml), 2-nitroxyethylamine nitrate (1.01 g, 6.0 mmol) and triethylamine (1.01 g, 10.0 mmol) were added. The mixture was stirred at room temperature for 46 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (300:1). The eluted fractions were concentrated under reduced pressure and crystallized from diethyl ether to give the title compound (0.18 g, 0.78 mmol, yield: 26%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)[CH:16]=[C:4]2[N:3]=1.O.[NH2:24][NH2:25]>O1CCOCC1>[N:8]1([C:6]2[N:5]3[N:14]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[N:21][CH:22]=4)[CH:16]=[C:4]3[N:3]=[C:2]([NH:24][NH2:25])[CH:7]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: NN
Reactant: Clc1cc(N2CCOCC2)n2nc(-c3cncnc3)cc2n1
Solvent: O
Solvent: C1COCCO1
Product: NNc1cc(N2CCOCC2)n2nc(-c3cncnc3)cc2n1
Reaction time: 6 h
Yield: 96 %

Procedure:
There was suspended, in 1,4-dioxane (1.0 mL), 5-chloro-7-morpholin-4-yl-2-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidine (20 mg, 2.4 mM) prepared in the preceding step 1, then hydrazine monohydrate (29 μL, 0.6 mM) was added to the suspension and the mixture was stirred for 6 hours while refluxing the same with heating. After the stirring operation, the reaction liquid was concentrated, the concentrate was diluted with water and then the mixture was extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate and the solvent was distilled off to thus give a crude product of the title compound (18 mg, yield: 96%).