Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[N:27][OH:28])[NH2:26].[CH:29](OCC)(OCC)OCC.Cl>>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25]1[N:26]=[CH:29][O:28][N:27]=1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=NO)OCO3
Reactant: CCOC(OCC)OCC
Agent: Cl
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1c1ncon1)OCO3
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A mixture of 1.50 g (3.91 mmol) of the starting material XXIV and 15 ml of triethyl orthoformate in the presence of 0.05 ml of 36% hydrochloric acid was stirred at 110° C. for 30 min, then concentrated in vacuum. The residue was stirred with water, the precipitated crystals were filtered off, washed with water and recrystallized from 2-methoxyethanol to yield 1.15 g (75%) of the title compound; Mp.: 190-196° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C(O[CH:18]=[C:19]([C:22]#[N:23])[C:20]#[N:21])C>C(O)C>[C:20]([C:19]([C:22]#[N:23])=[CH:18][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)#[N:21]
Reactant: CCOC=C(C#N)C#N
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: CCO
Product: N#CC(C#N)=CNc1ccc(C2=NNC(=O)CC2)cc1

Procedure:
A solution containing 0.38 g of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one and 0.3 g of ethoxymethylenemalononitrile in 5 ml of ethanol was refluxed for 1 h. Yield 0.25 g, mp 290°-295° C.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][O:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33]C)[CH:29]=3)[O:16][C:17]3[CH:22]=[N:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][N:18]=3)=[CH:10][CH:9]=2)=[N:4]1)[CH3:2].B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([C@@H:3]1[CH2:7][O:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:29]=[C:28]([CH:27]=[C:15]([O:16][C:17]4[CH:22]=[N:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][N:18]=4)[CH:14]=3)[O:30][C@@H:31]([CH3:35])[CH2:32][OH:33])=[CH:10][CH:9]=2)=[N:4]1)[CH3:2]
Reactant: CC[C@@H]1COC(c2ccc(-c3cc(Oc4cnc(S(C)(=O)=O)cn4)cc(O[C@@H](C)COC)c3)[nH]2)=N1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC[C@@H]1COC(c2ccc(-c3cc(Oc4cnc(S(C)(=O)=O)cn4)cc(O[C@@H](C)CO)c3)[nH]2)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
2-(3-{5-[(4R)-4-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenoxy)-5-(methylsulfonyl)pyrazine (417 mg, 0.83 mmol) synthesized in Example (108c) was dissolved in methylene chloride (10 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 1.00 mL, 1.00 mmol) was added dropwise at −78° C., followed by stirring at room temperature for 1 hour under nitrogen atmosphere. To this reaction solution, a 1N aqueous sodium hydroxide solution (20 mL) was added, and extraction was carried out with methylene chloride (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=3%-4%) to afford the desired compound (325 mg, yield 80%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].[F:15][C:16]1[C:17]([CH3:34])=[C:18](C2C=CC(C(O)=O)=CC=2COC)[CH:19]=[CH:20][CH:21]=1.FC1C(C)=C(B(O)O)C=CC=1.[F-].[Cs+]>O1CCOCC1.CC(OC)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:15][C:16]1[C:17]([CH3:34])=[C:18]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH2:12][O:13][CH3:14])[CH:19]=[CH:20][CH:21]=1
Reactant: COCc1cc(C(=O)O)ccc1-c1cccc(F)c1C
Reactant: COCc1cc(C(=O)OC)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1c(F)cccc1B(O)O
Agent: [Cs+]
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: COCc1cc(C(=O)OC)ccc1-c1cccc(F)c1C
Temperature: 100 °C

Procedure:
A mixture of methyl 4-bromo-3-(methoxymethyl)benzoate (Intermediate 1, Step 2, 5.00 g, 19.3 mmol), 3-fluoro-2-methylphenylboronic acid (4.46 g, 29.0 mmol), bis(triphenylphosphine)palladium(II) chloride (271 mg, 0.39 mmol) and cesium fluoride (8.79 g, 57.9 mmol) was prepared in dioxane (50 mL) and water (20 mL) under nitrogen atmosphere. The reaction mixture was heated at 100° C. for 1 hour. The reaction mixture was cooled at RT, diluted with MTBE (250 mL) and the layers were separated. The organic layer was washed with water (100 mL) and brine (100 mL). The aqueous layers were extracted with MTBE (150 mL). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure. After purification by flash chromatography (silica, EtOAc/n-hexane), the title compound was obtained as a colorless oil (4.85 g, 87%). HPLC (Method A), Rt 5.0 min (purity: 99.5%). LC/MS (Method B): 289.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:10][C:5]2(OCC[O:6]2)[C:4]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=[CH:3]1.Cl>C1COCC1>[CH3:1][C:2]1([CH3:17])[CH2:10][C:5](=[O:6])[C:4]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=[CH:3]1
Reactant: Cn1nccc1C1=CC(C)(C)CC12OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: Cn1nccc1C1=CC(C)(C)CC1=O
Yield: 89.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 67c by using the 5-(8,8-dimethyl-1,4-dioxaspiro[4.4]non-6-en-6-yl)-1-methyl-1H-pyrazole (1.07 g, 4.56 mmol) prepared in Example 93b, 2 M hydrochloric acid (5.0 mL) and THF (5.0 mL), to yield the title compound (780 mg, 90%) as a light brown solid.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=O)=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][NH2:28])[CH3:24]>O>[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][NH:28][C:17](=[O:19])[C:16]1[CH:21]=[CH:22][C:13]([C:3]2[C:4]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[NH:1][N:2]=2)=[CH:14][CH:15]=1)[CH3:24]
Reactant: COC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reactant: CCN(CC)CCN
Solvent: O
Product: CCN(CC)CCNC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoate (0.3 g) and N,N-diethylethylenediamine (1 ml) was heated at 150° C. for 3.5 hours and then at 180° C. for 2 hours. The mixture was cooled and dissolved in industrial methylated spirit and this solution was preabsorbed onto silica which was applied to the top of a flash column. The column was eluted with dichloromethane/industrial methylated spirit/triethylamine (25:2:1) to give a solid which was stirred with water for 1 hour, filtered and dried under vacuum at 60° C. to give N-(2-diethylaminoethyl)-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, m.p. 172-174° C.
Reaction SMILES: C([N:8]1[CH2:20][C@H:19]2[C@:10](C(OCC)=O)([C:11](=O)[N:12]3[CH2:23][CH2:22][CH2:21][C:14]4[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]3=4)[CH2:9]1)C1C=CC=CC=1.[ClH:30]>O1CCOCC1>[ClH:30].[ClH:30].[CH:17]1[CH:16]=[CH:15][C:14]2[CH2:21][CH2:22][CH2:23][N:12]3[C:13]=2[C:18]=1[C@@H:19]1[CH2:20][NH:8][CH2:9][C@@H:10]1[CH2:11]3
Reactant: CCOC(=O)[C@@]12CN(Cc3ccccc3)C[C@@H]1c1cccc3c1N(CCC3)C2=O
Agent: Cl
Solvent: C1COCCO1
Product: c1cc2c3c(c1)[C@@H]1CNC[C@@H]1CN3CCC2
Temperature: 100 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a solution of (±)-cis ethyl 10-benzyl-8-oxo-5,6,9,10,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-8a(8H)-carboxylate (36.6 g, 93.7 mmol) in 400 mL of 1,4-dioxane was added 400 mL of 3M HCl and the resulting mixture was stirred at 100° C. for 24 h. The dioxane and most of the water was removed in vacuo, and the residue was basified with 1N NaOH and extracted with ethyl acetate. The layers were separated and the organics were washed with brine, dried (MgSO4) and concentrated to afford 28.0 g (94%) of the title compound of Part C, which was sufficiently pure to be used without purification. 1H NMR (CDCl3) δ: 7.25-7.15 (m, 5H), 6.93-6.78 (m, 3H), 4.02-3.93 (m, 1H), 3.78-3.66 (m, 1H), 3.63 (8, 2H), 3.55-3.45 (m, 1H), 3.35 (dd, 1H, J=9.7, 8.3 Hz), 3.20-3.07 (m, 2H), 2.96 (dd, 1H, J=9.5, 5.1 Hz), 2.75-2.68 (m, 2H), 2.32 (app t, 1H, J=9.4 Hz), 1.92-1.82 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[CH:12]2[CH2:13][C:14](=[O:16])[CH2:15][CH:11]2[CH2:10][NH:9]1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>C(#N)C>[CH3:23][N:24]([CH3:28])[C:25]([N:9]1[CH2:10][CH:11]2[CH2:15][C:14](=[O:16])[CH2:13][CH:12]2[CH2:8]1)=[O:26]
Reactant: O=C1CC2CNCC2C1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(C)C(=O)N1CC2CC(=O)CC2C1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one trifluoroacetate 1f obtained from the above step was dissolved in 15 mL of acetonitrile with stirring. Upon cooling by an ice-water bath, potassium carbonate (0.24 g, 1.71 mmol) was added followed by dimethylcarbamic chloride (0.14 mL, 1.56 mmol). The reaction mixture was warmed up to room temperature and reacted for 2 hours. The mixture was concentrated under reduced pressure and diluted with 50 mL of water. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound N,N-dimethyl-5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxamide 1g (0.19 g, yield 68.3%) as a light yellow oil.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([CH3:24])[CH2:11][N:12]1[C:17]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:23])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][C@@H:10]([CH3:24])[CH2:11][N:12]1[C:17]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:23]
Reactant: Cc1ccc2c(c1)N(C[C@H](C)CO[Si](C)(C)C(C)(C)C)C(=O)CO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(C[C@H](C)CO)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (S)-4-[3-(tert-butyldimethylsilanyloxy)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one (101IS60-1) (1.0 g, 2.9 mmol) was dissolved in dry THF (12 mL) and TBAF (1.2 g, 3.8 mmol) was added. The reaction was stirred at rt overnight and the solution was concentrated under reduced pressure, the remaining oil was diluted with EtOAc (60 mL) and washed with brine (3×30 mL), dried (Na2SO4) filtered and concentrated under reduced pressure. The remaining oil was purified by flash chromatography (SiO2; Heptane/EtOAc 30:70) to yield an oil which crystallized upon standing (0.69 g, 76%). 1H NMR (CDCl3) δ 6.88 (d, J=8.4 Hz, 1H), 6.83-6.78 (m, 2H), 4.59 (brs 2 H), 4.22 (dd, J=10.0, 14.4 Hz), 3.57-3.38 (m, 3H), 2.9 (vbrs, 1H), 2.33 (s, 3H), 2.04 (m, 1H), 1.08 (d, J=7.2 Hz); 13C NMR (CDCl3) δ 165.7, 143.4, 132.3, 124.9, 117.1, 115.9, 67.6, 63.7, 43.5, 34.2, 21.3, 15.1.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][CH2:6][CH:7]([OH:22])[CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17](=[NH:20])[NH:18][OH:19])=[CH:12][C:11]=1[CH3:21])=[O:4].[CH:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=O)=[CH:27][CH:26]=1)=[O:24].C(C1C=C(C2ON=C(C3C=C(C)C(OCC(O)CNC(=O)CO)=C(C)C=3)N=2)C=CC=1)=O>>[CH:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29]2[O:19][N:18]=[C:17]([C:13]3[CH:14]=[C:15]([CH3:16])[C:10]([O:9][CH2:8][CH:7]([OH:22])[CH2:6][NH:5][C:3](=[O:4])[CH2:2][OH:1])=[C:11]([CH3:21])[CH:12]=3)[N:20]=2)=[CH:27][CH:26]=1)=[O:24]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Agent: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Product: Cc1cc(-c2noc(-c3ccc(C=O)cc3)n2)cc(C)c1OCC(O)CNC(=O)CO

Procedure:
The title compound was prepared from rac-2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide and 4-formyl-benzoic acid in analogy to (rac)-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide. LC-MS: tR=0.88 min; [M+1]+=426.36.
Reaction SMILES: [N:1]1([C:6]2[CH2:7][CH2:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]([OH:18])=O)=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH3:19]>CN(C=O)C>[N:1]1([C:6]2[CH2:7][CH2:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16](=[O:18])[NH2:19])=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N
Reactant: O=C(O)c1ccc2c(c1)C=C(n1ccnc1)CC2
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2c(c1)C=C(n1ccnc1)CC2
Reaction time: 5 h

Procedure:
To a suspension of 1,2-dihydro-3-(1-imidazolyl)-6-carboxy-naphthalene (500 mg) in DMF (10 ml) SOCl2 (2 ml) was added. Cooling in an ice bath, NH3 was passed through the reaction mixture, with stirring, for 5 hours. The reaction mixture was allowed to stand for 12 hours. The ammonium salt was filtered off and Et2O was added giving a precipitate which was chromatographed on silica gel with CHCl3 :CH3OH:CH3COOH (45:5:2.5) as eluant; 350 mg of 1,2-dihydro-3-(1-imidazolyl)-6-carbamoyl-naphthalene were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[C:4]([C:3]1[C:6]([F:11])=[CH:7][CH:8]=[C:9]([F:10])[C:2]=1[N:1]=[CH:14][N:15]([CH3:17])[CH3:16])#[N:5]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1c(F)ccc(F)c1N
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1c(F)ccc(F)c1C#N
Yield: 797.9 %

Procedure:
A solution of 2-amino-3,6-difluorobenzonitrile (1.92 g, 12.5 mmol) and N,N-dimethylformamide dimethyl acetal (2.2 mL, 1.3 mmol) in 15 mL of toluene was heated to reflux for 1 h. The reaction was complete based on GC-MS. The solvent was removed in vacuo and the oily residue was suspended in hexane and a small amount of ether. The mixture was then cooled in a freezer for 20 min. The resulting solid was suction filtered, washed with hexane and dried to give 2.17 g (83% yield) of the product as a tan solid, M.P. 56-60°; GC/MS: m/z 209. 1H NMR (CDCl3): δ 7.86 (s, 1H), 7.16 (m, 1H), 6.63 (m, 1H), 3.12 (s, 3H), 3.10 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([NH:15][NH:16][C:17](=[O:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[CH2:18]([C:17]1[O:25][C:13]([C:3]2[C:2]([NH2:1])=[N:7][C:6]([C:8]([F:9])([F:11])[F:10])=[C:5]([Br:12])[N:4]=2)=[N:15][N:16]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)NNC(=O)Cc1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: Nc1nc(C(F)(F)F)c(Br)nc1-c1nnc(Cc2ccccc2)o1

Procedure:
To a solution of 3-amino-6-bromo-N′-(2-phenylacetyl)-5-(trifluoromethyl)pyrazine-2-carbohydrazide (step 1) (92 mg, 0.220 mmol) in THF (2 ml) was added a solution of TsCl (50 mg, 1.200 mmol) in THF (0.5 ml). The resulting solution was then added to PS-BEMP (384 mg, 1.100 mmol) and the mixture was heated using microwave radiation at 120° C. for 10 min. The reaction mixture was loaded onto an Isolute® PE-AX/SCX-2 cartridge (10 g, Solid Phase Extraction) pre-wetted with THF. The cartridge was eluted with THF (40 ml) and the organic portion was concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 20% EtOAc/iso-hexane followed by further purification by preparative HPLC to afford the title compound; 1H NMR (400 MHz, DMSO-d6) δ 7.35 (5H), 4.49 (2H, s). LC-MS Rt=5.76 min [M+H]+ 400.1 Method 10minLC_v002.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])/[C:7](=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)=[C:14]([O:24][CH3:25])[CH:13]=1)/[CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(O)(=O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:26])/[C:7](=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)=[C:14]([O:24][CH3:25])[CH:13]=1)/[CH2:8][CH2:9][NH:10][CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[C:28]([F:27])[CH:29]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1cccc(F)c1
Reactant: COc1cc(/C=C(\CCN)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(/C=C(\CCNCc2cccc(F)c2)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1

Procedure:
To a methylene chloride (2.0 mL) solution of (E)-4-amino-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid tert-butyl ester (71 mg), 3-fluorobenzaldehyde (21.1 μL), acetic acid (0.1 mL) and sodium triacetoxy borohydride (63.3 mg) were added one by one. After agitating reaction solution at room temperature for 5.5 hours, a saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by NH silica gel chromatography (elution solvent: ethyl acetate->ethyl acetate:ethanol=20:1), and 47.5 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [Na].[OH:2][C:3]1([C:16]([OH:18])=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.O=O.S(=O)(O)[O-].[Na+].[CH3:26]O>O>[CH3:26][O:17][C:16]([C:3]1([OH:2])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:18]
Reactant: O=C(O)C1(O)c2ccccc2-c2ncccc21
Reactant: CO
Agent: O=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)C1(O)c2ccccc2-c2ncccc21
Reaction time: 1 h

Procedure:
To a stirred solution of sodium (1.1 eq, 60.1 mmol. 1.38 g) in 150 mL dry methanol was added a solution of 5-hydroxy-5H-indeno[1,2-b]pyridine-5-carboxylic acid methol ester (22) (12.3 g, 54.6 mmol) in 50 mL dry methanol. The solution was cooled in ice and, after 15 min., a flow of dry oxygen was begun and continued for 1 h. Then the reaction mixture was poured into a solution of 12 g sodium bisulfite in 200 mL water. After 30 min. the mixture was evaporated to dryness. The resulting solid was triturated with 2×100 mL acetone and filtered. The remaining inorganic salts were removed by filtration. The filtrate was evaporated to yield 24.2 g wet pink solid of (23). Drying in vacuo over phosphorus pentaoxide yielded 12.5 g crude (23). Recrystallization from ethyl acetate yielded two crops 8.06 g (61%) and 2.54 g (19%) of (23).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20]S(C)=O.CI>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17])[CH3:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)NCCOCCO)cc1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(CCOCCO)S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 3.3 g (31 mmol) of 2-(2-aminoethoxy)ethanol in 30 mL of MeOH was added 7.0 g (30 mmol) of N-acetylsulfanilyl chloride, followed by 3.3 g (33 mmol) of TEA. The reaction mixture was stirred for 30 min at rt and then acidified with 5 mL (60 mmol) of concentrated HCl and stirred at reflux for 75 min. After cooling, the mixture was diluted with 40 mL of water and made basic with solid NaHCO3. MeOH was removed on a rotary evaporator, and the residual aqueous solution was extracted with four 50-mL portions of EtOAc. The combined extracts were dried over Na2CO3, and the solvent was removed on a rotary evaporator to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide as a viscous oil (7.5 g, 96%): 1H NMR (DMSO-d6): δ 2.77 (q, J=6.0 Hz, 2H), 3.30 (t, J=4.9 Hz, 2H), 3.31 (t, J=6.5 Hz, 2H), 3.41 (q, J=5.2 Hz, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.89 (s, 2H), 6.57 (d, J=8.7 Hz, 2H), 7.10 (t, J=7.37 (d, J=8.6 Hz, 2H); ESI−MS m/s 259 (M−H)−. To a solution of 0.63 g (2.4 mmol) of 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide in 10 mL of THF was added 0.10 g (2.5 mmol) of 60% sodium hydride. The mixture was stirred for 1 h at rt, 1 mL of DMSO and ˜0.2 mL (˜3 mmol) of methy iodide were added to the resulting suspension. The reaction mixture was stirred 2 h at rt and then poured into 15 mL of half saturated NaCI solution and extracted with 30 mL of EtOAc. The organic solution was dried with MgSO4 and concentrated on a rotary evaporator. The residue was chromatographed on silica gel with EtOAc to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-benzenesulfonamide as an oil (0.43 g, 65%): 1H NMR (DMSO-d6): δ 2.59 (s, 3H), 2.96 (t, J=5.9 Hz, 2H), 3.36 (t, J=5.2 Hz, 2H), 3.43 (t, J=5.2 Hz, 2H), 3.47 (t, J=5.9 Hz, 2H), 4.55 (t, J=5.4 Hz, 1H), 5.99 (s, 2H), 6.59 (d, J=8.7 Hz, 2H), 7.34 (d, 8.8 Hz, 2H); APCI−MS m/z 297 (M+Na)+. The title compound was prepared from 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-benzenesulfonamide and 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one according to Procedure J: mp 165° C.; 1H NMR (DMSO-d6): δ 2.71 (s, 3H), 3.11 (t, J=5.6 Hz, 2H), 3.37 (t, J=5.0 Hz, 2H), 3.44 (dt, J=5.1, 5.0 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 4.56 (br t, J=5.2 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.5 Hz, 1H), 8.06 (d, J=12.0 Hz, 1H), 9.25 (s, 1H), 10.91 (s, 1H), 11.16 (d, J=12.0 Hz, 1H); APCI−MS m/z 474 M−. Anal. Calcd for C21H22N4O5S2.H2O: C, 51.21; H, 4.91; N, 11.37. Found: C, 51.18; H, 4.88; N, 11.33.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[C:13]([C:20]([F:23])([F:22])[F:21])=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[H][H]>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH:13]([C:20]([F:23])([F:22])[F:21])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C=C(c1c(C)[nH]c2ccc(OC)cc12)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(c1c(C)[nH]c2ccc(OC)cc12)C(F)(F)F
Yield: 99.8 %

Procedure:
A solution of the indole from Step 2 (23 g, 70 mmol) in 200 mL EtOH was treated with 60 psi hydrogen over 5% palladium on carbon (2.3 g) in a Parr shaker for 18 h. The mixture was filtered through celite and evaporated to give 23 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH3:25][N:26]1[CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[C:6]([N:28]3[CH2:29][CH2:30][N:26]([CH3:25])[C:27]3=[O:31])[CH:5]=[CH:4][C:3]=2[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])[C:27]1=[O:31]
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3Br)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3N3CCN(C)C3=O)CC2)c(C)c1
Yield: 29.8 %

Procedure:
Using (2,4-dibromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (136 mg) described in Preparation Example 237 and 1-methylimidazolidin-2-one (90 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (44 mg) was obtained.