Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([OH:24])[CH2:15][CH2:16]2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=[CH:3][CH3:4].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[CH3:1][C:2]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1)=[CH:3][CH3:4]
Reactant: CC=C(C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC=C(C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
20,21-Dimethylpregna-5,20-dien-3β-ol (6, 400.3 mg, 1.218 mmol) in 5 ml of methylene chloride was oxidized with pyridinium chlorochromate (525.4 mg 2.437 mmol) for 42 h. Ether (3.5 ml) was added and the suspension was filtered through a 5 mm dia.×60 mm high column of silica gel. The column was further eluted with 3.5 ml of ether and the combined filtrates were concentrated under reduced pressure. Flash chromatography of the resin followed by recrystallization from aqueous ethanol gave yellow crystals (43.6 mg, 0.134 mmol 11%). m.p. 157-165° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22]([S:25][CH2:26][CH:27]([CH3:31])[C:28](Cl)=[O:29])(=[O:24])[CH3:23]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[CH2:7][N:8]([C:28](=[O:29])[CH:27]([CH3:31])[CH2:26][S:25][C:22](=[O:24])[CH3:23])[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNC1CCCC1
Reactant: CC(=O)SCC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Yield: 77.7 %

Procedure:
To a stirred and chilled (0°-5° C.) solution of N-cyclopentylglycine t-butyl ester (60 g, 0.3 mol) and triethylamine (75 ml, 0.5 mol) in methylene chloride (200 ml) was added dropwise 3-acetylthio-2-methylpropanoyl chloride (54 g, 0.3 mol) dissolved in methylene chloride (250 ml). The reaction mixture was stirred overnight. It was filtered free of solid material which was then washed with fresh methylene chloride. Washings and filtrate were combined and concentrated. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate (1000 ml), brine (600 ml), 5% HCl (3×500 ml), brine (500 ml), saturated sodium bicarbonate (5×500 ml). The organic layer was now separated, dried (Na2SO4 and MgSO4), filtered and concentrated to yield the desired product (80.1 g, 78%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH2:11]([Mg]Br)[CH2:12][CH:13]=[CH2:14]>C1COCC1.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH2:14][CH2:13][CH:12]=[CH2:11])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: C=CCC[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CCCC(=O)c1cccc(Cl)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of 3-chlorobenzoyl chloride (7 ml, 54.7 mmol) in THF (60 mL) was added copper (I) iodide (0.521 g, 2.73 mmol). The slurry was cooled to −10° C. and 3-butenylmagnesium bromide (0.5M in THF) (112 ml, 55.8 mmol) was added dropwise via cannula over 30 min. The reaction mixture was stirred at −10° C. for 1 h and then warmed to room temperature. The reaction mixture was concentrated to 25 mL and diluted with 100 mL DCM and 100 mL 1M HCl. The layers were separated and the organic layer was filtered. The filtrate was washed with sat. NaHCO3, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 50% DCM in hexanes) to give the title compound.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([NH:26][C@H:27]([C:31]([OH:33])=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].O[CH2:35][CH2:36][CH2:37][C:38]([CH3:52])([CH3:51])[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)=[O:40]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:16]([NH:26][C@H:27]([C:31]([O:33][CH2:35][CH2:36][CH2:37][C:38]([CH3:51])([CH3:52])[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)=[O:40])=[O:32])[CH:28]([CH3:29])[CH3:30])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)C(C)(C)CCCO)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C(C)(C)CCCOC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
To a mixture of DCC (9.41 g, 46 mmol), DMAP (0.586 g, 4.8 mmol) and N-CBz-L-valine (12.1 g, 48 mmol) in CH2Cl2 (200 mL) at 0° C., was added dropwise a solution of 4-methoxybenzyl 5-hydroxy-2,2-dimethyl-valerate (6.40 g, 24 mmol) in CH2Cl2 (50 mL). After 1 h at 0° C., the temperature of the reaction mixture was allowed to assume room temperature and theft the mixture was stirred for 5 h at room temperature. The mixture was filtered through a glass filter and the solvent was removed under reduced pressure. The crude product was column chromatographed (silica gel, 1→4% MeOH in CH2Cl2), to give 8.61 g 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH2:7]([O:9][C:10]([O:12][CH2:13][CH3:14])=[CH2:11])[CH3:8]>CCCCC>[CH2:7]([O:9][C:10]1([O:12][CH2:13][CH3:14])[CH2:11][CH:5]2[CH:4]1[CH2:3][CH2:2][C:1]2=[O:6])[CH3:8]
Reactant: O=C1C=CCC1
Reactant: C=C(OCC)OCC
Solvent: CCCCC
Product: CCOC1(OCC)CC2C(=O)CCC21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of cyclopent-2-enone (3.7 g, 45 mmol) in pentane (80 mL) was added 1,1-diethoxyethene (89 mL, 677 mmol). The mixture was put in an ACE Photo Reactor (450 W lamp), and stirred at RT for 20 hr. It was concentrated to give the title compound as a pale yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC(C)(O)[C:9]#[N:10].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:18](=[O:28])/[C:17]/2=[C:29](/[C:34]#[N:35])\[C:30]([O:32][CH3:33])=[O:31]>O.O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:18](=[O:28])[C:17]2([CH:29]([C:34]#[N:35])[C:30]([O:32][CH3:33])=[O:31])[C:9]#[N:10]
Reactant: CC(C)(O)C#N
Reactant: COC(=O)CN1C(=O)/C(=C(/C#N)C(=O)OC)c2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CN1C(=O)C(C#N)(C(C#N)C(=O)OC)c2cc(Cl)ccc21
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A solution of potassium carbonate (1.39 g, 10.03 mmol) in water (8.2 ml) was treated with acetone cyanohydrine (4.0 ml, 43.5 mmol) at ambient temperature and continuously stirred for 15 min. A fine suspension of methyl (2Z)-[5-chloro-1-(2-methoxy-2-oxoethyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene](cyano)acetate, intermediate 45, (11.19 g, 33.43 mmol) in tetrahydrofuran (500 ml) was added dropwise and the resulting suspension was heated to reflux for 3 hours. The solid was filtered off, the residue was washed with tetrahydrofuran (3×40 ml) and the collected filtrates were evaporated to dryness. The solid was dissolved in dichloromethane (250 ml), washed with saturated NaHCO3 (2×100 ml), water (100 ml) and dried (MgSO4) to obtain the title compound (10.82 g, 89%) as red-brown solid (HPLC purity: 91%). MS (ESI+): 362.2; MS (ESI−): 360.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:43])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[C:28]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])[C:27]([O:38][CH3:39])=[CH:26][C:25]=3[O:40][CH2:41][CH3:42])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:46][S:47]([CH2:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)(=[O:49])=[O:48]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:43])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:56]3[CH2:55][CH2:54][N:53]([CH2:52][CH2:51][CH2:50][S:47]([CH3:46])(=[O:48])=[O:49])[CH2:58][CH2:57]3)=[O:22])[C:10]([C:24]3[CH:29]=[C:28]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])[C:27]([O:38][CH3:39])=[CH:26][C:25]=3[O:40][CH2:41][CH3:42])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(OC)c(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(OC)c(S(=O)(=O)N2CCCC2)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-methoxy-5-(pyrrolidine-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C39H50N5O7S2Cl2 [(M+H)+] 834.2523, observed 834.2524.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][N:75]1[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]1>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([N:78]4[CH2:79][CH2:80][N:75]([CH3:74])[CH2:76][CH2:77]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CN1CCNCC1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)COc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)CC1
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (100 mg, 0.24 mmol), PyBOP® (125 mg, 0.24 mmol), DIEA (125 μL, 0.24 mmol) in CH2Cl2 (5 mL) stirred at RT for 10-15 minutes. To this solution of activated acid was added 1-methylpiperazine (27 μL, 0.24 mmol) and the reaction mixture was stirred at RT for 1.5 h. Concentrated in vacuo and the crude product was purified using prep HPLC (method 10-35_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone. (32 mg, 0.065 mmol, 27%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][C:10]1[O:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(-c2ccco2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(-c2ccc(Br)o2)c1
Reaction time: 18 h
Yield: 91.7 %

Procedure:
A stirred solution of 10.0 g (0.063 mol) of 2-(3-methylphenyl)furan in 250 mL of carbon tetrachloride was heated to reflux, and 0.1 g of benzoyl peroxide was added. The solution was heated at reflux for ten minutes, then an additional 0.1 g of benzoyl peroxide followed by 11.2 g (0.063 mol) of N-bromosuccinimide, were added. Upon complete addition, refluxing was continued for an additional 18 hours. The reaction mixture was cooled, filtered, and the filtrate washed with 200 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 13.7 g of 2-bromo-5-(3-methylphenyl)furan.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([C@H:17]2[CH2:21][CH2:20][O:19][CH2:18]2)([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pt](=O)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@:12]([C@H:17]2[CH2:21][CH2:20][O:19][CH2:18]2)([C:14]([OH:16])=[O:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@](C(=O)O)([C@H]2CCOC2)C1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@](C(=O)O)([C@H]2CCOC2)C1
Yield: 0.1 %

Procedure:
(1R,4S)-4-[(tert-Butoxycarbonyl)amino]-1-[(3R)-tetrahydrofuran-3-yl]cyclopent-2-ene-1-carboxylic acid (0.79 g, 2.6 mol) was dissolved in ethanol (20.0 mL), degassed-purged with N2, followed by the addition of platinum dioxide (0.150 g, 0.528 mol). The reaction mixture was placed on a Parr apparatus and hydrogenated under hydrogen at 55 psi for 18 h. The mixture was filtered through celite pad, washed with MeOH, concentrated to provide the desired product (730 mg, 91.8%). MS calculated for C15H26NO5 (M+H) 300.2; found 200.2 (M+H-Boc).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[Cl:47][C:48]1[CH:53]=[CH:52][C:51]([N:54]=[C:55]=[O:56])=[CH:50][N:49]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:47][C:48]1[N:49]=[CH:50][C:51]([NH:54][C:55]([N:43]2[CH2:44][CH2:45][CH:40]([C:38]([NH:37][C:29]3[CH:30]=[CH:31][C:32]4[NH:33][C:34]5[N:35]=[C:19]([NH:20][C:21]6[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=6)[CH2:26][CH2:27][C:28]=3[CH:36]=4)[N:18]=[CH:17][C:16]=5[Cl:15])=[O:39])[CH2:41][CH2:42]2)=[O:56])=[CH:52][CH:53]=1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Reactant: O=C=Nc1ccc(Cl)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCN(C(=O)Nc2ccc(Cl)nc2)CC1
Yield: 23 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 2-chloro-5-isocyanatopyridine as starting materials in 23% yield. LCMS for C30H29Cl2N8O2 (M+H)+: m/z=603.2.
Reaction SMILES: CC[O-].[Na+].[CH3:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[CH:14]=O)=[CH:8][CH:7]=1.[N:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N+:17]=[N-:18]>C(O)C>[N:16](/[C:19](=[CH:14]\[CH:13]=[CH:12]\[C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][CH:10]=1)/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N+:17]=[N-:18]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: Cc1ccc(/C=C/C=O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)/C(=C/C=C/c1ccc(C)cc1)N=[N+]=[N-]

Procedure:
Following General Procedure I, a 1.38 M solution of NaOEt in ethanol (30 ml), (E)-3-(4-methylphenyl)acrylaldehyde (Compound 43, 1.1 g, 7.5 mmol) and ethyl azidoacetate (12 ml, 37.5 mmol) in EtOH (20 ml) were reacted to produce the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.6 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(2-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (98 mg, 83%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22].O>CO>[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)CCCCl
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: O
Solvent: CO
Product: CN(C)CCCOc1ccc(C(=O)c2ccc(OCCCN(C)C)cc2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of bis-(4-hydroxy-phenyl)-methanone (7.00 g) in methanol (130 mL) was added at room temperature t-Bu3OK (14.7 g) followed by (3-chloro-propyl)-dimethyl-amine (10.3 g). The reaction mixture was heated under reflux for 18 h and was allowed to cool down to room temperature. Water (50 mL) was added and the solvent was removed in vacuo. Methylene chloride (650 mL) was added and the organic layer was washed with water (2×150 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The crude products were separated and purified by flash chromatography on silica gel (chloroform/2 M ammonia in methanol) to give the title compound bis-[4-(3-dimethylamino-propoxy)-phenyl]-methanone as a colorless residue (250 mg). 1H NMR (400 MHz, CD3OD): 7.78 (d, 4 H), 7.09 (d, 4 H), 4.22 (t, 4 H), 3.37-3.40 (m, 4 H), 2.96 (s, 12 H), 2.24-2.31 (m, 4 H). And title compound [4-(3-dimethylamino-propoxy)-phenyl]-(4-hydroxy-phenyl)-methanone as a colorless residue (150 mg). 1H NMR (400 MHz, CD3OD): 7.88-7.99 (m, 4 H), 7.25-7.29 (m, 2 H), 7.08-7.13 (m, 2 h), 4.48 (t, 2 H), 2.69-2.76 (m, 2 H), 2.56 (s, 6 H), 2.23-2.30 (m, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl.Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(#N)C>[N:14]1([CH2:13][CH2:12][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=Cc1cccc(O)c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Solvent: CC#N
Product: O=Cc1cccc(OCCN2CCCCC2)c1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a mixture of 3-hydroxybenzaldehyde (5.42 g, 44.38 mmol), K2 CO3 (13.5 g) and acetonitrile was added N-(2-chloroethyl)piperidine hydrochloride (9.8 g). The reaction mixture was refluxed overnight, cooled to room temperature and filtered. The filtrate was stripped to give an oil which was partitioned between CHCl3 (350 ml) and 1M NaOH (200 ml). The organic layer was separated, washed with 1M NaOH (2×200 ml), treated with DARCO®, then MgSO4, filtered, and stripped to afford, as a dark oily liquid, 6.28 g of 3-[2-(1-piperdinyl)ethoxy]benzaldehyde.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[C:34]1([NH:40][NH2:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21]/[C:22](/[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[N:41]\[NH:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Reactant: NNc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC/C(=N\Nc3ccccc3)c3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
Prepared by Procedure E and Scheme AX using 2-methyl-N-(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and phenylhydrazine: ESMS m/e: 542.4 (M+H)+.
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O1CCCC1.C(O)C>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH:2]2[C:14]3[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]2=3)[CH2:20][CH2:19]1
Reactant: CN1CCNCC1
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCN(C2c3ccccc3-c3[nH]c(=O)c(=O)[nH]c32)CC1
Reaction time: 20 h
Yield: 38.3 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (1.50 g, 6.39 mmol) was suspended in 15 ml of dry tetrahydrofuran, while cooling in an ice bath. N-Methylpiperazine (1.42 ml, 12.78 mmol) dissolved in 3 ml of dry tetrahydrofuran was added over 20 min, and the ice bath was removed and stirring was continued for 20 hours at room temperature. The precipitate was filtered off and washed with tetrahydrofuran and dried to give 2.42 g of a remanence, which was dissolved in 100 ml of boiling ethanol, and treated with 300 mg of activated carbon. The mixture was filtered and concentrated to 10 ml. The precipitate was filtered off, washed with ethanol and dried to give 0.65 g of the crude product. From the filtrate another crop of 0.57 g could be isolated. Recrystallization from 6M HCl afforded 0.73 g (30%) of the title compound as a dihydrochloride. M.p. 263°-265° C. 1H-NMR (DMSO-d6, δ): 2.6 (m, 1H), 2.73 (s, 3H), 2.78-3.52 (m, 7H), 4.84 (s, 1H), 5.9-7.0 (broad, 2H), 7.2 (t, 1H), 7.35 (t, 1H), 7.48 (d, 1H), 7.58 (d, 1H), 10.92 (s, 1H), 11.76 (s, 1H), 12.34 (s, 1H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:18]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:18]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:23][CH2:22]2)=[O:19])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(NC(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccccc2)CC1
Yield: 60 %

Procedure:
The compound obtained in Example 13 (435 mg, 1.00 mmol) and triethylamine (0.335 ml) were dissolved in THF (10 ml). To the solution was added methanesulfonyl chloride (0.155 ml) under ice cooling with stirring, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (15 ml) under ice cooling, and the mixture was extracted with ethyl acetate (15 ml×3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel, 10 g, ethyl acetate/methanol=1/0 to 9/1 to 4/1), and the desired fraction was concentrated under reduced pressure. To the concentrate was added ethyl acetate and resulting precipitates were filtered off. The filtrate was concentrated under reduced pressure. To the concentrate was added diethyl ether and resulting precipitates were collected by filtration. The precipitates were washed with diethyl ether, and dried under reduced pressure to give the titled compound (310 mg, 0.60 mmol, Yield 60%) as white solid.