Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:24])[N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5])C.C(O)C.[OH-].[Na+]>O>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:24])[N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:16][CH2:17]2)=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(N2CCN(C(=O)N(CC)CC)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCN(CC)C(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Reaction time: 3.5 h
Yield: 49.1 %

Procedure:
To 3.3 g (0.01 mole) of 1-(4-ethoxycarbonylphenyl)-4-diethylcarbamoylpiperazine obtained in Example 6 were added 90 ml of ethanol, 10 ml of water and 1.0 g of sodium hydroxide, and the mixture was heated and refluxed under stirring for 3.5 hours. The solvent was removed by distillation under reduced pressure, and 100 ml of water was added to the residue and the insoluble substance was removed. The pH value of the filtrate was adjusted to 3 by 2 N hydrochloric acid. The precipitate was recovered by filtration and dissolved in a dilute aqueous solution of sodium hydroxide, and the pH value was adjusted to 3 again by 2 N hydrochloric acid. The precipitate was recrystallized from methanol to obtain 1.5 g of 1-(4-carboxyphenyl)-4-diethylcarbamoylpiperazine having a melting point of 207° to 209.5° C. The elementary analysis values are as follows.
Reaction SMILES: C(O[C@H]1CN([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)C[C@H]1NC1C(CC)=NC(C2C(C)=NC(OC)=CC=2)=C(CC)N=1)C.[CH3:35][N:36]([CH3:63])[C:37]1[N:42]=[CH:41][C:40]([C:43]2[N:44]=[C:45]([CH2:60][CH3:61])[C:46]([NH:51][C@H:52]3[C@@H:56]([O:57][CH2:58][CH3:59])[CH2:55][NH:54][CH2:53]3)=[N:47][C:48]=2[CH2:49][CH3:50])=[C:39]([CH3:62])[CH:38]=1>>[CH3:63][N:36]([CH3:35])[C:37]1[N:42]=[CH:41][C:40]([C:43]2[N:44]=[C:45]([CH2:60][CH3:61])[C:46]([NH:51][C@H:52]3[C@@H:56]([O:57][CH2:58][CH3:59])[CH2:55][N:54]([C:9]4[N:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[CH2:53]3)=[N:47][C:48]=2[CH2:49][CH3:50])=[C:39]([CH3:62])[CH:38]=1
Reactant: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC
Product: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of N-[(3R,4S)-4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine but substituting 5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine provided the title compound as an amporphous solid: 1H NMR (400 MHz, CDCl3) δ) 8.36, 7.99, 6.53, 6.46, 5.19, 4.91, 4.22, 3.95, 3.73, 3.58–3.44, 3.13, 2.71, 2.54, 2.12, 1.32–1.26, 1.16; IR (diffuse reflectance) 2969, 2931, 2403 (w), 2351 (w), 2306 (w), 2212 (w), 2168 (w), 1606 (s), 1583 (s), 1568 (b), 1547 (s), 1508 (s), 1474 (s), 1393 (s), 798 cm−1 HRMS (ESI) calcd for C26H36N8O+H1 477.3090. found 477.3113.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]([OH:20])=O)=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][C@H:28]2[CH2:32][O:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:23][CH2:22]1>>[CH3:1][C:2]1[C:3]([C:18]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[CH2:32][O:33][C:34](=[O:41])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:23][CH2:22]2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[CH:7]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)O
Reactant: O=C(OC[C@@H]1CCCN1C1CCNCC1)c1ccccc1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)N1CCC(N2CCC[C@H]2COC(=O)c2ccccc2)CC1

Procedure:
In analogy to the procedures described for example 1 and for intermediate 1B, 3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (intermediate 1B) was reacted with benzoic acid (S)-1-piperidin-4-yl-pyrrolidin-2-ylmethyl ester (intermediate 6) to give benzoic acid (S)-1-{1-[3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-piperidin-4-yl}-pyrrolidin-2-ylmethyl ester, which was subsequently saponified to give the title compound as light brown solid. MS: 448.1 (MH+).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[CH2:31][C@@H:32](O)[CH2:33][CH2:34][C@@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Br)(Br)(Br)[Br:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[CH2:31][CH:32]([Br:39])[CH2:33][CH2:34][C@@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](O)CN2C[C@H]1Cc1c[nH]c2ccccc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CCC(Br)CN2C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a suspension of 3,5-bis(trifluoromethyl)phenyl-[(3R,7S,9aR)-7-hydroxy-3-(1H-indol-3-ylmethyl)-octahydropyrido[1,2-a]pyrazin-2-yl]-methanone (3.85 g) in acetonitrile was added carbon tetrabromide (11.6 g) and triphenylphosphine (9.18 g), the resulting mixture was stirred at room temperature overnight. The formed precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash-chromatography (SiO2, CH2Cl2/MeOH 98:2) to afford 3,5-bis(trifluoromethyl)phenyl-[(3R,9aR)-7-bromo-3-(1H-indol-3-ylmethyl)-octahydropyrido[1,2-a]pyrazin-2-yl]-methanone (3.5 g). MH+ 588, Rf 0.38 (CH2Cl2/MeOH 97:3) (intermediate 17).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC=CC=1>CCOCC>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:24]([NH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[S:25])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccccc1
Reactant: Cc1ccccc1COc1cccnc1N
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccccc1COc1cccnc1NC(=S)Nc1ccccc1

Procedure:
A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (1.67 g, 0.0078 mol), phenyl isothiocyanate (1.26 g, 0.0093 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with ether to induce crystallisation of the product. Yield 1.8 g (66%), m.p. 150°-151 ° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:12][CH2:13][OH:14])[C:10]=1[OH:11])[C@H:7]([CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH2:6][CH2:5]2.C(N(CC)CC)C>[C].[Pd].CO>[OH:11][C:10]1[C:9]([CH2:12][CH2:13][OH:14])=[C:8]2[C:4]([CH2:5][CH2:6][C@H:7]2[CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20])=[CH:3][CH:2]=1
Reactant: CCC(=O)NCC[C@@H]1CCc2cc(Br)c(O)c(CCO)c21
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC(=O)NCC[C@@H]1CCc2ccc(O)c(CCO)c21
Yield: 91.2 %

Procedure:
A methanol suspension of (S)-N-[2-(5-bromo-6-hydroxy-7-(2-hydroxyethyl)indan-1-yl)ethyl]propionamide (590 mg, 1.66 mmol.), triethylamine (184 mg, 1.82 mmol.) and 5% palladium-carbon (100 mg) was subjected to catalytic reduction under hydrogen atmosphere. At the time when the calculated volume of hydrogen was absorbed, the catalyst was filtered off. The filtrate was made weakly acidic with dilute hydrochloric acid, followed by extracting the organic matter with a mixture of ethyl acetate:butanol=1.1. The extract solution was dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure, followed by washing with diethyl ether to afford the title compound (yield 0.42 g, 91%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[C:19](=[O:26])[CH:20]=[C:21]([CH2:24][OH:25])[O:22][CH:23]=2)=[N:3][CH:2]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:25][CH2:24][C:21]1[O:22][CH:23]=[C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][N:3]=2)[C:19](=[O:26])[CH:20]=1)(=[O:37])=[O:36]
Reactant: O=c1cc(CO)occ1OCCCCCOc1ncnc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ncnc3ccccc23)co1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 5-(5-(quinazolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 15 (0.53 g, 1.49 mmol) in CH2Cl2 (20 mL) was added at 0° C. triethylamine (252 μL, 1.78 mmol), methanesulfonyl chloride (138 μL, 1.78 mmol). The solution was stirred at RT for 1 h. Dichloromethane (50 mL) was added and the solution was washed with water (2×100 mL), dried over MgSO4, filtered and evaporated. (5-(5-(Quinazolin-4-yloxy)pentyloxy)-4-oxo-4H-pyran-2-yl)methyl methanesulfonate 20 was obtained (0.64 g, 99% yield) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]3=[O:30])=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C(O)(C(F)(F)F)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C:18]3=[O:30])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)C(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(N2CCNCC2=O)cc1

Procedure:
A mixture of 1 g of methyl 4-iodobenzoate, 920 mg of 4-Boc-piperazinone, 1.1 g of potassium carbonate, 32 mg of N,N′-dimethylethylenediamine and 70 mg of copper iodide in 10 mL of toluene was heated to 150° C. in a sealed microwave reactor for 3 h. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (20-80% ethyl acetate/hexane) to afford tert-butyl 4-(4-(methoxycarbonyl)phenyl)-3-oxopiperazine-1-carboxylate. 500 mg of tert-butyl 4-(4-(methoxycarbonyl)phenyl)-3-oxopiperazine-1-carboxylate was hydrolyzed via Procedure M to give 4-(4-(tert-buthoxycarbonyl)-2-oxopiperazin-1-yl)benzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(4-(tert-buthoxycarbonyl)-2-oxopiperazin-1-yl)benzoic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N sodium hydroxide and brine, dried (MgSO4) and evaporated to afford tert-butyl 4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenyl)-3-oxopiperazine-1-carboxylate. 300 mg of crude tert-butyl 4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenyl)-3-oxopiperazine-1-carboxylate was treated with TFA (2 mL) containing trace amounts of H2O for 1 h. The reaction mixture was evaporated and the crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxopiperazin-1-yl)benzamide. MS (Q1) 407.3 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([CH3:23])[C:17]=1[CH3:24].[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37](=[O:38])[C:36]([C:39](O)=[O:40])=[CH:35][N:34]([CH:42]([CH3:44])[CH3:43])[C:33]2=[O:45])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:39]([C:36]2[C:37](=[O:38])[N:32]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[C:33](=[O:45])[N:34]([CH:42]([CH3:44])[CH3:43])[CH:35]=2)=[O:40])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: CC(C)n1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4cn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)c(C)c3C)c2cc1OC

Procedure:
This compound was synthesized using 4-(6,7-Dimethoxy-quinolin-4-yloxy)-2,3-dimethyl-phenylamine and 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=238-240° C.; LCMS m/z=599 (M+1); 1H NMR (DMSO-d6) δ: 10.82 (s, 1H), 8.68 (s, 1H), 8.43 (d, 1H, J=5.5 Hz), 8.06 (d, 1H, J=9 Hz), 7.56 (s, 1H), 7.47-7.42 (m, 2H), 7.39-7.34 (m, 2H), 7.09 (d, 1H, J=9 Hz), 6.27 (d, 1H, J=5.5 Hz), 4.78 (p, 1H, J=8 Hz), 3.95 (s, 6H), 2.21 (s, 3H), 2.07 (s, 3H), 1.43 (d, 6H, J=6 Hz).
Reaction SMILES: [NH:1]([C:5]1[C:13]2[C:8](=[C:9]([CH3:15])[N+:10]([O-])=[CH:11][CH:12]=2)[S:7][CH:6]=1)[C:2]([CH3:4])=[O:3].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[SH:27][C:28]1[NH:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC=CC=1.CN(C=O)C>[NH:1]([C:5]1[C:13]2[C:8](=[C:9]([CH2:15][S:27][C:28]3[NH:29][C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[N:10]=[CH:11][CH:12]=2)[S:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1csc2c(C)[n+]([O-])ccc12
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)Nc1csc2c(CSc3nc4ccccc4[nH]3)nccc12
Reaction time: 2.5 h
Yield: 25.9 %

Procedure:
To a refluxing solution of 202 mg (0.909 mmol) of 3-acetamino7-methylthieno[2, 3-c]pyridine N-oxide in anhydrous benzene was added 258 mg (1.5 equivalents) of TsCl, and the mixture was continued to be refluxed for 4 hr. After concentration under reduced pressure, the solution was subjected to silica gel column chromatography (silica gel : 30 g), eluting with CH2Cl2 : MeOH=20:1 v/v, whereby 3-acetamino-7-chloromethylthieno[2, 3-c]pyridine was separated. The produce was treated with 3 ml of anhydrous DMF, 136 mg (1 equivalent) of 2-mercaptobenzimidazole, and 502 mg (4 equivalents) of anhydrous K2CO3, and the mixture was stirred for 2.5 hr. at room temperature. After concentration under reduced pressure, the residue was extracted with ethyl acetate, and washed with water. The organic layer gave 237 mg of the crude crystals. The crystals were subjected to silica gel column chromatography (silica gel : 60 g), eluting with a solution of CH2Cl2 : MeOH=10:1 v/v, whereby 83 mg (Yield : 26.8%) of 2-[(3-acetaminothieno[2, 3-c]pyridin-7-yl]methylthio]benzimidazole (Ia-12) was obtained as an objective compound.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:10]([O:12][C:13](=[O:25])[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH3:11].C([O-])([O-])=O.[K+].[K+]>>[CH2:10]([O:12][C:13](=[O:25])[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:17]=1)=[O:15])[CH3:11]
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: ClCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(=O)c1cn(CCN2CCCCC2)c2ccccc12
Yield: 65.7 %

Procedure:
The general procedure 1 was then followed using 1-(2-chloroethyl)piperidine (10 mmol, 1.5 g), ethyl-2-(1H-indol-3-yl)-2-oxoacetate (7 mmol, 1.5 g) and K2CO3 (10.9 mmol, 1.5 g). The purification was achieved by column chromatography (petrol-ether:ethylacetate:diethylamine 8:1:1) to yield ethyl-2-{1-[2-(piperidin-1-yl)ethyl]-1H-indol-3-yl}2-oxoacetate (4.6 mmol, 66%) as an pale yellow oil. IR {tilde over (ν)} [cm−1]=2936; 2857; 1730; 1638. EI-MS m/z (rel. int.)=328 (18.99%; M+•). 1H NMR (300 MHz, CDCl3) 8.43 (m; 2H; indole-H); 7.35 (m; 3H; indole-H); 4.40 (q; 3J=7.1 Hz; 2H; OCH2CH3); 4.25 (t; 3J=6.8 Hz; 2H; indole-CH2CH2N); 2.72 (t; 3J=6.8 Hz; 2H; indole-CH2CH2N); 2.43 (m; 4H; piperidin-CH2 (C-2+6)); 1.57 (m; 4H; piperidin-CH2 (C-3+5)); 1.43 (m; 5H; piperidin-CH2 (C-4)+OCH2CH3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH:24]=[CH2:25])[CH2:11][CH2:10][CH:9]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CN(C=[O:30])C>O.Cl.Cl[Cu].Cl[Pd]Cl>[O:21]=[C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:22])[N:12]1[CH:9]1[CH2:8][CH2:7][C:6]([CH2:23][C:24](=[O:30])[CH3:25])([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1
Reactant: C=CCC1(C(=O)OCC)CCC(N2C(=O)c3ccccc3C2=O)CC1
Reactant: CN(C)C=O
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: Cl
Solvent: O
Product: CCOC(=O)C1(CC(C)=O)CCC(N2C(=O)c3ccccc3C2=O)CC1
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of CuCl (147 mg, 1.484 mmol) and PdCl2 (46.1 mg, 0.26 mmol) in DMF (24 ml) and water (4 ml) was stirred under an oxygen (balloon) for 3 hours. A solution of 1-Allyl-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-cyclohexanecarboxylic acid ethyl ester (Intermediate 73, 362 mg, 1.06 mmol) in DMF (16 ml) was added and the mixture was stirred at room temperature for 66 hr under O2. LCMS shows 100% conversion to product and the reaction mixture was diluted with water and 1M HCl, then extracted with ethyl acetate (×3). The organic layers were washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a yellow oil (410 mg, >100%) which was taken to the next step without further purification. LCMS [M+H]=358.3
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[C:18]([OH:26])[CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].[Cl:28]CCl.Cl>C(O)(C)C.C(N(CC)CC)C>[CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[CH:20]=[CH:19][C:18]([OH:26])=[C:17]([CH2:10][N:12]([CH3:24])[CH3:13])[C:16]2=[CH:15][C:14]=1[CH2:13]3)=[O:11].[ClH:28]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(O)ccc3nc2-1
Reactant: ClCCl
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(CN(C)C)c(O)ccc3nc2-1
Reaction time: 0.12 h
Yield: 175.1 %

Procedure:
10-hydroxy-camptothecin (0.1 g), N,N-dimethylmethyleneiminium iodide (about 0.06 g), dichloromethane (about 1.3 g), and isopropanol (about 0.8 g) were charged into a suitable reactor. The resulting mixture was stirred for 5-10 minutes. Then triethylamine (0.002-0.03 g) was added, and the resulting mixture was stirred at room temperature. After the reaction was complete, the mixture of hydrochloride acid (37%, 0.003-0.045 g) and isopropanol (about 0.14 g) was added to the resulting mixture. The resulting mixture was stirred over 4 hours, and then the solid was filtered, washed with dichloromethane (about 1 g) and dried under vacuum to give about 0.11 g of topotecan HCl.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[F:21][CH:22]([F:35])[O:23][C:24]1[CH:31]=[C:30]([CH2:32][CH:33]=O)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]>>[F:21][CH:22]([F:35])[O:23][C:24]1[CH:31]=[C:30]([CH2:32][CH2:33][N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][C:4]3[C:3]([CH3:2])=[C:11]4[C:7](=[CH:6][CH:5]=3)[C:8](=[O:12])[O:9][CH2:10]4)[CH2:16][CH2:17]2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Reactant: N#Cc1ccc(CC=O)cc1OC(F)F
Agent: Cl
Product: Cc1c(CCN2CCN(CCc3ccc(C#N)c(OC(F)F)c3)CC2)ccc2c1COC2=O

Procedure:
2-(Difluoromethoxy)-4-[2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-(difluoromethoxy)-4-(2-oxoethyl)benzonitrile. LC-MS (IE, m/z): 456.5 [M+1]+. (0.16 μM)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:12]Br)=[CH:8][C:9]=1[C:10]#[N:11])=[O:4].O.CC[O:17]C(C)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:12][OH:17])=[CH:8][C:9]=1[C:10]#[N:11])=[O:4]
Reactant: COC(=O)c1sc(CBr)cc1C#N
Reactant: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1sc(CO)cc1C#N
Temperature: 70 °C
Yield: 17 %

Procedure:
A mixture of 5-Bromomethyl-3-cyano-thiophene-2-carboxylic acid methyl ester (0.89 g, 3.42 mmol) and water (15 ml) in THF (2 ml) was heated at 70° C. for 2 d. The reaction mixture was cooled. The reaction mixture was poured into EtOAc (50 ml), washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column (0-40% EtOAc in hexane) to give 0.1114 g (17%) yellow solid product.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([NH:19][C:20](=[O:29])[C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)(=[O:3])[CH3:2].[Br-:30].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:30][CH2:2][C:1]([C:4]1[N:5]=[C:6]([NH:19][C:20](=[O:29])[C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)=[O:3]
Reactant: [Br-]
Reactant: CC(=O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
Into a solution of Compound 84 (132 mg, 0.33 mmol) in THF (10 mL) at 0° C. was added phenyltrimethylammonium tribromide (125 mg, 0.33 mmol). The mixture was stirred at 0° C. for 1 hour, quenched by ice addition, extracted with methylene chloride. The combined extracted was dried (Na2SO4), filtered and concentrated. The residue was purified on silica (eluted with methylene chloride) to give Compound 85 (128 mg, 85%) as a white solid.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:19][S:20][CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:39]OS([O-])=O.[K+]>CO.O>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:10][C:9]=2[CH2:19][S:20]([CH3:21])=[O:39])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S([O-])OO
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(-c3ccccc3)oc2CSC)C2CCCCC2)cc1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(-c3ccccc3)oc2CS(C)=O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{2-[(methylsulfanyl)methyl]-5-phenylfuran-3-yl}methyl)amino]phenyl}carbonyl)amino]propanoate (267 mg) was dissolved in methanol (9 mL) and water (1 mL), OXONE (277 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (40% ethyl acetate/hexane to 100% ethyl acetate/hexane) to give the title compound (196 mg, 79%) as an amorphous compound.