Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:29][NH:30][CH3:31]>>[CH3:29][N:30]([CH3:31])[CH2:21][CH2:20][CH2:19][CH2:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:27])[F:1])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: CNC
Reactant: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: CN(C)CCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1; Methanesulfonic acid 4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and Dimethylamine were converted to yield Dimethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-amine as yellow oil, MS: 379 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:69])[NH:10][CH:11]([C:37](=[O:68])[N:38]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[CH:56][CH:55]=1)[CH2:39][C:40](=[O:52])[NH:41][CH2:42][C:43]([CH3:51])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH3:44])[CH2:12][C:13]1[N:14](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:15]=[N:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>O>[CH2:1]([O:8][C:9](=[O:69])[NH:10][C@H:11]([C:37](=[O:68])[N:38]([CH2:53][C:54]1[CH:55]=[CH:56][C:57]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[CH:58][CH:59]=1)[CH2:39][C:40](=[O:52])[NH:41][CH2:42][C:43]([CH3:51])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH3:44])[CH2:12][C:13]1[NH:14][CH:15]=[N:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CNC(=O)CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)C(Cc1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCc1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(CNC(=O)CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@H](Cc1cnc[nH]1)NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
To a solution of the trityl compound from Step 5 (2.25 g, 2.4 mmol) was added glacial acetic acid (20 mL) and water (5 mL). The mixture was stirred at 90° C. for 30 minutes, then cooled and concentrated. The residue was taken up in ethyl acetate. The organic solution was washed twice with saturated NaHCO3, brine, and dried over MgSO4. The solution was concentrated and the compound purified by flash chromatography (0%-8% methanol in methylene chloride) to give the title compound (1.5 g, 2.2 mmol, 93%) as a white foam; ES-MS 674 (m+1).
Reaction SMILES: [CH2:1]([CH:8]([CH:14]([OH:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH2:1]([CH:8]([CH:14]([O:16][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)O
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C(Cc1ccccc1)C(C)OC(=O)c1ccccc1
Yield: 85 %

Procedure:
A mixture of 0.04 mol of ethyl 2-benzyl-3-hydroxybutyrate, 0.045 mol of pyridine, 0.05 mol of benzoyl chloride and 40 ml of dried tetrahydrofuran (THF) was refluxed by heating for 8 hrs, and then was allowed to react at room temperature for further 12 hrs. Upon the completion of the reaction, the reaction mixture was filtered, and the solid component was wished with diethyl ether for three times. The organic phases were combined, wished well with saturated saline, and then dried over anhydrous sodium sulfate. After removing the solvent, residue was subjected to column chromatography to give a colorless liquid. Yield 85%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]1[C:20]([N:21]3[CH2:25][CH2:24][CH2:23][C@@H:22]3[CH3:26])=[N:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:27]([O:29]C)=[O:28])[CH:17]=3)[N:12]=1)=[CH:6][CH:5]=2.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]1[C:20]([N:21]3[CH2:25][CH2:24][CH2:23][C@@H:22]3[CH3:26])=[N:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:27]([OH:29])=[O:28])[CH:17]=3)[N:12]=1)=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2cc(-c3nc4ccc(C(=O)O)cc4nc3N3CCC[C@@H]3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To a solution of methyl 2-(2-methyl-1H-indol-5-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (140 mg, 0.35 mmol) in methanol (30 mL) and water (2 mL) was added sodium hydroxide (56 mg, 1.40 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL) and adjusted to pH 5 with acetic acid. The solids were collected by filtration to afford 2-(2-methyl-1H-indol-5-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylic acid as a light yellow solid (100 mg, 74%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[N:7]=1.[CH3:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][C:36]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:33])[C:26]=1[N:21]1[C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]4[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]4)[CH2:10][CH2:9]3)[N:7]=[C:2]([C:36]3[CH:37]=[C:38]([CH:42]=[CH:43][C:35]=3[CH3:34])[C:39]([OH:41])=[O:40])[C:3]=2[CH:24]=[CH:23][C:22]1=[O:25]
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC1CCN(C2CCN(c3nc(Cl)c4ccc(=O)n(-c5c(F)cccc5F)c4n3)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 150 °C
Yield: 68 %

Procedure:
To the compound 4-chloro-8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (47.5 mg, 0.1 mmol) in dioxane (3 mL) and water (1 mL) were added 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (38.4 mg, 0.15 mol), potassium carbonate (83 mg, 0.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.6 mL, 0.005 mmol). The mixture was heated with microwave at about 150° C. for about 15 min. The mixture was concentrated & then mixed with DMSO (0.75 mL) and water (0.25 mL). Separation by HPLC afforded the title compound (39 mg, 68%). LC-MS m/z 574 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]([NH2:18])([CH3:17])[CH3:16]>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:18][CH:15]([CH3:17])[CH3:16])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)N
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(C)C)c([N+](=O)[O-])c1
Yield: 81.4 %

Procedure:
4-Isopropylamino-3-nitro-benzoic acid methyl ester (900.0 mg) was prepared by following General Procedure A starting from methyl 4-chloro-3-nitrobenzoate (1.0 g) and isopropyl amine (325.0 mg) in DMF (10.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: O.[C:2]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:5])[CH:3]=[O:4].O.[O:18]=[C:19]1[CH:26]2[CH:21]([CH2:22][CH:23]=[CH:24][CH2:25]2)[NH:20]1>C1C=CC=CC=1>[OH:4][CH:3]([N:20]1[C:19](=[O:18])[CH:26]2[CH:21]1[CH2:22][CH:23]=[CH:24][CH2:25]2)[C:2]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5]
Reactant: O=CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C1NC2CC=CCC12
Solvent: c1ccccc1
Solvent: O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C(O)N1C(=O)C2CC=CCC21
Reaction time: 3.5 h

Procedure:
p-Nitrobenzyl glyoxylate hydrate (9.08 g) was refluxed in benzene (150 ml) with provision for the removal of water. After 1 hour 8-oxo-7-azabicyclo[4.2.0]oct-3-ene (1) (2.46 g) was added and refluxing continued for 3.5 hours. The cooled solution was washed with water (x 2), then brine. After back extraction of the first aqueous extract with ethyl acetate, the organic solutions were dried over magnesium sulphate, filtered combined, and evaporated. Chromatography on silica, eluting with ethyl acetate-petroleum ether mixtures gave two separate isomers of the alcohol (54) (43%). Less polar isomer I m.p. 153-5° (crystalline plates ex ethyl acetate/ether), νmax (CHCl3) 3400 (broad), 1760, 1745, 1520, 1350 cm-1. δ ppm (CDCl3) 1.90-2.83 (4H, m, 2-CH2), 3.23-3.55 (1H, m, β-lactam proton), 4.00-4.20 (1H, m, β-lactam proton), 4.27 (1H, d, J 8 Hz, exchangeable with D2O, OH), 5.33 (2H, s, CH2Ar)-obscuring 1H, CHOH; 5.67-5.88 (2H, m, CH=CH), 7.55 (2H, d, J 8.5 Hz, Ar), 8.23 (2H, d, J 8.5 Hz, Ar) (Found: C, 58.07; H, 5.15; N, 8.51%, C16H16N2O6 requires C, 57.83; H, 4.85; N, 8.43%). More polar isomer II m.p. 118°-120° (fine crystalline needles ex ethyl acetate/ether). νmax (CHCl3) 3400 (broad), 1760-1745, 1520, 1350 cm-1. δ ppm (CDCl3) 1.83-2.77 (4H, m, 2-CH2), 3.25-3.55 (1H, m, β-lactam proton), 4.02-4.37 (2H, m, β-lactam proton and CHOH, -OH exchangeable with D2O), 5.31-5.98 [5H, 5.35 (2H, s, CH2Ar), obscuring, 1H, which sharpens to s, at δ 5.40 on D2O exchange, CHOH, and 2H, m, CH=CH], 7.56 (2H, d, J 8 Hz, Ar), 8.23 (2H, d, J 8 Hz, Ar) (Found: C, 57.95; H, 4.95; N, 8.50%. C16H16N2O6 requires C, 57.83; H, 4.85; N, 8.43%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1)=[O:2].FC(F)(F)C([O-])=O.[Tl+3].FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[I-:35].[Na+]>FC(F)(F)C(O)=O.O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:7]([I:35])[CH:8]=1)=[O:2]
Reactant: [I-]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Agent: [Tl+3]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(C=O)cc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(4-formyl-phenyl)-acetamide (1.25 g, 7.67 mmol) in trifluoroacetic acid (70 mL) was slowly added thallium(III)trifluoroacetate (5.00 g, 9.20 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Then, a solution of sodium iodide (1.19 g, 7.95 mmol) in water (10 mL) was added slowly. The color changed to dark purple and a lot of solid was formed. Stirring continued at room temperature for 16 hours. Solvent was evaporated to half of the volume, and water (50 mL) was added. The pH was adjusted to approximately 13 with 4 N NaOH solution. The mixture was extracted with ethyl acetate (2×100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated on a rotary evaporator. The solid obtained was washed with ethyl acetate (2×5 mL), ether (2×10 mL), and dried under vacuum to give N-(4-formyl-2-iodo-phenyl)-acetamide as an off-white solid. Yield: 0.760 g (34%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16]3[C:28]4[NH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:20]=4[C:19]4[C:37](=[O:41])[NH:38][C:39](=[O:40])[C:18]=4[C:17]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:44]([O:51][CH2:52]Cl)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C.O>[CH2:44]([O:51][CH2:52][N:38]1[C:39](=[O:40])[C:18]2[C:17]3[C:13]4[C:14](=[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:10]=[CH:11][CH:12]=4)[NH:15][C:16]=3[C:28]3[NH:27][C:26]4[C:25]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:24][CH:23]=[CH:22][C:21]=4[C:20]=3[C:19]=2[C:37]1=[O:41])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: ClCOCc1ccccc1
Reactant: O=C1NC(=O)c2c1c1c3cccc(OCc4ccccc4)c3[nH]c1c1[nH]c3c(OCc4ccccc4)cccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2c(c3c4cccc(OCc5ccccc5)c4[nH]c3c3[nH]c4c(OCc5ccccc5)cccc4c23)C(=O)N1COCc1ccccc1
Yield: 61.7 %

Procedure:
143.8 mg of 1,11-dibenzyloxy-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione was dissolved in 50 ml of DMF, 128.8 mg of 60% oily sodium hydride (NaH) was added, 36.5 μl of benzyloxymethyl chloride was gradually added under ice cooling over a period of 10 minutes, and the mixture was subjected to reaction at 0° C. for further 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate, the ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Kiezel gel 60; eluted with chloroform) to give the desired 6-benzyloxymethyl-1,11-dibenzyloxy-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (yield: 61.7%).
Reaction SMILES: [N:1]([CH2:4][C:5](=[O:28])[NH:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N+:2]=[N-:3].[CH2:29]([O:32][C:33]1[CH:45]=[CH:44][C:36]2[N:37]=[C:38]([S:40]([NH2:43])(=[O:42])=[O:41])[S:39][C:35]=2[CH:34]=1)[C:30]#[CH:31].CCN(C(C)C)C(C)C>[Cu]I.C1COCC1>[O:28]=[C:5]([NH:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:4][N:1]1[CH:31]=[C:30]([CH2:29][O:32][C:33]2[CH:45]=[CH:44][C:36]3[N:37]=[C:38]([S:40](=[O:42])(=[O:41])[NH2:43])[S:39][C:35]=3[CH:34]=2)[N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)NCCCOCCOCCOCCCNC(=O)CN=[N+]=[N-]
Reactant: C#CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCOCCOCCOCCCNC(=O)Cn1cc(COc2ccc3nc(S(N)(=O)=O)sc3c2)nn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a 25 mL round bottomed flask equipped with a magnetic stir bar, rubber septum, and argon inlet containing tert-butyl 1-azido-2-oxo-7,10,13-trioxa-3-azahexadecan-16-ylcarbamate (130 mg, 0.36 mmol), 6-(prop-2-ynyloxy)benzo[d]thiazole-2-sulfonamide (Alkyne, 107 mg, 0.4 mmol), CuI (6.9 mg, 0.036 mmol), and THF (3 mL) was added DIPEA (52 mg, 0.4 mmol). The mixture was stirred at rt for 15 h and concentrated. The crude material was purified with silical chromatography (gradient 10% to 90% EtOAc in hexane) to afford compound 142 as a clear wax (125 mg, 52%). MS (ESI) m/z 694(M+Na+).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]([CH3:49])[C:40](=[O:48])[CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:45]3[CH2:44][CH2:43][N:42]([CH2:41][C:40]([N:39]([CH3:49])[CH3:38])=[O:48])[CH2:47][CH2:46]3)=[O:36])[C:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C:17]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C36H46N7O3Cl2 [(M+H)+] 694.3034, observed 694.3035.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([NH2:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[C:1]1([CH2:7][CH2:8][NH:20][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCc1ccccc1
Reactant: Nc1cccc2ccccc12
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: c1ccc(CCNc2cccc3ccccc23)cc1
Temperature: 210 °C
Yield: 85 %

Procedure:
122 parts of phenylethyl alcohol, 250 parts of α-naphthylamine and 10 parts of triphenyl phosphite are mixed and heated to 210° C. The elimination of water commences at this temperature. The mixture is heated to an internal temperature of 245° C in the course of 12 hours, after which the elimination of water has ended (33 parts of water). After removing excess amine and alcohol under reduced pressure, the N-(2'-phenylethyl)-1-naphthylamine distils at 225° - 230° C/5 mm Hg. 210 parts of N-(2'-phenylethyl)-1-naphthylamine (85% of theory) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+]([O-])=O)[CH:9]=1)=[O:7].C1(OC)C(=CC=CC=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].[N+:36](C1C=CC(C(Cl)=O)=CC=1)([O-:38])=[O:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([N+:36]([O-:38])=[O:37])=[CH:12][CH:13]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1OC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1OC
Product: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1OC

Procedure:
3,4-Dimethoxy-4'-nitrobenzophenone was prepared analogously to 3,4-dimethoxy-3'-nitrobenzophenone using veratrole (3.8 mL, 30 mmol), aluminum chloride (4.4 g, 33 mmol) and 4-nitrobenzoyl chloride (5.7 g, 30 mmol) with a reaction time of 48 hours at reflux. The crude mixture was purified by flash column chromatography (silica gel, 4% ethyl acetate/methylene chloride) to afford 1.69 g (78%) of the product as a white solid: mp 172-173° C.; 1H NMR (CDCl3) δ 8.43-8.31 (m, 2 H), 7.97-7.86 (m, 2 H), 7.55-7.46 (m, 1 H), 7.40-7.30 (m, 1 H), 7.00-6.89 (m, 1 H), 3.99 (s, 3 H), 3.96 (s, 3 H), 13C NMR (CDCl3) δ 193.4, 153.8, 149.4, 149.3, 143.8, 130.2, 130.0, 125.8, 123.4, 111.7, 109.9, 56.1, 56.0; Anal. Calcd for C15H13NO5. Theoretical: C, 62.72; H, 4.56; N, 4.88. Found: C, 62.49; H, 4.68; N, 4.86.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[OH:9][CH:10]1[CH2:14][CH2:13][C:12](=O)[C:11]1([CH3:17])[CH3:16].Cl>C(O)C.O>[OH:9][CH:10]1[CH2:14][CH2:13][C:12](=[N:7][OH:8])[C:11]1([CH3:17])[CH3:16]
Reactant: CC1(C)C(=O)CCC1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)C(=NO)CCC1O
Temperature: 25 °C
Yield: 92.1 %

Procedure:
Sodium acetate (3.58 g, 43.7 mmol) and hydroxylamine hydrochloride (2.85 g, 41.0 mmol) were added to a solution of 3-hydroxy-2,2-dimethylcyclopentanone (3.50 g, 27.3 mmol, from Step 1) in ethanol (50 mL) and water (10 mL). The resultant mixture was heated to 80° C. for 15 h, cooled to room temperature and acidified to pH 2-3 with 1 N hydrochloric acid. After removal of ethanol in vacuo, the aqueous residue was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated, to give 3-hydroxy-2,2-dimethylcyclopentanone oxime (3.60 g, 92% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 3.76 (1 H, t, J=6.16 Hz), 2.51-2.80 (1 H, m), 2.32-2.53 (1 H, m), 1.91-2.16 (1 H, m), 1.58-1.81 (1 H, m), 0.92-1.13 (6 H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[O:10]1[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][C:12]([C:20](O)=O)=[N:11]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:20]([C:12]3[CH2:13][C:14]4([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]4)[O:10][N:11]=3)=[N:9][C:4]=2[CH:3]=1
Reactant: O=C(O)C1=NOC2(CCCCC2)C1
Reactant: Nc1ccc(Br)cc1N
Product: Brc1ccc2[nH]c(C3=NOC4(CCCCC4)C3)nc2c1

Procedure:
The title compound was prepared from 4-bromo-benzene-1,2-diamine and 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (as prepared in Example 1, step B) according to the procedures described in Example 1, steps F and G. 1H-NMR (400 MHz, d4-MeOH) δ: 7.74 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.40 (dd, J=8.6, 1.8 Hz, 1H), 3.25 (s, 2H), 1.69-1.87 (m, 6H), 1.45-1.63 (m, 4H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2c1ccn2C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)n1ccc2c(O)cccc21
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 70.5 %

Procedure:
A solution of 10 (28.62 g, 75 mmol) in tetrahydrofuran (375 mL) containing acetic acid (4.5 g, 75 mmol) was treated at 0° C. with 1 M tetrabutylammonium fluoride (75 mL, 75 mmol) and the mixture was stirred at 0° C. for 40 min. The solvent was evaporated and the residue was dissolved in diethyl ether (250 mL) and washed with saturated aq. sodium bicarbonate and brine, dried and evaporated to give a brown solid which was washed with cold hexanes to give 11 as white fluffy needles (14.13 g, 70%), mp 118-120° C. (from dichloromethane-hexanes), (lit.11 mp 121-124° C.).
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:14]2[C:15]([C:22]([O:24]C)=O)=[C:16]([CH3:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=O)=[CH:7][C:6]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([O:34][CH3:35])[CH2:30][CH2:29]1)=[O:27]>C(O)(=O)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:14]3[C:15](=[C:16]([CH3:21])[N:17]([CH3:20])[C:18]=3[CH3:19])[C:22](=[O:24])[NH:2][N:3]=2)=[CH:7][C:6]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([O:34][CH3:35])[CH2:30][CH2:29]1)=[O:27]
Reactant: COC(=O)c1c(C(=O)Cc2ccc(F)c(C(=O)N3CCC(OC)CC3)c2)c(C)n(C)c1C
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c(C)n(C)c(C)c34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 5.5 %

Procedure:
Hydrazine hydrate (0.014 mL, 0.19 mmol) was added to methyl 4-(2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetyl)-1,2,5-trimethyl-1H-pyrrole-3-carboxylate (59) (0.076 g, 0.17 mmol) in acetic acid (4 mL). The resulting solution was stirred at room temperature for 2 days. The resulting mixture was evaporated to dryness and the residue was azeotroped with toluene to afford crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (4.00 mg, 5.49% yield); m/z (LC-MS, ESI+), RT=1.60 min (M+H=427.11).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N[C:32](=[O:50])[C:33]2C=CC=NC=2NC2CC(C)(C)NC(C)(C)C2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([CH2:33][CH2:32][OH:50])[CH2:18]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(Nc2ncccc2C(=O)Nc2cccc(Cl)c2)CC(C)(C)N1
Reactant: O=C(Nc1cccc(Cl)c1)c1cccnc1N[C@H]1CCCNC1
Product: O=C(Nc1cccc(Cl)c1)c1cccnc1N[C@H]1CCCN(CCO)C1
Yield: 60.8 %

Procedure:
The title compound was prepared in the same manner as in Example 21, with the exception that (S)—N-(3-chlorophenyl)-2-(3-piperidylamino)nicotinamide of Example 20-B, instead of N-(3-chlorophenyl)-2-(2,2,6,6-tetramethylpiperidin-4-ylamino)nicotinamide, was used in the same molar amount (Yield: 60.8%). 1H NMR (CDCl3) δ 8.50 (br, 1H), 8.22 (d, 1H), 7.97 (s, 1H), 7.73 (d, 1H), 7.61 (s, 1H), 7.45 (d, 1H), 7.25 (t, 1H), 7.09 (d, 1H), 6.53-6.47 (m, 1H), 4.33 (br, 1H), 3.61 (t, 2H), 2.76-2.45 (m, 6H), 1.85-1.58 (m, 4H) ppm.