Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([CH2:18][F:19])[CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22][C:23]1[N:28]=[C:27]([N:29]([CH:39]2[CH2:41][CH2:40]2)CC2C=CC(OC)=CC=2)[C:26]2=[N:42][CH:43]=[C:44]([C:45]#[N:46])[N:25]2[N:24]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:15][O:16][CH2:17]3)[CH:10]([CH2:18][F:19])[CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22][C:23]1[N:28]=[C:27]([NH:29][CH:39]2[CH2:40][CH2:41]2)[C:26]2=[N:42][CH:43]=[C:44]([C:45]#[N:46])[N:25]2[N:24]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C5COC5)C(CF)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: COc1ccccc1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCN(C3COC3)C(CF)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(+/−) 2-((2-chloro-5-cyano-3-(3-(fluoromethyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (131 mg, 0.204 mmol) was taken up in DCE (2 mL) and anisole (0.067 mL, 0.611 mmol) was added, followed by TFA (0.314 mL, 4.07 mmol). The reaction was stirred at rt overnight. An additional 40 eq. of TFA was added and the reaction was stirred for 2 h, then an additional 60 eq. of TFA and was added, followed by stirring for 1 h. The solvent was removed in vacuo and the material was dissolved in MeOH. The material was loaded onto an SCX column (5 g, benzenesulfonic acid) and the column was flushed with MeOH, then 1:1 DCM/7N NH3 in MeOH to obtain the product. The solvent was removed in vacuo and the material was dissolved in DMF. A solid precipitated out, which was collected by vacuum filtration and rinsed with MeOH. The solid was suspended in 1 ml of 1:1 CH3CN/H2O and lypholized overnight. (+/−) 2-((2-chloro-5-cyano-3-(3-(fluoromethyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile was obtained as a beige solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:18])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([F:31])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C1(C)C=CC(S([C:46]#[N:47])(=O)=O)=CC=1.[NH4+].[Cl-]>C1COCC1.CCOCC.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:18])=[N:15][C:16]([C:46]#[N:47])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([F:31])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: Cc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nc(C#N)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(F)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A cooled (−78° C.) solution of 8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-1-iodo-3-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (0.666 g; 1.204 mmol) in anhydrous THF (20 ml) was treated dropwise with 1.6M n-BuLi in hexanes (0.76 ml; 1.204 mmol). The resulting reaction mixture was further stirred at −78° C., under nitrogen, for 15 min., and a solution of para-toluenesulfonyl cyanide (0.379 g; 1.987 mmol) in anhydrous THF (5 ml) was then added dropwise. Stirring at −78° C. was continued for 20 min. before aq. sat. NH4Cl (2 ml) was added. The resulting mixture was allowed to warm-up to rt, and water (50 ml), followed by ether (50 ml) were added. The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH, 50/1) afforded 1-cyano-8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-3-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a pale yellow solid (0.271 g; 50%). LC-MS: tR=0.96 min.; [M+H]+=453.31 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[C:19]([O:21]CC)=[O:20])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[C:19]([OH:21])=[O:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnn(-c2ccccc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To a solution of the compound (1.00 g, 3.22 mmol) obtained in step 1 in ethanol (5.0 ml) was added 2N aqueous sodium hydroxide solution (4.70 mL, 9.40 mmol) at room temperature, and the mixture was heated under reflux for 3 hr. The reaction mixture was cooled to room temperature, and 2N hydrochloric acid was added until the mixture became pH 6. The precipitate was collected by filtration with ethyl acetate to give 5-(4-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboxylic acid (852 mg, 94%) as a white powder.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=O)C1C=CC(OC)=CC=1.[CH2:21]([NH2:24])[CH2:22][NH2:23]>>[NH:23]1[CH:10]2[C:5]3[C:4]([C:3](=[O:20])[N:24]2[CH2:21][CH2:22]1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(OC)cc1
Reactant: NCCN
Product: O=C1c2ccccc2C2NCCN12

Procedure:
Condense methyl-o-(p-methoxybenzoyl)benzoate (7 g.) and ethylenediamine (8 ml.) by procedure of Example 1 to obtain 9b-p-methoxyphenyl)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one, m.p. 159° C. (elemental analysis confirms the empirical formula C17H16N2O2), reduce with lithium aluminum hydride, and treat with hydrogen chloride as described in Example 1 to obtain 1,2,3,4,5,6-hexahydro-1-(p-methoxyphenyl)-2,5-benzodiazocine dihydrochloride, m.p. 260° C.
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[NH2:21][C@H:22]([C:25]([OH:27])=[O:26])[CH2:23][SH:24]>>[NH2:21][C@@H:22]([CH2:23][S:24][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1)[C:25]([OH:27])=[O:26]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Product: CC1(c2ccccc2)OC(CC(SC[C@H](N)C(=O)O)c2ccsc2)=CC1=O

Procedure:
Following the procedure of Method C, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with L-cysteine to provide (2R)-2-amino-3-{[2-(5-methyl-4-oxo-5-phenyl-4,5-dihydrofuran-2yl)-1-thien-3-ylethyl]thio}propanoic acid: 1H NMR (DMSO-d6) δ1.50-1.60 (overlapping singlets, 3H), 2.70-3.10 (m, ˜2H), 4.00-4.25 (m, 1H), 4.64 (m, 1H), 5.50-5.57 (overlapping singlets, 1H), 7.12-7.38 (m, 6H), 7.52-7.63 (m, 2H), 8.35 (br s, ˜2H); MS (LR-ESI) m/z 402 (M-H calcd. for C20H20NO4S2 402)
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[CH:22]1([CH2:28][S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>ClCCl>[CH:22]1([CH2:28][S:29]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=3)=[CH:10][CH:11]=2)(=[O:31])=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=S(=O)(Cl)CC1CCCCC1
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)CC1CCCCC1

Procedure:
In analogy to example 25, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with cyclohexyl-methane-sulfonylchloride and dimethylketene-methyltrimethylsilylacetal in dichloromethane to give C-cyclohexyl-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-methanesulfonamide as an off-white solid. MS: 500.9 ([M+NH4]+)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>[OH-].[Na+]>[C:20]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Commercially available 4-aminomethylbenzoic acid (5 g) was dissolved in 1 mol/l aqueous solution of sodium hydroxide (33 ml). Benzylchloroformate (5.2 ml) and 1 mol/l aqueous solution sodium hydroxide (40 ml) were gradually and simultaneously added while stirring at room temperature. After 3 hours, 1 mol/l hydrochloric acid was added to the reaction solution to adjust the pH to 3, and the deposited precipitate was collected by filtration through glass filter G4. The precipitate was washed with water and hexane, and dried under reduced pressure to obtain the title compound (8.162 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C@H:12]2[C@@H:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+].CO.O>O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C@@H:12]([N:15]=[N+:16]=[N-:17])[C@H:10]([OH:11])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2O[C@H]2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](O)C1
Yield: 31.2 %

Procedure:
Heat a mixture of racemic trans-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (0.56 mol, 112 g), sodium azide (1.12 mol, 73.08 g), ammonium chloride (0.56 mol, 30.07 g) and methanol/water (3:1) (1 L) at 65° C. for 16 h. Dilute the reaction mixture with water, extract with dichloromethane, and wash the organic layer with saturated sodium bicarbonate and brine solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Purify the residue on a silica gel column using 6% ethyl acetate in hexanes as eluent to obtain the title compound (42.3 g, 42%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 9H), 1.84 (br s 1H), 1.97-2.01 (m, 1H), 2.74-2.82 (m, 1H), 2.88 (br s, 1H), 3.37-3.40 (m, 1H), 3.50 (br s, 1H), 3.91 (br s, 1H), 4.09 (dd, 1H). ES-MS m/z 143 [M−Boc]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:14]=[C:13]([CH3:15])[C:11]([NH2:12])=[C:10]([CH3:16])[CH:9]=1.C([Li])CCC.CCCCCC.[Br:28][C:29]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][C:30]=1[O:31][C:32]([CH3:37])([CH3:36])[C:33](Cl)=[O:34].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])O.[Na+]>ClCCl.O1CCCC1.C(=O)=O.CC(C)=O.CN(C)C=O>[Br:28][C:29]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][C:30]=1[O:31][C:32]([CH3:37])([CH3:36])[C:33]([NH:12][C:11]1[C:13]([CH3:15])=[CH:14][C:8]([F:7])=[CH:9][C:10]=1[CH3:16])=[O:34]
Reactant: Cc1cc(F)cc(C)c1N
Reactant: CC(C)(Oc1cc([N+](=O)[O-])ccc1Br)C(=O)Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(F)cc(C)c1NC(=O)C(C)(C)Oc1cc([N+](=O)[O-])ccc1Br
Reaction time: 0.08 h

Procedure:
To a solution of the compound obtained in the above step (1) (295 mg) in dichloromethane (10 mL) were added oxalyl chloride (253 μL) and a drop of N,N-dimethylformamide, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give crude 2-(2-bromo-5-nitro-phenoxy)-2-methylpropionyl chloride. To a solution of 4-fluoro-2,6-dimethyl-aniline (149 mg) in tetrahydrofuran (15 mL) was added dropwise 1.6N n-butyl lithium/hexane solution (680 μL) over a period of one minute under cooling in dry ice-acetone bath under argon atmosphere. The mixture was stirred at the same temperature for 5 minutes. Thereto was added quickly a solution of 2-(2-bromo-5-nitrophenoxy)-2-methylpropionyl chloride in tetrahydrofuran (10 mL), and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added an aqueous citric acid solution, and the mixture was basified with an aqueous saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel; solvent; n-hexane/ethyl acetate=19/1→3/1) to give 2-(2-bromo-5-nitro-phenoxy)-N-(4-fluoro-2,6-dimethylphenyl)-2-methylpropionamide (262 mg) as a colorless solid.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8]2[CH2:20][CH2:21][C:22](=[O:23])[C:7]=2[C@@H:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[S:32]([CH3:35])(=[O:34])=[O:33])[NH:5]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>O1CCCC1>[CH3:35][S:32]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:24]=1[CH:6]1[N:5]([S:37]([CH3:36])(=[O:39])=[O:38])[C:4](=[O:3])[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)[C:8]2[CH2:20][CH2:21][C:22](=[O:23])[C:7]1=2)[C:28]#[N:29])(=[O:33])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% in mineral oil, 20 mg, 0.50 mmol) is added to a solution of (S)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 10A, 100 mg, 0.18 mmol based on 85% purity) in tetrahydrofuran (4.0 mL), and the mixture is stirred at room temperature for 20 min Methanesulfonyl chloride (29 μL, 0.38 mmol) is added and the mixture is stirred at room temperature for 2 h. Water is added and the mixture is extracted with dichloromethane. The phases are separated and the organic layer is concentrated under a) reduced pressure. The residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 76 mg; ESI mass spectrum [M+H]+=554; Retention time HPLC: 0.57 min (X012_S01).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:17][CH2:16][CH2:15][C@@:14]2([CH3:18])[C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C@H:19]([CH3:22])[CH2:20][OH:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1.[CH3:31][Si:32]([CH3:50])([CH3:49])[O:33][C:34]([CH3:48])([CH3:47])[C@H:35]([CH3:46])[CH2:36]S(C1C=CC=CC=1)(=O)=O>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Si:1]([O:8][C@H:9]1[CH2:17][CH2:16][CH2:15][C@@:14]2([CH3:18])[C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C@@H:19]([CH:20]([OH:21])[CH2:36][C@@H:35]([CH3:46])[C:34]([CH3:48])([O:33][Si:32]([CH3:50])([CH3:31])[CH3:49])[CH3:47])[CH3:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reactant: C[C@H](CS(=O)(=O)c1ccccc1)C(C)(C)O[Si](C)(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: C[C@H](C(O)C[C@@H](C)C(C)(C)O[Si](C)(C)C)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 10E (200 mg, 0.61 mmol) was dissolved in 2 mL of dichloromethane; 100 mg of 4 Å molecular sieves were added, followed by 15 mg of tetrapropylammonium perruthenate and 75 mg of 4-methylmorpholine N-oxide. The mixture was stirred for 2 hours at ambient temperature, and then filtered through diatomaceous earth to removed solids. The crude product was purified by silica gel chromatography using an Analogix IntelliFlash™ 40, eluting with a gradient of 5% to 30% ethyl acetate in hexanes. The compound of Example 10C (200 mg, 0.63 mmol) was combined with this aldehyde according to the coupling procedure described by Kutner et al. in J. Org. Chem. 1988, 53, 3450-3457. The named product, the result of desulfurization without elimination, was isolated after chromatographic purification using an Analogix Intelliflash 280™, eluting with a gradient of 0% to 50% ethyl acetate in hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:13]=2[Cl:14])=[CH:4][C:3]=1[N+:21]([O-])=O.[Sn]>C(O)C>[NH2:21][C:3]1[CH:4]=[C:5]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:13]=2[Cl:14])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cn1c(C(F)(F)F)cc(Cl)c(-c2ccc(Cl)c([N+](=O)[O-])c2)c1=O
Agent: [Sn]
Solvent: CCO
Product: Cn1c(C(F)(F)F)cc(Cl)c(-c2ccc(Cl)c(N)c2)c1=O
Temperature: 25 °C
Yield: 86.6 %

Procedure:
0.5 g (1.37 mmol) of 3-(4-chloro-3-nitrophenyl)-4-chloro-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 20 ml of ethanol, and 0.8 g (6.78 mmol) of tin was added thereto with stirring at room temperature, followed by stirring for 1 hour. After completion of the reaction, excess ethanol was distilled off under reduced pressure, and ethyl acetate and a saturated sodium hydrogencarbonate aqueous solution were added. The precipitate was collected by filtration and washed with water and a 10% citric acid aqueous solution. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained crude crystals were washed with isopropyl ether to obtain 0.40 g (yield: 87%) of the desired product.
Reaction SMILES: C([N:4]1[C:16]2[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=O)C.[C:18]1([N:24]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]4[C:43]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[NH:37][C:35]4=3)[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Cu]=O>[C:18]1([N:24]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]4[C:43]5[CH:42]=[CH:41][CH:40]=[C:39]([C:8]6[CH:7]=[CH:6][C:5]7[NH:4][C:16]8[C:11]([C:10]=7[CH:9]=6)=[CH:12][CH:13]=[CH:14][CH:15]=8)[C:38]=5[NH:37][C:35]4=3)[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)n1c2ccccc2c2cc(Br)ccc21
Reactant: c1ccc(-n2c3ccccc3c3ccc4c5ccccc5[nH]c4c32)cc1
Agent: O=[Cu]
Product: c1ccc(-n2c3ccccc3c3ccc4c5cccc(-c6ccc7[nH]c8ccccc8c7c6)c5[nH]c4c32)cc1
Temperature: 170 °C
Yield: 84 %

Procedure:
A mixture of 2.0 g of 9-acetyl-3-bromocarbazole prepared as described above and 2.4 g of N-phenylindolo[2,3-a]carbazole (IC-1) were stirred together in 20 ml N,N′-dimethylacetamide. To this was added 0.8 g of copper oxide and heated to 170° C. for 24 h. The reaction was quenched with water and the solid was filtered, washed with methanol, and dried under vacuum. The solid (4.5 g) was then taken up for further deprotection using 0.8 g KOH with THF (4 ml), methanol (8 ml) and water (8 ml) at reflux temperature. The reaction mixture was then extracted using ethylacetate; and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. Subsequent silica gel column chromatography using toluene:hexane (1:2) as eluent, yielded 2.9 g of 3-(N-phenyindolo[2,3-a]carbazolyl)carbazole as a light yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:19]C1C=CC(O)=CC=1>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([I:19])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc(I)cc1
Reactant: Brc1ccc(OCCCCc2ccccc2)cc1
Product: Ic1ccc(OCCCCc2ccccc2)cc1
Yield: 80 %

Procedure:
Using the preparative procedure for 4-(4-phenylbutoxy)bromobenzene, except using 4-iodophenol in place of 4-bromophenol, gave 4-(4phenylbutoxy)iodobenzene in 80% yield.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([O:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[O:26][C:27]=1[CH3:28]>>[CH2:16]([O:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[O:26][C:27]=1[CH3:28])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:20])[CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)OC
Reactant: Cc1ccccc1-c1nc(CCl)c(C)o1
Product: C=CCCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3C)oc2C)c1)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-but-3-enyloxy-3-(1H-indol-5-yl)-propionic acid methyl ester (preparation 9) was reacted with 4-chloromethyl-5-methyl-2-o-tolyl-oxazole to give rac-2-but-3-enyloxy-3-[1-(5-methyl-2-o-tolyl-oxazol-4-ylmethyl)-1H-indol-5-yl]-propionic acid as light brown solid.
Reaction SMILES: [CH2:1]=[C:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12].C[Si](Cl)(C)C.[C:23](Cl)(=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].O.N>N1C=CC=CC=1.O>[CH2:1]=[C:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH:15][C:23](=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:13][C:11]1=[O:12]
Reactant: C=C1[C@H](n2ccc(N)nc2=O)O[C@H](CO)[C@H]1O
Reactant: CCCCCCCCCC(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: c1ccncc1
Solvent: O
Product: C=C1[C@H](n2ccc(NC(=O)CCCCCCCCC)nc2=O)O[C@H](CO)[C@H]1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.6 %

Procedure:
2'-Deoxy-2'-methylidenecytidine, 239 mg, was dissolved in 5 ml of pyridine, and to the solution was added dropwise 0.63 ml of trimethylsilyl chloride under ice cooling. The mixture was stirred at room temperature for 5 minutes and then 0.83 ml of decanoyl chloride was added dropwise to the mixture under ice cooling, followed by stirring at room temperature for 2 hours. After the reaction, 2 ml of water was added to the reaction solution, stirring was conducted at room temperature for 5 minutes, and then 2 ml of concentrated ammonia water was added to the solution, followed by stirring for 15 minutes. After the reaction, the solution was partitioned with chloroform, and the chloroform layer was distilled off under reduced pressure. The residue was treated with a silica gel chromatography (elution solvent-chloroform: methanol=25:1) to give 179 mg of the objective compound as an oleaginous product. Yield: 45.6%
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=1)C>>[Cl:28][C:23]1[CH:22]=[C:21]([CH2:20][CH2:19][C:18]([OH:29])=[O:17])[CH:26]=[CH:25][C:24]=1[O:27][CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Reactant: ClCc1cccnc1SC1CCCC1
Product: O=C(O)CCc1ccc(OCc2cccnc2SC2CCCC2)c(Cl)c1
Yield: 80.5 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (28 mg, 0.13 mmol) obtained in Step C of Preparation Example 8 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (33 mg, 0.14 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (41 mg, 91%).