Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[H-].[Na+].Cl[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][N:19]=1>O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:9][CH:8]=1
Reactant: Fc1cccnc1Cl
Reactant: OCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccnc1OCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
To an N,N-dimethylformamide (15 mL) solution of (4-bromo-phenyl)-methanol (1.56 g, 8.34 mmol) was added sodium hydride (401 mg, 8.35 mmol, 50% in oil), which was stirred for 5 minutes at room temperature. Then, an N,N-dimethylformamide (5 mL) solution of 2-chloro-3-fluoropyridine (967 mg, 7.35 mmol) was added to this mixture, which was stirred for 1 hour and 10 minutes at room temperature. Water was to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (2.03 g, 98%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:22])OCC(Cl)(Cl)Cl)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:23]1([C:29]2[N:33]=[C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[S:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([N:37]3[CH2:38][CH2:39][N:34]([C:32]4[S:31][N:30]=[C:29]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[N:33]=4)[CH2:35][CH2:36]3)=[O:22])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(NC(=O)OCC(Cl)(Cl)Cl)cn2)CC1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(NC(=O)N3CCN(c4nc(-c5ccccc5)ns4)CC3)cn2)CC1
Yield: 10.3 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl [6-(4-methylpiperazin-1-yl)pyridin-3-yl]carbamate (271 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 1 day. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 35.4 mg (10.3%) of the desired product as a solid.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10](O)[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1O)(=[O:3])[CH3:2].[CH3:16][C:17]([NH:19][C@H:20]1[C@H:25]([O:26][C@@H:27]([C@H:32]([OH:40])[C@@H:33]([NH:36][C:37]([CH3:39])=[O:38])[CH:34]=[O:35])[C@H:28]([OH:31])[CH2:29][OH:30])[O:24][C@H:23]([CH2:41][OH:42])[C@@H:22]([OH:43])[C@@H:21]1[OH:44])=[O:18].[CH3:45][C:46]([NH:48][C@H:49]1[C@H:54]([O:55][C@H:56]2[C@H:61]([OH:62])[C@@H:60]([NH:63][C:64]([CH3:66])=[O:65])[C@H:59]([O:67][C@@H:68]([C@H:73]([OH:81])[C@@H:74]([NH:77][C:78]([CH3:80])=[O:79])[CH:75]=[O:76])[C@H:69]([OH:72])[CH2:70][OH:71])[O:58][C@@H:57]2[CH2:82][OH:83])[O:53][C@H:52]([CH2:84][OH:85])[C@@H:51]([OH:86])[C@@H:50]1[OH:87])=[O:47]>O>[CH3:16][C:17]([NH:19][C@H:20]1[C@H:25]([O:26][C@H:27]2[C@H:32]([OH:40])[C@@H:33]([NH:36][C:37]([CH3:39])=[O:38])[C@H:34]([O:35][C@H:10]3[C@H:11]([OH:12])[C@@H:5]([NH:4][C:1]([CH3:2])=[O:3])[C@H:6]([O:86][C@H:51]4[C@H:50]([OH:87])[C@@H:49]([NH:48][C:46]([CH3:45])=[O:47])[C@H:54]([O:55][C@H:56]5[C@H:61]([OH:62])[C@@H:60]([NH:63][C:64]([CH3:66])=[O:65])[C@H:59]([O:67][C@@H:68]([C@H:73]([OH:81])[C@@H:74]([NH:77][C:78]([CH3:80])=[O:79])[CH:75]=[O:76])[C@H:69]([OH:72])[CH2:70][OH:71])[O:58][C@@H:57]5[CH2:82][OH:83])[O:53][C@@H:52]4[CH2:84][OH:85])[O:8][C@@H:9]3[CH2:14][OH:15])[O:31][C@@H:28]2[CH2:29][OH:30])[O:24][C@H:23]([CH2:41][OH:42])[C@@H:22]([OH:43])[C@@H:21]1[OH:44])=[O:18]
Reactant: CC(=O)N[C@H]1[C@H](O[C@@H]([C@H](O)[C@H](C=O)NC(C)=O)[C@H](O)CO)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2NC(C)=O)[C@@H]1O
Reactant: CC(=O)N[C@H]1[C@H](O[C@@H]([C@H](O)[C@H](C=O)NC(C)=O)[C@H](O)CO)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: O
Product: CC(=O)N[C@H]1[C@H](O[C@@H]([C@H](O)[C@H](C=O)NC(C)=O)[C@H](O)CO)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O[C@@H]4O[C@H](CO)[C@@H](O[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5NC(C)=O)[C@H](O)[C@H]4NC(C)=O)[C@H](O)[C@H]3NC(C)=O)[C@H](O)[C@H]2NC(C)=O)[C@@H]1O

Procedure:
The combined effluent fractions were freeze-dried to give 36 g of a solid mixture comprising tetra-N-acetylchitotetraose (NACOS-4), penta-N-acetyl-chitopentaose (NACOS-5) and hexa-N-acetyl-chitohexaose (NACOS-6), together with minor proportions of N-acetylglucosamine, di-N-acetyl-chitobiose, tri-N-acetyl-chitotriose. This mixture comprising the water-soluble chitin-oligomers was then chromatographed by a high pressure liquid chromatography on a column of μ-Bondapack CH (a product of Waters Company, U.S.A.) as eluted with methylnitrile-water (70:30 by volume), to effect the isolation of the chitin-oligomers from each other, affording 3.10 g of hexa-N-acetylchitohexaose having an [α]D of -11.2° and a decomposition temperature of 300° C., 7.6 g of penta-N-acetyl-chitopentaose having an [α]D of -9.0° and a decompsition temperature of 304° C.; and 8.1 g of tetra-N-acetyl-chitotetraose having an [α]D of -4.2° and a decomposition temperature of 299° C.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([Cl:15])=[O:14].[OH-].[NH4+].[OH-].[Na+]>CCOCC.CO.O>[ClH:15].[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([NH:1][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=1[F:10])[CH2:3]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(Cl)c1ccccc1F
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: Cl
Product: O=C(NC1CN2CCC1CC2)c1ccccc1F
Yield: 64.4 %

Procedure:
In a closed system, a solution of 3-aminoquinuclidine (2.52 g, 0.020 mole) in 10 ml anhydrous ether was added dropwise to a stirred solution of 2-fluorobenzoyl chloride (3.13 g, 0.020 mole) in 100 ml anhydrous ether. After the addition was complete, the mixture was stirred another hour and the solid product (as the hydrochloride salt) was collected by filtration under nitrogen to give 4.75 g (84%). TLC analysis (3% conc. ammonium hydroxide in methanol) showed the presence of 3-aminoquinuclidine. The salt was dissolved in 10 ml water, basified with 6N sodium hydroxide solution, and extracted three times with 50 ml portions of methylene chloride. The combined extract was dried over magnesium sulfate and concentrated to give 3.67 g of the product as the free base. Recrystallization from tolueneisooctane gave 2.33 g of a white solid (some toluene insoluble material was removed by decanting the hot toluene solution). The solid free base was dissolved in 10 ml methanol, treated with excess ethereal hydrogen chloride and 100 ml isopropyl ether was added. The salt separated from solution as an oil, but crystallized on trituration. The white solid was collected under nitrogen to give 2.60 g; m.p. 233°-234° C. Mass spectrum (E.I.) m/e (% relative intensity): 248 (15), 125 (13), 123 (100), 109 (80), 96 (24), 95 (45), 84 (14), 75 (19), 70 (64), 42 (44), 41 (18).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][Si](C)(C)C)([CH3:4])([CH3:3])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
A solution of tert-butyl{4-chloro-2-[(trimethylsilyl)ethynyl]phenoxy}acetate (Intermediate 2, 17.70 g; 52.2 mmol) in THF (180 mL) was treated with tetrabutylammonium fluoride trihydrate (16.48 g; 52.2 mmol). The reaction mixture was stirred for 4 hours, then ethyl acetate (450 mL) was added and the organic phase was washed with water (750 mL) then with brine (750 mL), dried over MgSO4, filtered and concentrated under vacuum to give a brown oily residue which was purified by flash chromatography (silica) eluting with cyclohexane containing increasing amounts of ethyl acetate. The title compound was obtained as a brown oil which solidified after prolonged standing.
Reaction SMILES: [C:1]([N:11](C)[C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:20]([C:24]1[CH:25]=[C:26]([CH2:31][CH:32]([NH2:38])[C:33]2[O:34][CH:35]=[N:36][N:37]=2)[CH:27]=[CH:28][C:29]=1[OH:30])([CH3:23])([CH3:22])[CH3:21].O>C1COCC1>[C:20]([C:24]1[CH:25]=[C:26]([CH2:31][CH:32]([NH:38][C:16](=[O:18])[CH:12]([NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH:13]([CH3:14])[CH3:15])[C:33]2[O:34][CH:35]=[N:36][N:37]=2)[CH:27]=[CH:28][C:29]=1[OH:30])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cc(CC(N)c2nnco2)ccc1O
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nnco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of Z-N-Me-Val-OH (914 mg, 3.45 mmol), 2-(3-t-butyl-4-hydroxyphenyl)-1-(1,3,4-oxadiazol-2-yl)ethylamine (0.75 g, 2.87 mmol) and CMPI (881 mg, 3.45 mmol) in THF (30 ml), TEA (0.96 ml) was added under cooling with ice and stirred at room temperature for 2 hours. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1), giving 2-benzyloxycarbonylamino-3-methylbutyric acid 2-(3-t-butyl-4-hydroxyphenyl)-1-(1,3,4-oxadiazol-2-yl)ethylamide (1.28 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][C@@H:12]2[CH3:30])=[O:10])=[CH:4][CH:3]=1.[CH2:31]([NH2:33])[CH3:32].CO>C(O)(C)C>[ClH:1].[CH2:31]([NH:33][C:2]1[CH:3]=[CH:4][C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][C@@H:12]2[CH3:30])=[O:10])=[C:6]([CH3:8])[N:7]=1)[CH3:32]
Reactant: CCN
Reactant: Cc1nc(Cl)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Solvent: CO
Solvent: CC(C)O
Product: CCNc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]2C)c(C)n1
Product: Cl
Temperature: 120 °C
Reaction time: 18 h

Procedure:
(2S)-1-[(6-Chloro-2-methyl-3-pyridinyl)carbonyl]-2-methyl-4-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Example 24) (67 mg, 0.15 mmol) was weighed into a microwave vial, and dissolved in isopropanol (0.7 ml). Ethylamine, 2.0M in methanol (1.5 ml, 3.0 mmol) was added, and the clear solution was heated in the microwave to 120° C. for 6 h with stirring. LCMS analysis showed <20% conversion. The mixture was treated with further ethylamine, 2.0M in methanol (0.75 ml, 1.50 mmol) and returned to the microwave for 18 h at 120° C. with stirring. LCMS analysis showed ˜50% conversion. The reaction mixture was treated with further ethylamine, 2.0M in methanol (1.5 ml, 3.0 mmol), and again heated in the microwave for 18 h at 120° C. with stirring. LCMS now showed adequate conversion, >65%. The reaction mixture was concentrated to give the crude material as a yellow gum (76 mg). This was purified by MDAP to give the free base of the title compound as a pale yellow gum (34 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][C:8](C)=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1C(O)=O.F[C:17](F)(F)[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19].N1C=CC=C[CH:33]=1>>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][C:18]([C:17]2[C:4]([CH3:3])=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[C:10]([CH3:33])[CH:9]=[CH:8][N:7]=3)=[O:19])=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: c1ccncc1
Reactant: Cc1ccc2c(O)c(C(=O)O)cnc2n1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Product: Cc1nc2nccc(C)c2c(O)c1C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of 1 g of 4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylic acid and 25 ml of anhydrous pyridine was heated on an oil bath at 50 to 60°C while stirring. Then, 1.38 g of p-nitrophenyl trifluoroacetate were added thereto and, after the heating was interrupted, stirring was carried out for 2 hours. The precipitated crystals were collected by filtration and washed with ethanol to give 4-hydroxy--methyl--methyl-1,8-naphthyridine-3-carboxylic acid p-nitrophenyl ester as pale yellow crystalline powder melting at 311 to 313°C (decomp.). Yield, 1.2 g. IR νC=0 1700 cm-1 ; νNO2 1520 cm-1, 1345 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:23][CH3:24])=[C:11]([CH:13]3[C:19](=[O:20])[CH:18]4[CH2:21][CH:15]([CH2:16][CH2:17]4)[C:14]3=[O:22])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:23][CH3:24])=[C:11]([C:13]3[C:14](=[O:22])[CH:15]4[CH2:21][CH:18]([CH2:17][CH2:16]4)[C:19]=3[O:20][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)C2CCC(C2)C1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1sc(-c2ccc(Cl)cc2)nc1C1=C(OC(=O)C(C)(C)C)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of the 3-[2-(4-chlorophenyl)-5-ethylthiazol-4-yl]bicyclo[3.2.1]octane-2,4-dione (100 mg, 0.28 mmol) in dichloromethane (5 ml) and triethylamine (140 μl, 1 mmol) is added pivaloyl chloride (123 μl, 1 mmol) at room temperature. The reaction mixture is stirred overnight at room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 2,2-dimethylpropionic acid 3-[2-(4-chlorophenyl)-5-ethylthiazol-4-yl]-4-oxobicyclo[3.2.1]oct-2-en-2-yl ester (101 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[CH:17](O)=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:17]=[O:18]
Reactant: O=CO
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=CNc1ccccc1-c1cc2ccccc2[nH]1

Procedure:
To a solution prepared from 20 g of 2-(2-aminophenyl)indole, 12.7 ml of formic acid and 500 ml of THF was added 26 g of dicyclohexyl carbodiimide at room temperature under N2. The resultant solution was stirred overnight at room temperature. The mixture was then filtered and the filtrate washed with aqueous NaHCO3 (2x), H2O and saturated NaCl solution and dried (MgSO4). Concentration gave a red oil which was purified by HPLC, using 1% EtOAc/CH2Cl2 as an eluent, to afford 11.45 g of solid, m.p. 147°-149° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[C:9]([C:11]1[NH:12][C:13]([CH2:16][CH2:17][CH3:18])=[CH:14][CH:15]=1)=O)([O-])=O.Br[CH2:23][CH2:24][CH3:25].C[N:27](C)[CH:28]=[O:29]>>[CH2:23]([N:12]1[C:13]([CH2:16][CH2:17][CH3:18])=[CH:14][CH:15]=[C:11]1[CH2:9][C:8]1[CH:19]=[CH:20][CH:21]=[C:6]([NH:3][C:28]([NH2:27])=[O:29])[CH:7]=1)[CH2:24][CH3:25]
Reactant: CCCc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)[nH]1
Reactant: CCCBr
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCCc1ccc(Cc2cccc(NC(N)=O)c2)n1CCC
Yield: 98 %

Procedure:
2.5 g (100 mmol) of 50% sodium hydride were suspended, under nitrogen atmosphere, in 150 ml of anhydrous dimethylformamide. A solution of 11.5 g (44 mmol) of 2-(3'-nitrobenzoyl)-5-propylpyrrole in 50 ml of anhydrous dimethylformamide was added thereto, in a dropwise fashion and under stirring. The resulting mixture was stirred at room temperature for an additional hour and then 10 ml (110 mmol) of 1-bromopropane was added. The reaction mixture was stirred at room temperature for 48 hours, and thereafter poured into 500 ml of ice-ethyl acetate. The organic phase was separated. The aqueous phase was extracted with more ethyl acetate (2×500 ml), and the combined orgainc extracts were washed with water (5×300 ml), dried and evaporated in vacuo. Purification of the residue by column chromatography on 500 g of silica gel, using hexane-acetone (90:10) as eluant provided 13.9 g (98%) of the title compound, 1,5-dipropyl-2-(3'-nitrobenzoyl)pyrrole, as an oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:23].C(C(C(C)C)([NH-])C)(C)C.[Li+].C([C:36]([O:38][CH3:39])=[O:37])#N>O1CCCC1>[CH3:13][C:14]1([C:36]([O:38][CH3:39])=[O:37])[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:23]
Reactant: COC(=O)C#N
Reactant: CC1Cc2ccccc2C1=O
Agent: CC(C)C(C)([NH-])C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(C)Cc2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
To a flask cooled at 0 degrees Centigrade containing diisopropylamine (2.06 mL, 14.58 mmol) in tetrahydrofuran (14 mL) was added dropwise over 15 minutes a solution of n-butyl lithium (5.55 mL of 2.5 M in hexanes, 14.58 mmol). This mixture was stirred for 30 min. A second flask containing the 2-methyl-1-indanone (2.03 g, 13.89 mmol) in tetrahydrofuran (10 mL) was cooled to −78 degrees Centigrade under N2. The freshly prepared lithium diisopropylethylamide was cooled to −78 degrees centigrade and added drop wise via cannula. The orangish mixture became somewhat heterogeneous over 30 minutes and then neat methyl cyanoformate (1.32 mL, 16.66 mmol) was added and the reaction mixture stirred an additional 40 minutes while allowing the reaction to warm to −20 degrees centigrade. The reaction was quenched with saturated aqueous NH4Cl solution and the organics extracted 2×25 mL diethyl ether, washed one time in brine, then dried (Na2SO4), filtered and concentrated to give methyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate. No further purification was necessary.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16](Cl)=[O:17])=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH:19]([N:22]([CH:25]([CH3:27])C)CC)([CH3:21])C.N1CCCC1>C(#N)C>[N:22]1([C:16]([C:12]2[CH:13]=[CH:14][C:15]3[C:2](=[O:1])[C:3]4[C:8]([O:9][C:10]=3[CH:11]=2)=[CH:7][CH:6]=[CH:5][CH:4]=4)=[O:17])[CH2:19][CH2:21][CH2:27][CH2:25]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1ccc2c(=O)c3ccccc3oc2c1
Solvent: CC#N
Solvent: C1CCNC1
Product: O=C(c1ccc2c(=O)c3ccccc3oc2c1)N1CCCC1
Reaction time: 2 h

Procedure:
9-oxo-9H-xanthene-3-carboxylic acid (9 g, 37.4 mmol) was added to thionyl chloride (28 mL, 334 mmol). The mixture was refluxed for 5 h. At that time, the thionyl chloride was removed under vacuum and the remaining residue was diluted with toluene and concentrated to dryness to give 9-oxo-9H-xanthene-3-carbonyl chloride. A portion of 9-oxo-9H-xanthene-3-carbonyl chloride (0.25 g, 0.96 mmol) was dissolved in acetonitrile (7 mL). Diisopropylethylamine (335 μL, 1.9 mmol) was then added to the mixture with the subsequent addition of pyrrolidine (113 μL, 1.3 mmol). After stirring 2 h, the solvent was concentrated and the residue was purified by reverse phase preparative HPLC, using a gradient of acetonitrile (10%- 90%) in water with trifluoroacetic acid (0.1%) to afford the 3-(pyrrolidine-1-carbonyl)-xanthen-9-one. MS m/z (MH+) 294.1.
Reaction SMILES: S(=O)(=O)(O)O.C(O)(=O)C.C(OC([CH:15](C(OCC)=O)[C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[N:20]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[N:19]=1)=[O:17])=O)C>O>[C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[N:20]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[N:19]=1)(=[O:17])[CH3:15]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)n1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)n1

Procedure:
A mixture of sulfuric acid (3.9 ml), acetic acid (23.6 ml) and water (19.6 ml) was added to 3-bis(ethoxycarbonyl)acetyl-1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole. The mixture was refluxed for 5 hours and concentrated. The residue was dissolved in ethyl acetate, and the solution was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (150 g) eluting with a mixture of chloroform and ethyl acetate (3:1) to give pale brown crystals of 3-acetyl-1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (4.2 g).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=5)[C:22]([C:30]#[N:31])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].S([O-])(=O)(=O)C.[C:37](=[O:40])([O-])[O-].[K+].[K+].Cl.CN(C)[CH:46]=[O:47]>O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH2:2][C:1]([C:37]([O:47][CH3:46])=[O:40])([CH3:4])[CH3:3])=[CH:26][CH:27]=5)[C:22]([C:30]#[N:31])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(C#N)c5cc(O)ccc54)ccc3o2)n1
Agent: CS(=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COC(=O)C(C)(C)COc1ccc2c(c1)c(C#N)cn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1

Procedure:
Methansulfonyl chloride (0.13 ml) was added to the solution of methyl 3-hydroxy-2,2-dimethylpropionate (0.13 g) and triethylamine (0.28 ml) in dichloromethane over 20 minutes at -40° C. After 1 hour, the reaction mixture was allowed to warm to room temperature and concentrated under reduced pressure. The residue was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate, and the ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give the corresponding mesylate (0.21 g). A mixture of 1-{[2-(4-tert-butylthiazol-2-yl]benzofuran-5-yl]methyl}-5-hydroxyindole-3-carbonitrile (0.35 g), the mesylate (0.21 g) and potassium carbonate (0.23 g) in N,N-dimethylformamide (5 ml) was stirred at 100° C. for 20 hours. After cooling, the reaction mixture was poured into water and made acidic with diluted hydrochloric acid. The resulting precipitates were collected by filtration and washed with water and subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and toluene. The fractions containing the objective compounds were combined and concentrated under reduced pressure to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(2-methoxycarbonyl-2-methylpropoxy)indole-3-carbonitrile (0.18 g).