Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]([CH2:14][CH:15]([O:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:16])[CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:44]=[C:45]=[O:46])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>N1C=CC=CC=1>[C:1]([O:9][CH2:10][CH:11]([CH2:14][CH:15]([O:17][C:18](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:16])[CH2:12][O:13][C:45](=[O:46])[NH:44][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: CC(CC(CO)COC(=O)c1ccccc1)OC(=O)c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COC(=O)c1ccccc1)CC(C)OC(=O)c1ccccc1
Temperature: 70 °C
Yield: 91.1 %

Procedure:
A mixture of 3.70 g (11.2 mM) of 2-(2-benzoyloxypropan-1-yl)-3-hydroxypropyl benzoate m5 and 4.964 g (16.8 mM) of octadecyl isocyanate in 74 ml of pyridine is heated at 70° C. for 15 hours and the solvent is evaporated. To the residue with cooling, is added 2N aqueous hydrochloric acid and the product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated. Purification of the product by column silica gel chromatography using n-hexane-ethyl acetate (1:1) as an eluent gives 6.28 g (87.8% yield) of the titled compound m6.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26](OC)=[O:27])[CH:21]=[CH:22][C:23]=1[F:24].[H-].[Na+].CCOC(C)=O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[CH2:15][C:26](=[O:27])[CH2:25][C:20]2[CH:21]=[CH:22][C:23]([F:24])=[C:18]([F:17])[CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: COC(=O)Cc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CC(=O)C1CCN(Cc2ccccc2)CC1)Cc1ccc(F)c(F)c1
Yield: 67 %

Procedure:
The title compound was prepared in 67% yield from 2.18 g 1-benzyl-4-acetylpiperidine from the last step, 5.58 g methyl 3,4-difluorophenylacetate from Fisher esterification, and 0.8 g 60% NaH in 15 mL anhydrous THF using a procedure similar to that described in Example 1, Step A Method B. RF: 0.28 (15% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3): δ7.32˜7.35 (m, 4H), 7.26˜7.30 (m, 1H), 7.06˜7.15 (m, 3H), 6.95˜6.98 (m, 1H), 5.47 (s, 1H), 3.57 (s, 2H), 3.54 (br s, 2H), 2.96 (br d, 11.5 Hz, 2H), 2.17˜2.21 (m, 1H), 2.02˜2.10 (m, 2H), 1.70˜1.83 (m, 4H).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].[CH3:20]C([N-]C(C)C)C.CI>C1COCC1>[CH3:20][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of O1-tert-butyl O4-ethyl piperidine-1,4-dicarboxylate (1.5 g, 5.84 mmol) in THF (25 mL) was cooled to −78° C. followed by dropwise addition of LDA (1.80 M in THF, 6.5 mL, 11.68 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 45 min followed by addition of methyl iodide (1.2 mL, 17.52 mmol). The temperature was slowly raised up to RT and left at RT for 6 h. The reaction was cooled to 0° C. and quenched by the dropwise addition of saturated NH4Cl solution (50 mL). The reaction was extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by chromatography on silica eluting with 2% EtOAc in hexane gave i (1.0 g, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:6][CH2:7][C:8]([NH:10][NH:11][C:12]([C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=O)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:6][CH2:7][C:8]1[S:40][C:12]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:11][N:10]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(OCC(=O)NNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Solvent: Cc1ccccc1
Product: COc1ccc(OCc2nnc([C@@H]3CCCN3C(=O)OC(C)(C)C)s2)cc1OC
Temperature: 90 °C
Reaction time: 6 h
Yield: 54.1 %

Procedure:
To a toluene (30 ml) solution of the compound (540 mg) obtained in Example 8-(1), Lawesson's reagent (750 mg) was added and the mixture was stirred at 90° C. for 6 hours. After adding water, extraction was conducted with AcOEt. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (AcOEt/hexane) to give the titled compound (291 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=[C:6]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:5]=1.[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH3:31])[N:30]=1)[C:25](O)=[O:26])=[O:21]>>[CH3:2][O:3][C:4]1[C:9]([CH2:10][NH:11][C:25]([C:24]2[CH:28]=[C:29]([CH3:31])[N:30]=[C:22]([C:20]([O:19][CH3:18])=[O:21])[CH:23]=2)=[O:26])=[CH:8][CH:7]=[C:6]([O:12][CH2:13][C:14]([F:17])([F:15])[F:16])[N:5]=1
Reactant: COC(=O)c1cc(C(=O)O)cc(C)n1
Reactant: COc1nc(OCC(F)(F)F)ccc1CN
Agent: Cl
Product: COC(=O)c1cc(C(=O)NCc2ccc(OCC(F)(F)F)nc2OC)cc(C)n1

Procedure:
The title compound is prepared from (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (Amine-24) and 2-(methoxycarbonyl)-6-methylisonicotinic acid by the similar manner in Step-1 of Example 8.
Reaction SMILES: Cl.[Si]([O:9][CH2:10][CH2:11][C:12]1[CH:38]=[CH:37][C:15]([CH2:16][CH2:17][N:18]2[CH2:36][CH2:35][C:21]3([O:26][CH2:25][CH2:24][N:23]([C:27]([C:29]4[N:30]=[C:31]([CH3:34])[S:32][CH:33]=4)=[O:28])[CH2:22]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C>CO>[OH:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH2:17][N:18]2[CH2:36][CH2:35][C:21]3([O:26][CH2:25][CH2:24][N:23]([C:27]([C:29]4[N:30]=[C:31]([CH3:34])[S:32][CH:33]=4)=[O:28])[CH2:22]3)[CH2:20][CH2:19]2)=[CH:37][CH:38]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCO[Si](C)(C)C(C)(C)C)cc4)CC3)C2)cs1
Agent: Cl
Solvent: CO
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCO)cc4)CC3)C2)cs1
Reaction time: 1 h

Procedure:
Concentrated hydrochloric acid (0.5 mL) was added to a solution of (9-(4-(2-(tert-butyldimethylsilyloxy)ethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylthiazol-4-yl)methanone (example 5, step d) (0.3 g) in methanol (5 mL) and the resulting solution stirred for 1 h.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:13]1[C:12]([CH3:11])=[CH:16][N:15]=[CH:14]1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Cc1c[nH]cn1
Product: Cc1cncn1-c1ccc(C=O)cc1F

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 4-methyl-1H-imidazole.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.C(N(CC)CC)C.Cl.[CH2:21]([NH2:30])/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:30][CH2:21]/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: NC/C=C/c1ccccc1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1csc2c(NC/C=C/c3ccccc3)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To 10 ml of a solution of 438 mg (2.0 mmol) of 2,4-dichloro-7-metylthieno[3,2-d]pyrimidine and 445 mg (4.4 mmol) of triethylamine in DMF was added 339 mg (2.0 mmol) of trans-cinnamylamine hydrochloride under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 2 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 341 mg (yield: 54.0%) of the title compound.
Reaction SMILES: [CH:1]([CH:3]=[O:4])=[O:2].[NH2:5][C:6]([NH2:8])=[O:7]>>[OH:2][C@@H:1]1[C@H:3]([OH:4])[N:5]2[C:6](=[O:7])[N:8]1[C@H:3]([OH:4])[CH:1]2[OH:2]
Reactant: NC(N)=O
Reactant: O=CC=O
Product: O=C1N2C(O)[C@@H](O)N1[C@H](O)[C@@H]2O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To 290 g of a 40% solution of glyoxal (116 g active) in a three neck round bottom flask equipped with stirrer, condenser and temperature control added 60 g urea (1 mole) at ambient temperature. After all urea dissolved, the temperature was increased to 90° C. and kept for 60 min until all reactants were consumed and (2R,3S,6R)-2,3,5,6-tetrahydroxy-1,4-diazabicyclo[2.2.1]heptan-7-one product was formed as determined by HPLC. This solution was added to a 50% solution of six moles of dextrose (1080 g) in water at 60° C. After the two solutions mixed, enough water was added to bring the final concentration to 50%.
Reaction SMILES: [K+].[CH3:2][O:3][C:4]([C:6]1[N:11]=[C:10]([C:12]([O-:14])=O)[CH:9]=[CH:8][CH:7]=1)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:37][CH2:38][C:39]1[C:44]([CH2:45][CH3:46])=[N:43][C:42]2[N:47]([CH2:50][CH3:51])[N:48]=[CH:49][C:41]=2[C:40]=1[NH:52][CH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>CN(C)C=O>[CH2:50]([N:47]1[C:42]2=[N:43][C:44]([CH2:45][CH3:46])=[C:39]([CH2:38][NH:37][C:12]([C:10]3[N:11]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[CH:7]=[CH:8][CH:9]=3)=[O:14])[C:40]([NH:52][CH:53]3[CH2:54][CH2:55][O:56][CH2:57][CH2:58]3)=[C:41]2[CH:49]=[N:48]1)[CH3:51]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: COC(=O)c1cccc(C(=O)[O-])n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)n1

Procedure:
To a suspension of 6-[(methyloxy)carbonyl]-2-pyridinecarboxylate potassium salt (39.5 g, 180 mmol) in a 500 mL 3-neck flask was added N,N-dimethylformamide (DMF) (1,700 mL) followed by TBTU (60.4 g, 188 mmol) [still a suspension]. After 2 min the 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (55.6 g, 164 mmol) was added as a solid and after 15 min nearly all the material had gone into solution. After 2.5 h the slightly cloudy mixture was evaporated off to remove as much DMF as possible using high vacuum and this gave a beige oily solid which was partitioned between saturated sodium bicarbonate and ethyl acetate. Solid started to come out of solution from the organics so they it was filtered off dried under high vacuum. This gave 29.56 g (39%) of the above named compound as a white solid. Lab HPLC of this material showed 95.8% of desired product (ret time 1.87 min) contaminated with 3.4% of HOBt. (ret time 1.16 min). LC-MS m/z 467 (M+H)+, 0.78 min (ret time).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([OH:20])=O)=[N:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH:43][C:44]1([C@@H:48]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH3:49])[CH2:47][NH:46][CH2:45]1>CN(C=O)C.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([N:46]2[CH2:47][C:44]([C@@H:48]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH3:49])([OH:43])[CH2:45]2)=[O:20])=[N:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1
Reactant: Cn1nc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C1(O)CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C1(O)CN(C(=O)c2nn(C)c(=O)cc2Nc2ccc(I)cc2F)C1
Reaction time: 2 h
Yield: 72 %

Procedure:
To a suspension of 4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (50 mg, 0.13 mmol) in DMF (2 mL), prepared using similar procedures to those described in Reference 4, at room temperature was added 1-hydroxybenzotriazole (36.3 mg, 0.27 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (52 mg, 0.27 mmol) and the reaction was stirred for 2 hours. 1,1-Dimethylethyl [(1S)-1-(3-hydroxyazetidin-3-yl)ethyl]carbamate (30 mg, 0.13 mmol), prepared using procedures similar to those in Example 28, and triethylamine (0.04 mL) were added and the mixture was stirred for 15 hours. The reaction mixture was partitioned between saturated sodium chloride and ethyl acetate. The organic layer was washed with 5% lithium chloride solution, saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude product as yellow oil. The oil was purified by column chromatography (silica gel, ethyl acetate) to afford 1,1-dimethylethyl {(1S)-1-[1-({4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate as a yellow oil (55 mg, 73% yield): 1H NMR (400 MHz, CDCl3): 10.24-10.23 (m, 1H), 7.52-7.50 (m, 2H), 7.12-7.07 (m, 1H), 6.10-6.09 (m, 1H), 5.13-5.09 (m, 1H), 4.91-4.82 (m, 1H), 4.60-4.39 (m, 2H), 4.10-4.08 (m, 1H), 4.00-3.87 (m, 2H), 3.70 (d, 3H), 1.43 (s, 9H), 1.24-1.20 (m, 3H); MS (EI) for C22H27FIN5O5: 588 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1([CH3:25])[O:22][CH:21]([CH2:23][NH2:24])[CH2:20][O:19]1.CO>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]([NH:24][CH2:23][CH:21]1[CH2:20][O:19][C:18]([CH3:25])([CH3:17])[O:22]1)[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Reactant: CC1(C)OCC(CN)O1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(CNC(=O)OC(C)(C)C)NCC1COC(C)(C)O1
Yield: 32.6 %

Procedure:
The commercially available Tert-butyl-N-(2-hydroxypropyl)carbamate (10 g, 57.0 mmol)) and trietylamine (12 ml, 85.6 mmol) were dissolved in dichloromethane (60 mL) and cooled to 0° C. Methanesulfonyl chloride (4.9 ml, 62.7 mmol) was added dropwise to the ice-cold solution and the reaction was allowed to warm up to room temperature with stirring overnight. The reaction was then quenched with NaOH (1M, 5 ml). The organics were washed with water (2×100 ml) and then brine, collected, dried over MgSO4, filtered and evaporated under reduced pressure to give methanesulfonic acid 3-tert-butoxycarbonylamino-propyl ester (13.5 g). The crude methanesulfonic acid 3-tert-butoxycarbonylamino-propyl ester (13.5 g, 53 mmol) and 2,2-dimethyl-1,3-dioxolane-4-methanamine (12 g, 91.6 mmol) were stirred overnight at room temperature. The mixture was dissolved in ethyl acetate (100 ml) and washed with water (3×100 ml) and brine. The organics were collected, dried over MgSO4, filtered and evaporated under reduced pressure to give an oil. This was purified by silica column chromatography eluting with ethyl acetate: methanol to give the desired product {2-[(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-amino]-propyl}-carbamic acid tert-butyl ester (4.74 g, 17.3 mmol). Mass Spec (ESI) m/z: [M+H]+=289.12. 1H NMR (CDCl3; 300 MHz) δ=5.15 (s, br, 1H), 4.19 (quin, 1H), 4.02 (t, 1H), 3.66 (t, 1H), 3.18 (q, 2H), 2.70 (m, 4H), 1.63 (quin, 2H), 1.42 (s, 9H), 1.40 (s, 3H), 1.40 (s, 3H). 13C NMR (CDCl3; 300 MHz) δ=156.00, 109.05, 78.85, 75.23, 67.47, 52.30, 47.91, 39.20, 29.69, 28.35, 26.81, 25.37.
Reaction SMILES: [C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([O:45][CH3:46])[C:42]=1[O:43][CH3:44])[CH2:38]Cl.Cl>C(OCC)(=O)C>[C:1]([O:9][C:10]1([CH2:38][C:37]2[CH:40]=[C:41]([O:45][CH3:46])[C:42]([O:43][CH3:44])=[C:35]([O:34][CH3:33])[CH:36]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CCN1C(=O)C(Cc2cc(OC)c(OC)c(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21
Reaction time: 8 h

Procedure:
To an oven dried flask cooled under argon equipped with a stir bar was added 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate (0.05 grams, 0.17 mmol, 0.5 M in toluene). While stirring at room temperature LiHMDS (0.3 mL, 0.3 mmol, 1.0 M, purchased from Fisher Scientific) was added. After approximately ten minutes a solution of 3,4,5 trimethoxybenzyl chloride (0.0553 grams, 0.26 mmol, purchased from Aldrich, 0.5 M in anhydrous DMF) was added. The reaction continued to stir overnight. The next day the reaction was acidified with 0.1M HCl, diluted with ethyl acetate and the two layers were separated. The aqueous layer was salted out and washed twice more with ethyl acetate. The combined organic solution was dried with sodium sulfate, filtered and concentrated. Purification was done on a Teledyne ISCO with silica gel using a hexanes/ethyl acetate gradient. This was followed by a subsequent reverse phase purification using Teledyne ISCO with a C18 column and a water with 0.1% formic acid, acetonitrile gradient. Yield (20%) 1H-NMR δ 8.05 (d, 2H), 7.57 (dd, 1H), 7.43 (m, 2H), 7.08 (d, 1H), 6.97 (s, 1H), 6.62 (d, 1H), 6.17 (s, 2H), 3.78 (s, 3H), 3.76 (m, 1H), 3.68 (s, 6H), 3.53 (m, 1H), 3.29 (d, 1H), 3.24 (d, 1H), 2.28 (s, 3H), 1.00 (t, 3H). Calculated mass for C28H29NO6, 475.20. Observed 498.2 (M+Na).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].N#N.[CH2:17]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21][NH2:22])[CH3:18].[OH:30][P:31]([OH:34])([OH:33])=[O:32].C>C1COCC1.CCO>[P:31]([OH:34])([OH:33])([OH:32])=[O:30].[CH2:17]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21][NH:22][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=1)[CH3:18]
Reactant: CCCCCCCN(CC)CCN
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Agent: N#N
Agent: O=P(O)(O)O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCN(CC)CCNC(=O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
Dissolve 5.66 g (0.024 moles) 4-[(methylsulfonyl)amino]benzoyl chloride in 40 ml THF. Chill the solution on an ice/MeOH bath under a stream of N2. Add dropwise 4.5 g (0.024 moles) N-ethyl-N-heptyl-1,2-ethanediamine to the room temperature for about 24 hours. Follow the progress of the reaction by thin layer chromatography on silica gel (Acetonitrile: MeOH: Ammonia, 85:10:5). At the completion of the reaction, remove the solvents in vacuo. Dissolve the resulting oil in 10% K2CO3 solution and extract with 5×100 ml Et2O. Dry the organics over Na2SO4. Evaporate the solvents to provide an oil. Crude wt: 3.38 g. Dissolve the oil in 25 ml EtOH and acidify with 1.02 g 85% H3PO4. Treat the solution with activated charcoal, filter and evaporate the solvents to provide the title compound. Recrystallize the product from EtOH/Et2O.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](=O)[CH3:15])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:17]=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[CH:3]=2)[C:14]=1[CH3:15])=[O:26])[CH3:10]
Reactant: Nc1cccc(Br)c1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(Br)c2)c1C

Procedure:
m-Bromoaniline (5 mmol, 0.9 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The named product was recrystallized from ethanol (m.p. 111° C.-112.7° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[CH2:38][CH2:37][S:36](=[O:40])(=[O:39])[CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]5[CH2:38][CH2:37][S:36](=[O:40])(=[O:39])[CH2:35][CH2:34]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:30])[F:31])[CH:3]=1
Reactant: O=S1(=O)CCNCC1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCS(=O)(=O)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(1,1-dioxidothiomorpholin-4-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and thiomorpholine 1,1-dioxide following General Procedure B.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]1.S(=O)(=O)(O)[OH:16].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:13]([NH2:14])=[O:16])[CH2:12][CH2:11][CH2:10]1
Reactant: COc1ccccc1C1(C#N)CCC1
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1C1(C(N)=O)CCC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 1-(2-methoxyphenyl)cyclobutanecarbonitrile (4.29 g) was added sulfuric acid (20 mL, 95-98%)/water (20 mL) and the reaction warmed to 60° C. After 1 h the solution was warmed to 80° C. and heating was continued for 3 h. The reaction was cooled to room temperature and stirred for 16 h. Heating was resumed and after 1 h acetic acid (10 mL) was added. The temperature was increased to 90° C. and heating was continued for 1.75 h. The reaction was cooled to room temperature and then poured onto ˜300 ml of ice and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford the subtitle product (4.19 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc2c(c1)CCO2
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CCC(=O)c1ccc2c(c1)CCO2

Procedure:
2,3-dihydrobenzofuran of formula II, ##STR5## is condensed with succinic anhydride in the presence of aluminum chloride in a chlorinated organic solvent and at a temperature below 5° C., to form 4-(2,3-dihydro-5-benzofuranyl)-4-oxobutanoic acid of formula III, ##STR6## which is reduced in acid medium in the heated state and in the presence of zinc and mercuric chloride to form 4-(2,3-dihydro-5-benzofuranyl)butanoic acid of formula IV, ##STR7## which is then subjected to the action of polyphosphoric acid in an apolar organic solvent and at a temperature of between 80° C. and 100° C. to form 2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan-8-one of formula V, ##STR8## which is then: