Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[N:14]=1.[CH2:15](Br)[CH3:16]>>[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][N:11]([CH2:15][CH3:16])[CH2:10][CH2:9][C:8]=2[N:14]=1
Reactant: Nc1cnc2c(n1)CCNCC2
Reactant: CCBr
Agent: Br
Product: CCN1CCc2ncc(N)nc2CC1

Procedure:
This compound was prepared analogous to Example 31 by alkylation of 2-amino-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine dihydrobromide with ethyl bromide.
Reaction SMILES: [CH2:1]([C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C:8]1=[CH:7][CH2:6][C:5]12[O:26][CH2:25][CH2:24][O:23]1)[CH2:2][CH3:3].[H][H]>C1C=CC=CC=1.[Pd]>[CH2:1]([C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C@@H:8]1[CH2:7][CH2:6][C:5]12[O:23][CH2:24][CH2:25][O:26]1)[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: CCC[C@]12CCC3=C(CCc4cc(OC)ccc43)C1=CCC21OCCO1
Agent: [Pd]
Solvent: c1ccccc1
Product: CCC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CCC21OCCO1
Yield: 71.6 %

Procedure:
Shake 13β-Propyl-3-methoxy-17,17-ethylenedioxygona-1,3,5(10),8,14-pentaene (2.5 g.) in benzene (80 cc.) with hydrogen at atmospheric pressure in the presence of a 2% palladium on calcium carbonate catalyst (0.9 g.); hydrogen uptake ceases after the requisite amount (161 cc.) for monohydrogenation has been absorbed. Filter and evaporate to obtain a gum, which one crystallizes from ethanol to obtain the title product (1.8 g.), m.p. 119°-120°; ultraviolet absorption peak at 278 mμ (ε15,300).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C@@H:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:19]([OH:30])[CH2:18][CH2:17]2.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C@@H:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:19]([O:30][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:18][CH2:17]2
Reactant: COc1ccc2c(c1)CC[C@@H](O)[C@@H]2c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(c1)CC[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@@H]2c1ccccc1
Yield: 108.1 %

Procedure:
A solution of para-toluenesulfonyl chloride (1.8 g, 9.43 mmol) in dichloromethane (10 mL) was added to a solution of trans-6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ol 29 (2.0 g, 7.86 mmol), N,N-diisopropylethylamine (4.8 mL, 27.5 mmol) and 4-dimethylaminopyridine (1.15 g, 9.43 mmol) in dichloromethane (40 mL) at 0C. The resultant solution was stirred at ambient temperature for 16 h. The solution was washed successively with 1 N aqueous sodium hydroxide (×2) and a saturated aqueous solution of sodium chloride, then dried over sodium sulfate. The solvent was evaporated in vacuo to give crude trans-6-methoxy-1-phenyl-2-(4-methylbenzenesulfonyl)oxy-1,2,3,4-tetrahydronaphthalene 30 (3.47 g), as a pale yellow solid which was used without further purification in the subsequent step. 1H NMR(CDCl3) δ1.90-2.04 (m, 1H), 2.14-2.24 (m, 1H), 2.42 (s, 3H), 2.83-3.07 (m, 2H), 3.77 (s, 3H), 4.16 (d, 1H), 4.80-4.87 (m, 1H), 6.60-6.67 (m, 3H), 6.82-6.90 (m, 2H), 7.13-7.23 (m, 5H), 7.58 (d, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7]1)=[O:5])[CH3:2].[Br:16]Br>>[Br:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:15]2
Reactant: CCOC(=O)C1CNc2ccccc2C1
Reactant: BrBr
Product: CCOC(=O)C1CNc2ccc(Br)cc2C1

Procedure:
Analogously to Example 33b), starting from 410 mg of 3(R,S)-ethoxycarbonyl-1,2,3,4-tetrahydroquinoline and 0.11 ml of bromine, 6-bromo-3(R,S)-ethoxycarbonyl-1,2,3,4-tetrahydroquinoline is obtained: Rf (D)=0.15; MS: (M)+ =285.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[N:12]([CH3:15])=[C:13]=[S:14].CCN(CC)CC>CCO>[Br:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[NH:1][C:13](=[S:14])[N:12]([CH3:15])[C:4]2=[O:5]
Reactant: Nc1c(Br)cccc1C(=O)O
Reactant: CN=C=S
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1c(=S)[nH]c2c(Br)cccc2c1=O
Temperature: 75 °C
Reaction time: 24 h
Yield: 76.3 %

Procedure:
A solution of 2-amino-3-bromobenzoic acid (Maybridge, Trevillett, UK; 3.03 g, 14.02 mmol) and isothiocyanatomethane (Aldrich; 1.151 mL, 16.82 mmol) in EtOH (28 mL) was stirred at 75° C. for 3.5 d. Additional isothiocyanatomethane (2.302 mL, 33.64 mmol) and Et3N (2.74 mL, 19.63 mmol) were added, and the resulting mixture was stirred at 75° C. for 1 d. The mixture was concentrated in vacuo and the residue was triturated with Et2O (40 mL) to provide 8-bromo-3-methyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (2.90 g, 10.70 mmol, 76% yield) as a yellow-orange solid: 1H NMR (400 MHz, CDCl3) δ ppm 9.52 (1H, br. s.), 8.11 (1H, d, J=8.0 Hz), 7.85 (1H, dd, J=7.9, 1.3 Hz), 7.20 (1H, t, J=7.9 Hz), 3.83 (3H, s). m/z (ESI, +ve) 271.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[CH2:17][C:18](=O)C>>[C:10]1([CH2:9][O:8][C:7]2[C:2]3[N:3]([CH:17]=[CH:18][N:1]=3)[N:4]=[CH:5][CH:6]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1nnccc1OCc1ccccc1
Reactant: CC(=O)CCl
Product: c1ccc(COc2ccnn3ccnc23)cc1

Procedure:
For example, condensation of 3-amino-4-phenylmethoxypyridazine with chloroacetone gives an 8-phenylmethoxyimidazo[1,2-b]pyridazine with a methyl at the 2-position and a hydrogen as shown in the following reaction Scheme II: ##STR14##
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:7]=[C:6](/[CH:20]=[CH:21]/[C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>O1CCCC1.C(O)C>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:7]=[C:6](/[CH:20]=[CH:21]/[C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(/C=C/c2ccc3c(c2)C(/C=C/c2ccccc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC=C(/C=C/c2ccccc2)c2cc(/C=C/c3ccc(C(=O)O)cc3)ccc21
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 4-[(E)-[5,6-dihydro-5,5-dimethyl-8-[(E)-phenylethenyl]-2-naphthalenyl]ethenyl]benzoate (0.206 g, 0.49 mmol) in a mixture of tetrahydrofuran/ethanol (1:1, 2 mL) was added aqueous sodium hydroxide (5N, 0.98 mL, 4.90 mmol). The mixture was stirred overnight. Hydrochloric acid 1N was then added to precipitate the acid and ≈half of the volume of the solvents was evaporated. The white solid was filtered and washed with water. The solid was then dissolved in dichloromethane/ethanol, filtered and recrystallized from this mixture by evaporating the solvents. The title compound was obtained (0.149 g, 75%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][CH:8]2[CH2:25][CH2:24][C:11]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[ClH:26]>CO>[ClH:26].[ClH:26].[N:1]1[CH:2]=[CH:3][C:4]([O:7][CH:8]2[CH2:25][CH2:24][C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Oc3ccncc3)CC2)CC1
Agent: Cl
Solvent: CO
Product: c1cc(OC2CCC3(CCNCC3)CC2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 9-(pyridin-4-yloxy)-3-azaspiro[5.5]undecane-3-carboxylate (1 g, 2.886 mmol) was dissolved in methanol (2 ml); hydrogen chloride in methanol (1.25 mol/l, 11.5 ml) was added, and the mixture was refluxed for 30 min. The solvent was removed in vacuo and the residue was dissolved in a small amount of ethanol. Acetone (about 25 ml) was then added, the mixture was stirred for 30 min. at 0° C. and finally the resulting solid was filtered out with suction. Yield: 0.96 g (>99%)
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O>C1COCC1>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([O:12][CH3:13])[C:2]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: OB(O)c1cccs1
Solvent: C1CCOC1
Product: COc1cc(OC)c(-c2cccs2)cc1C=O
Temperature: 60 °C
Yield: 93.9 %

Procedure:
An alternative procedure: 5-bromo-2,4-dimethoxybenzaldehyde (20.3 g), thiophene-2-boronic acid (11.6 g) and THF (200 mL) were sequentially charged into a clean reaction vessel fitted with a reflux condenser, mechanical stirrer and nitrogen inlet adapter. Nitrogen was bubbled into the resulting solution for 20 min followed by the sequential addition of KF (10.1 g), and Pd(tBu3P)2 (0.424 g). The solution was immediately heated to 60° C. and aged for 1.5 h. The reaction was diluted with H2O (200 mL) and transferred to a separatory funnel containing EtOAc (200 mL) and H2O (200 mL). The layers were cut and the aqueous layer was extracted with EtOAc (100 mL). The combined organic cuts were filtered through a pre-washed pad of solka floe (5 g). The pad of solka floe and spent catalyst were washed with fresh EtOAc (200 mL) and this wash combined with the batch. The resultant filtrate was concentrated to dryness. The crude product was dissolved in THF (38 mL) and crystallized upon heptane (152 mL) addition. The product was filtered and then dried to a constant weight in the vacuum oven (38° C., 20 mHg) affording 19.32 g (94% yield) of desired 2,4-dimethoxy-5-thiophen-2-yl-benzaldehyde as a light off-white solid. 1H-NMR identical as above.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@@H:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1)[CH3:2].C(O)=[O:19]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[O:19])[CH3:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=CO
Reactant: C#Cc1ccc(C[C@H](OC)C(=O)OCC)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(C(C)=O)cc1)OC
Temperature: 100 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To (2S)-3-(4-Ethynyl-phenyl)-2-methoxy-propionic acid ethyl ester (36 Mg, 0.15 mmol) (Example 29, Step A) were added 4 ml of formic acid. The solution was stirred for 1 hour at 100° C. and then cooled to room temperature. The mixture was taken up with methylene chloride and the solution was washed with water, sodium carbonate, and water, dried (MgSO4) and the solvent was evaporated under vacuum. Obtained a brown liquid (0.035 g, 95%). 1H-NMR (200.15 MHz, CDCl3): δ 7.43 (d, 1H, J=73), 7.12 (d, 1H, J=7.3), 4.18 (q, 2H, J=7.0), 3.97 (dd, 1H, J=7.3, 5.6), 3.32 (s, 3H), 3.06 (s, 1H), 3.03 (d, 1H, J=2.4 Hz), 2.56 (s, 2H), 1.22 (t, 3H, J=7.25).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br[CH:19]=[C:20]([CH3:22])[CH3:21].II.[Mg]>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH:19]=[C:20]([CH3:22])[CH3:21])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: CC(C)=CBr
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)=CC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (565 mg) in THF (5 mL) at 0° C. was added Grignard reagent, which was freshly prepared from 1-bromo-2-methyl-propene (0.51 mL), a small iodine flake, and magnesium powder (146 mg) in THF (5 mL). The resulting mixture was then stirred at room temperature for 3 hr. The reaction was quenched with NH4Cl (sat. aq), filtered through a pad of Celite®, rinsed with EtOAc, the layers were separated, the aqueous layer extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as a yellow solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][O:12][CH2:11][C@@H:10]1CS([O-])(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:19]([C@@H:10]1[CH2:11][O:12][CH2:13][C@@H:9]1[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1COC[C@@H]1CS(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1COC[C@H]1N=[N+]=[N-]
Temperature: 60 °C
Yield: 52.9 %

Procedure:
[(3S,4S)-4-(Tert-butyl(dimethyl)silyl)oxytetrahydrofuran-3-yl]methanesulfonate (3.00 g, 10.1 mmol) is dissolved in DMF (50 mL). Sodium azide (1.32 g, 20.2 mmol) is added and the reaction is heated to 60° C. for 72 h. Tetra-n-butylammonium iodide (0.400 g, 1.08 mmol) is added and the temperature is raised to 120° C. for 14 days. Water is added and the product is extracted into EtOAc. The organic layer is washed with water a second time and then dried over magnesium sulfate, filtered, and concentrated to give 2.9 g of crude product as a pale yellow oil. The crude product is purified on silica gel (120 g, 2-20% EtOAc/hexanes, observed on TLC with KMnO4 staining) to give the title compound as a colorless oil (1.3 g, 53%). GC-MS m/z 186 (M-tBu)+.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([N:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Br[CH2:37][C:38]([NH2:40])=[O:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([N:23]5[CH2:24][CH2:25][N:26]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:27][CH2:28]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1N1CCNCC1
Reactant: NC(=O)CBr
Product: NC(=O)CN1CCN(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
2-{4-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]piperazin-1-yl}acetamide was prepared from ((5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperazin-1-yl-1,3-thiazolidine-2,4-dione (Example 351) and 2-bromoacetamide following General Procedure S.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:7])[CH2:4][CH2:5][OH:6].[F:8][C:9]([F:21])([F:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17].C(OCC)(=O)C>C(Cl)Cl>[F:21][C:9]([F:8])([F:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([O:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH3:7])(=[O:17])=[O:18]
Reactant: COC(C)CCO
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(C)CCOS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To a solution of 3-methoxybutane-1-ol (0.63 g, 6.0 mmol) and TEA (0.42 g, 4.1 mmol), in CH2Cl2 (5 mL) was added o-(trifluoromethyl)benzenesulfonyl chloride (0.50 g, 2.0 mmol). The solution was stirred at rt for 2 h. The reaction mixture was diluted with CH2Cl2 (15 mL) and washed with 1 M HCl (3×15 mL), saturated aqueous NaHCO3 (1×15 mL) and saturated aqueous NaCl (1×15 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography with ethyl acetate in hexanes yielded the desired product (0.34 g, 50%). 1H NMR (400 MHz CDCl3) δ 8.23 (m, 1H), 7.91 (m, 1H), 7.75 (m, 2H), 4.24 (m, 2H), 3.40 (m, 1H), 3.21 (s, 3H), 1.80 (m, 2H), 1.10 (d, 3H, J=6.2 Hz). Anal. Calcd. For C12H15F3O4S: C, 46.15; H, 4.84. Found: C, 46.30; H, 4.88.
Reaction SMILES: C(OC/C=[C:7]1\[CH2:8][N:9]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10][CH2:11][CH:12]\1[O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])(=O)C.[O:28]=[O+][O-]>ClCCl>[C:24]([O:23][C:21]([N:9]1[CH2:10][CH2:11][CH:12]([O:13][Si:14]([C:17]([CH3:19])([CH3:18])[CH3:20])([CH3:15])[CH3:16])[C:7](=[O:28])[CH2:8]1)=[O:22])([CH3:25])([CH3:27])[CH3:26]
Reactant: CC(=O)OC/C=C1\CN(C(=O)OC(C)(C)C)CCC1O[Si](C)(C)C(C)(C)C
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of (E)-3-(2-acetoxyethylidene)-1-(t-butoxycarbonyl)-4-(t-butyldimethylsilyloxy)piperidine (9.9 g) in dichloromethane (100 ml) was introduced gaseous ozone at −78° C. for 2 hours. After the excess ozone was removed by bubbling nitrogen gas for 1 hour, triphenylphosphine (13 g) was added at the same temperature. The resulting mixture was stirred at room temperature for one hour, and concentrated in vacuo. The residue was purified by chromatography on silica gel using a mixture of hexane, ethyl acetate and dichloromethane (5:1:1 to 1:1:1) as the eluent to afford the title compound as a light yellow oil (4.6 g, yield: 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=[O:21])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.[F:23][C:24]1[CH:25]=[C:26]([CH2:30]C#N)[CH:27]=[CH:28][CH:29]=1>>[F:23][C:24]1[CH:25]=[C:26]([C:30]2[O:21][N:20]=[C:17]3[CH:16]=[CH:15][C:14]([C:13]4[N:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)[N:10]=[CH:11][CH:12]=4)=[CH:19][C:18]=23)[CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: N#CCc1cccc(F)c1
Product: COc1ccc(-n2nccc2-c2ccc3noc(-c4cccc(F)c4)c3c2)cc1

Procedure:
The title compound, light green solid (81 mg, 62%), MS (ISP) m/z=386.2 [(M+H)+], mp 203° C., was prepared in accordance with the general method of example 1 from 1-(4-methoxy-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate G) (100 mg, 353 μmol) and commercially available 2-(3-fluoro-phenyl)-acetonitrile.
Reaction SMILES: O1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][C:11](=[O:13])[NH:10][CH2:9]3)[CH2:7][CH2:6]2)[O:4]CC1.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O>[CH2:9]1[C:8]2([CH2:7][CH2:6][C:5](=[O:4])[CH2:15][CH2:14]2)[CH2:12][C:11](=[O:13])[NH:10]1
Reactant: O=C1CC2(CCC3(CC2)OCCO3)CN1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC2(CC1)CNC(=O)C2
Yield: 57.6 %

Procedure:
To a solution of 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-11-one (3.95 g, 18.7 mmol) in 160 mL of acetone was added 16 mL of water and pyridinium p-toluenesulfonate (1.41 g, 5.61 mmol). The resulting mixture was stirred at reflux for 20 h. Then, it was cooled and concentrated. The crude was purified by silica gel column chromatography using a 5% MeOH:EtOAc mixture as eluent to afford 2-aza-spiro[4.5]decane-3,8-dione (1.80 g, 58%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:19]1([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CC#N>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:30][CH:29]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc(N2CCCCC2)cc1
Solvent: CC#N
Product: CC(C)N1C(=O)C(Nc2ccc(N3CCCCC3)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 160 °C
Yield: 75.6 %

Procedure:
A mixture of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.525 mmol), (4-piperidin-1-ylphenyl)amine (0.093 g, 0.525 mmol) and TEA (0.053 g, 0.525 mmol) in MeCN (2 ml) was heated in a microwave at 160° C. for 30 mins. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography using 30% EtOAc in hexane as eluent, to give the title compound (0.169 g, 76%). 1H NMR (500 MHz CDCl3): δ 7.24-7.16 (m, 1H), 7.16-7.08 (m, 5H), 6.58 (d, 2H), 6.54 (d, 2H), 4.56-4.44 (m, 1H), 3.03 (t, 4H), 1.70-1.61 (m, 10H), 1.61-52(m, 3H); 13C NMR (125 MHz CDCl3): δ 159.2, 150.1, 131.1, 129.6, 128.8, 128.1, 127.6, 125.3, 123.6, 116.3, 109.3, 51.1, 47.9, 25.7, 24.4, 20.5; Mass Spectrum: M+H 426.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[N:36]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[C:1]([N:39]1[CH2:38][CH2:37][N:36]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40]1)(=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78 %

Procedure:
To a solution of isobutyric acid (6.608 g, 75 mmol) in anhydrous dichloromethane (130 mL) was added triethylamine (8.33 g, 82.5 mmol), 1-hydroxybenzotriazole (10.125 g, 75 mmol), followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14.25 g, 75 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0° C., and tert-butyl piperazine-1-carboxylate (13.97 g, 75 mmol) was added portion-wise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (200 mL), washed with saturated sodium bicarbonate (150 mL×2), 10% citric acid (150 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 4-isobutyrylpiperazine-1-carboxylate (15 g, yield 78%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.13-1.14 (d, J=6.8 Hz, 6H), 1.47 (s, 9H), 2.75-2.82 (m, 1H), 3.43-3.58 (m, 4H); LC-MS (ESI) m/z: 257(M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH3:34])[CH:9]([CH3:22])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]#[N:21])[CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].OO.[OH-].[Na+].C(O)(=[O:41])C>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]([CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH3:34])[CH:9]([CH3:22])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:21])=[O:41])[CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc(C#N)c2c(c1)CCN2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)NCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carbonitrile (120 mg) in dimethyl sulfoxide (2.5 ml) was added 30% hydrogen peroxide (0.26 ml), and the mixture was stirred at room temperature for 15 minutes. Then, to the reaction mixture was added a 5N sodium hydroxide solution (0.26 ml), and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added acetic acid. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 127 mg of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide as an oil.