Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:29])[CH2:28][C:22]2=[C:23]([CH3:27])[S:24][C:25]([CH3:26])=[C:21]2[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:29][C:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH2:20][C:21]2=[C:25]([CH3:26])[S:24][C:23]([CH3:27])=[C:22]2[CH2:28]1)=[O:18])[CH3:15]
Reactant: O=C(O)c1cccc2c1CCCC2
Reactant: CCOC(=O)C1(N)Cc2c(C)sc(C)c2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2c(C)sc(C)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (500 mg, 2.84 mmol), 5-amino-1,3-dimethyl-5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid ethyl ester (816 mg, 3.41 mmol), HATU (1.62 g, 4.26 mmol) in anhydrous DMF (15 mL) is added DIPEA (704 μL, 4.26 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (50 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (74) as white solid (1.10 g, 97%).
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]([C:17]([C:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH:20]=3)=[O:18])[C:6]=12.ClC1SC=C2C(=O)NC3C=CC=CC=3NC=12.Cl.C(Cl)(=O)C1C=CN=CC=1.ClC1SC=C2C(=O)NC3C=CC=CC=3N(C(C3C=CN=CC=3)=O)C=12>>[CH3:25][N:22]1[CH2:23][CH2:24][C:19]([C:17]([N:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]3=[CH:4][S:3][CH:2]=[C:6]23)=[O:18])=[CH:20][CH2:21]1
Reactant: CN1CC=C(C(=O)N2c3ccccc3NC(=O)c3csc(Cl)c32)CC1
Agent: Cl
Agent: O=C(Cl)c1ccncc1
Agent: O=C1Nc2ccccc2N(C(=O)c2ccncc2)c2c1csc2Cl
Product: CN1CC=C(C(=O)N2c3ccccc3NC(=O)c3cscc32)CC1

Procedure:
3-chloro-4,9-dihydro-4-[(1-methyl-1,2,5,6-tetrahydro-4-pyridinyl)carbonyl]-10H-thieno[3,4-b][1,5]benzodiazepin-10-one, prepared from 3-chloro-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and isonicotinic acid chloride hydrochloride via 3-chloro-4,9-dihydro-4-[(4-pyridinyl)carbonyl]-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 3-chloro-4,9-dihydro-4-[(4-pyridinyl)carbonyl]-10H-thieno[3,4-b][1,5]benzodiazepin-10-one methoiodide.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[CH2:14][CH2:13][CH2:12][C@@H:8]1[C:9]([NH2:11])=O>O1CCCC1>[N:11]1([CH2:9][CH:8]2[CH2:12][CH2:13][CH2:14][NH:7]2)[CH2:13][CH2:12][CH2:8][CH2:9]1
Reactant: NC(=O)[C@H]1CCCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1CNC(CN2CCCC2)C1

Procedure:
To a suspension of 0.380 gm of lithium aluminum hydride in 15 ml of dry tetrahydrofuran is carefully added a solution of the D-proline amide (prepared in B above) in 10 ml tetrahydrofuran. The mixture is refluxed for 2 hrs then cooled and quenched with 2 ml of 2.5N sodium hydroxide. The mixture is filtered through a pad of sodium sulfate and the filter cake washed with 2×50 ml of ether. The combined filtrates are concentrated in vacuo to yield 0.80 gm of desired 2-(1-pyrrolidinylmethyl) pyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])[C:5]([O:7][CH3:8])=[O:6].[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41](Cl)(=[O:43])=[O:42])=[CH:40][C:35]=2[O:34][CH2:33]1>>[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41]([NH:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)[C:11]=3[O:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=3[Cl:21])[C:5]([O:7][CH3:8])=[O:6])(=[O:42])=[O:43])=[CH:40][C:35]=2[O:34][CH2:33]1
Reactant: COC(=O)c1cc(N)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc3c(c2)OCO3)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1

Procedure:
Analogously to Example 77, by condensing methyl 3-amino-4-(2-chloro-5-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate with benzo[1,3]dioxol-5-sulphonyl chloride there was obtained methyl 3-(benzo[1,3]dioxol-5-sulphonyl-amino)-4-(2-chloro-5-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate und therefrom by treatment with 5.5M HCl there was obtained methyl 3-(benzo[1,3]dioxol-5-sulphonylamino)-4-(2-chloro-5-methoxy-phenoxy)-5-(2-hydroxy-ethoxy)-benzoate.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([N:27]2[CH2:32][CH2:31][CH2:30][C@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:28]2)=[C:11]2[CH:17]=[N:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12]2=[N:13][CH:14]=1)=O)(C)(C)C.Cl.O1CCOCC1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[NH2:8][C:9]1[C:10]([N:27]2[CH2:32][CH2:31][CH2:30][C@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:28]2)=[C:11]2[CH:17]=[N:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12]2=[N:13][CH:14]=1
Reactant: COc1ccc(Cn2ncc3c(N4CCC[C@H](NC(=O)OC(C)(C)C)C4)c(NC(=O)OC(C)(C)C)cnc32)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2ncc3c(N4CCC[C@H](NC(=O)OC(C)(C)C)C4)c(N)cnc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A mixture of tert-butyl {(3S)-1-[5-[(tert-butoxycarbonyl)amino]-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]piperidin-3-yl}carbamate (0.50 g, 0.90 mmol) and HCl in dioxane (4.0 M; 10 mL, 40 mmol) was stirred at room temperature for 2 h. The solution was then evaporated under reduced pressure. The resulting residue was dissolved in THF (10 mL), and di-tert-butyl dicarbonate (0.20 g, 0.92 mmol) in THF (5 mL) and triethylamine (0.37 g, 3.6 mmol) were added. The mixture was stirred at room temperature for 3 h. The reaction mixture was then diluted with EtOAc and the resulting solution was washed with aq. NaHCO3 and brine. The organic layer was then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CombiFlash® apparatus, eluting with 20 to 100% EtOAc in hexanes, to give 0.30 g (73%) of the sub-title compound. LCMS calc. for C24H33N6O3 (M+H)+: m/z=453.3. Found: 453.1.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([CH2:19][CH3:20])[CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8])(=O)C.N1CCCC1.Cl>O>[SH:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([CH2:19][CH3:20])[CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8]
Reactant: CCc1cc(NC(=O)C(CSC(C)=O)Cc2ccccc2)cc(C(=O)O)c1
Agent: Cl
Solvent: O
Solvent: C1CCNC1
Product: CCc1cc(NC(=O)C(CS)Cc2ccccc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
3-[(2-Acetylthiomethyl-3-phenylpropionyl)amino]-5-ethylbenzoic acid (compound of Example 64) (1.0 g) is suspended in water (10 ml), and thereto is added pyrrolidine (0.6 g) under nitrogen, and the mixture is stirred at room temperature for 20 minutes. The reaction mixture is adjusted to pH 1 with conc. hydrochloric acid and is extracted with ethyl acetate (100 ml). The extract is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and ethyl acetate is distilled off under reduced pressure. The residue is dissolved in methanol and purified by a medium pressure column chromatography with CHP-20P (eluant, water-methanol). The fractions containing the desired compound are collected and concentrated into dryness to give the title compound (0.3 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.B(O)(O)C1C=CC(C)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[ClH:33].O1CCOCC1>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[ClH:33].[C:10]1([CH3:9])[CH:15]=[CH:14][C:13]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(B(O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cccc(N)n2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a solution of 6-bromopyridin-2-amine (0.500 g, 2.89 mmol) in toluene (10 ml) was added benzaldehyde (0.313 g, 2.95 mmol), and the reaction was stirred for 30 minutes. To this, p-tolylboronic acid (0.471 g, 3.47 mmol), sodium carbonate (0.368 g, 3.47 mmol), and water (10 ml) were added, and the reaction was degassed with argon. Tetrakis(triphenylphosphine)palladium (0.167 g, 0.144 mmol) was added, and the reaction was heated to 100° C. for 60 hours. The reaction was diluted with 10 ml of toluene and 10 ml of water, and the organic layer was collected. The organic layer was treated with 4M hydrogen chloride in dioxane (1.44 ml, 5.78 mmol) dropwise with vigorous stirring. The resulting solid was collected via filtration to yield pure 6-p-tolylpyridin-2-amine hydrochloride (0.564 g, 2.56 mmol, 88.4% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH:17]=[C:18]([Cl:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:21].C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]([F:35])([F:34])[S:30](Cl)(=[O:32])=[O:31]>CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH:17]=[C:18]([Cl:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[O:21][S:30]([C:29]([F:35])([F:34])[F:28])(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCCC1(CC=C(C)Cl)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC1(CC=C(C)Cl)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Temperature: 10 °C
Yield: 98.1 %

Procedure:
6,7-Dichloro-2-(3-chloro-2-butenyl)-2,3-dihydro-5-hydroxy-2-propyl-1H-inden-1-one (24.5 g, 0.0716 mole) was stirred for 11/4 hours at 25° C. in a mixture of potassium carbonate (29.7 g, 0.215 mole) in dimethylformamide (85 ml). The suspension was cooled to 10° C. and trifluoromethanesulfonyl chloride (14.6 g, 0.087 mole) was added. The mixture was stirred 1/3 hour at 10° C., 11/2 hours at 25° C. and then poured over ice and extracted with diethyl ether. The organic extracts were washed with water, dried over MgSO4 and concentrated under vacuum to obtain 33.7 g of the product as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:38]3[CH:39]=[C:34]([CH:35]=[CH:36][CH:37]=3)[CH2:33][NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:28])[CH3:26])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)(C)O
Reactant: CC(C)(C)OC(=O)NCc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOCc1nc2c(N)nc3cc(-c4cccc(CNC(=O)OC(C)(C)C)c4)ccc3c2n1CC(C)(C)O
Yield: 84.8 %

Procedure:
1-(4-Amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (2.62 g, 6.67 mmol) and 3-(N-tert-butoxycarbonylaminomethyl)phenylboronic acid (2.0 g, 8.0 mmol) were coupled according to the procedure described in Part J of Example 1. Palladium (II) acetate was added as a 5 mg/mL solution in toluene. The reaction was heated for four hours, and the work-up procedure described in Examples 125-135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) to provide 2.94 g of tert-butyl {3-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]benzyl}carbamate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[CH2:9]([O:11][C:12](=[O:17])[CH2:13][N:14]=[N+]=[N-])[CH3:10].[NH4+].[Cl-]>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[NH:14][C:3]2[C:2]([Cl:1])=[CH:6][S:5][C:4]=2[CH:7]=1)=[O:17])[CH3:10]
Reactant: O=Cc1cc(Cl)cs1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc2scc(Cl)c2[nH]1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-Chloro-thiophene-2-carbaldehyde (Iriarte, J.; Martinez, E.; Muchowski, J. M., J. Heterocycl. Chem., 13: 393-4 (1976)) was annulated according to Procedure H (aldehyde and azido-acetic acid ethyl ester added as ethanol solution (1.2 M of ester) such that reaction temperature maintained at 0° C.; reaction mixture allowed to warm to 10° C., stirred for 1.5 h, poured into cold saturated aqueous NH4Cl; after ether extractions, combined acrylate organic phases washed with water until aqueous phase was neutral; acrylate not purified).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(CCc2ccccc2)n1
Yield: 78.3 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 200 mg, 1.77 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil (92 mg, 2.30 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 20 min, (2-bromo-ethyl)-benzene (426 mg, 2.30 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 2% methanol/methylene chloride to 5% methanol/methylene chloride) afforded 3-nitro-1-phenethyl-1H-pyrazole (301 mg, 78%) as a white solid: H1-NMR (400 MHz, CDCl3) δ: 3.21 (3H, t, J=7.0 Hz), 4.41 (3H, t, J=6.9 Hz), 6.76 (1H, d, J=2.3 Hz), 7.07 (2H, m), 7.15 (1H, d, J=2.3 Hz), 7.27 (3H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[S:11][C:12]([C:14]([O:16]C(C)(C)C)=[O:15])=[CH:13][C:9]=2[C:8]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[N:7]1)=[O:5])[CH3:2]>OC(C(F)(F)F)=O.ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:10]2[S:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[N:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccccc2[N+](=O)[O-])c2cc(C(=O)OC(C)(C)C)sc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)n1nc(NC(=O)c2ccccc2[N+](=O)[O-])c2cc(C(=O)O)sc21
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of 5.380 g of 3-(2-Nitro-benzoylamino)-thieno[2,3-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester in 25 mL of dichloromethane TFA (25 mL) is slowly added at room temperature. After stirring for 1 hour the reaction mixture is dried up. The colourless solid is taken up with ethyl ether and filtered affording 4.052 g (86%) of the titled compound.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[N:15]1[CH:23]([CH3:24])[C:22]2[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[C:19]([CH2:29][N:30]3[CH2:35][CH2:34][C:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)([C:36]#[N:37])[CH2:32][CH2:31]3)=[CH:18][C:17]=2[C:16]1=[O:44])(C(C)(C)C)(C)C.N1C=CC=CC=1.F.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[OH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[N:15]1[CH:23]([CH3:24])[C:22]2[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[C:19]([CH2:29][N:30]3[CH2:31][CH2:32][C:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)([C:36]#[N:37])[CH2:34][CH2:35]3)=[CH:18][C:17]=2[C:16]1=[O:44]
Reactant: CC1c2c(cc(CN3CCC(C#N)(c4ccccn4)CC3)c3ccccc23)C(=O)N1[C@H]1CCCC[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC1c2c(cc(CN3CCC(C#N)(c4ccccn4)CC3)c3ccccc23)C(=O)N1[C@H]1CCCC[C@@H]1O
Reaction time: 15 h

Procedure:
To a solution of 1-({2-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-1-methyl-3-oxo-2,3-dihydro-1H-benzo[e]isoindol-5-yl}methyl)-4-(pyridin-2-yl)piperidine-4-carbonitrile (0.120 g, 0.197 mmol) in 0.1 mL of pyridine was added hydrogen fluoride pyridine (0.098 g, 0.98 mmol). After 15 hr, the mixture was treated with saturated aqueous sodium bicarbonate and extracted 2× with ethyl acetate. The combined organic extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 10-100% ethyl acetate in hexanes, to provide the titled compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 495.2765 for [M+H]+ [calc'd for C31H35N4O2, [M+H]+=495.2755]: 1H NMR (400 MHz, CDCl3) δ 8.60-8.58 (m, 1H), 8.45-8.41 (m, 1H), 7.95-7.90 (m, 1H), 7.83-7.79 (m, 1H), 7.74-7.69 (m, 1H), 7.66-7.56 (m, 3H), 7.25-7.21 (m, 1H), 5.11-5.03 (m, 2H), 4.42 (br s, 1H), 4.03-3.98 (m, 2H), 3.79-3.72 (m, 1H), 3.65-3.59 (m, 1H), 3.06-3.02 (m, 2H), 2.88-2.86 (m, 1H), 2.67-2.59 (m, 2H), 2.35-2.17 (m, 2H), 2.09-2.06 (m, 1H), 2.04-1.81 (m, 2H), 1.42-1.22 (m, 4H), 0.96-0.83 (m, 4H) ppm.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O=[C:39]1[CH2:44][C@H:43]([C:45]([O:47][CH3:48])=[O:46])[C@@H:42]([C:49]([N:51]2[CH2:56][CH2:55][N:54]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH2:53][CH2:52]2)=[O:50])[CH2:41][CH2:40]1>C1COCC1>[CH:2](=[C:39]1/[CH2:40][CH2:41][C@H:42]([C:49]([N:51]2[CH2:56][CH2:55][N:54]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH2:53][CH2:52]2)=[O:50])[C@@H:43]([C:45]([O:47][CH3:48])=[O:46])[CH2:44]/1)/[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)[C@H]1CC(=O)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C/C(=C/c2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of benzyltriphenylphosphonium bromide (0.397 g, 0.000880 mol) in anhydrous THF (3.0 mL) at rt was added 1.00 M of sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.880 mL) dropwise. The resulting orange suspension was stirred at rt for 1 h, a solution of methyl (1S,2S)-5-oxo-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxylate (202 mg, 0.000586 mol) in anhydrous THF (3.0 mL) was then added via cannula. The reaction mixture was stirred at rt for 18 h. The reaction was quenched with water (20 mL), extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Combiflash with 20-60% EtOAc/Hex to give the product (141 mg, 57% in yield) as well as the S.M. (50 mg, 25% recovery of S.M.). MS (ESI): (M+H)+=419.2.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.[Br-:11].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Br:11]
Reactant: [Br-]
Reactant: CSc1ccccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CSc1ccccc1CBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
To a solution of 400 mg (2.59 mmol) of 2-methylthio-benzylalcohol in 8 mL of methanol was added 1.42 g (3.37 mmol) of triphenylphosphine dibromide and stirred at room temperature for 18 h. The mixture was concentrated and purified by silica gel flash chromatography, eluting with 2% ethyl acetate/hexane to give 289 mg of the title compound. NMR (CDCl3): δ 2.50 (s, 3H), 4.63 (s, 2H), 7.13 (m, 1H), 7.27 (m, 2H), 7.34 (d, 1).
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH3:43])[C@H:3]([NH:8][C:9](=[O:42])[C@@H:10]([CH2:18][C@@H:19]([OH:41])[CH2:20][S:21]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:4](=[O:7])[NH:5][CH3:6].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:43][C:2]([CH3:1])([CH3:44])[C@H:3]([NH:8][C:9](=[O:42])[C@@H:10]([CH2:18][C@@H:19]([OH:41])[CH2:20][SH:21])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:4](=[O:7])[NH:5][CH3:6]
Reactant: CCCCCCC[C@H](C[C@@H](O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCC[C@H](C[C@@H](O)CS)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a solution of 0.700 g (1.136 mmol) of the product of Example 33 and 0.363 mL (2.273 mmol) of triethylsilane dissolved in 10 mL of dichloromethane was dropwise added 10 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 0.5 h and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc/Hexanes (gradient: 1:3-1:1) to provide 0.263 g (62%) of the desired product as a colorless oil. Electrospray Mass Spec: 375.4 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](Cl)=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:13][NH:14][O:15][CH3:16].Cl.C(N(CC)CC)C>C(Cl)Cl>[CH3:16][O:15][N:14]([CH3:13])[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1)=[O:11]
Reactant: CNOC
Reactant: O=C(Cl)c1ccc2occc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc2occc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzofuran-5-carbonyl chloride (1 g, 5.54 mmol) in dry DCM (40 ml) is treated with N,O-dimethylhydroxylamine.HCl (0.594 g, 6.09 mmol) followed by triethylamine (1.930 ml, 13.84 mmol). After stirring at RT overnight, the mixture is diluted with DCM and washed with H2O, 1M HCl, 1M NaOH, brine, dried (MgSO4) and evaporated down to give a brown oil which is used without further purification; MS: m/z 206.1 [M+H]+
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH3:13])[C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: O=C(Cl)Cc1ccccc1
Product: CN(C)C(=O)Cc1ccccc1

Procedure:
Phenylacetyl chloride (25 ml) was added dropwise to a 50% aqueous solution of dimethylamine with ice-cooling. After the solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 solution, dried over MgSO4, and concentrated under reduced pressure to provide the title compound as colorless oil. Yield 28.90 g (95%) 1H-NMR (CDCl3) δ: 2.95(3H,s), 2.98(3H,s), 3.71(2H,s), 7.26-7.30(5H,m).