Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:6]([C:9](=[O:11])[CH3:10])[CH2:7][S:8][C@H:3]12.O1CCCC1.C(=O)(O)[O-].[Na+].[CH:40]([O:42][CH:43]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:44](Cl)=[O:45])=[O:41]>C(OCC)(=O)C>[CH:40]([O:42][CH:43]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:44]([NH:1][CH:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:6]([C:9](=[O:11])[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:45])=[O:41]
Reactant: CC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: O=COC(C(=O)Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(OC=O)c3ccccc3)[C@H]2SC1
Temperature: 5 °C
Yield: 51.2 %

Procedure:
To a cooled (5° C.), stirred solution of 0.270 g. of benzhydryl 7-amino-3-acetyl-3-cephem-4-carboxylate in 20 ml. of dry tetrahydrofuran was added 0.0612 g. of sodium bicarbonate and dropwise, a solution of 0.144 g. of 2-formyloxy-2-phenylacetyl chloride in 2 ml. of tetrahydrofuran. The reaction mixture was allowed to stir with cooling for 30 minutes after which time it was transferred to a separatory funnel with the aid of cold ethyl acetate and washed with water, and brine (2X) and then dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness provided a residue which was chromatographed on silica gel using a toluene-ethyl acetate gradient to give 0.194 g. (51.2 percent) of the title product as a white froth:
Reaction SMILES: [NH:1]([C:8]([N:10]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=3)=[N:22][CH:23]=2)[CH2:13][CH2:12]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:50])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[NH:1]([C:8]([N:10]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:11]1[CH2:12][CH2:13][N+:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])=[CH:27][CH:26]=3)=[N:22][CH:23]=2)([O-:50])[CH2:15][CH2:16]1)=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc(CN3CCC(N(C(=O)Nc4ccccc4)c4ccccc4)CC3)cn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1ccc(Oc2ccc(C[N+]3([O-])CCC(N(C(=O)Nc4ccccc4)c4ccccc4)CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the compound prepared in Example 8(10) (361 mg) in chloroform (6.1 ml) was added m-chloroperbenzoic acid (116 mg) on ice bath. The reaction mixture was stirred for 4 hours at room temperature. To reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was washed with chloroform and methanol, dried to give the compound of the present invention (194 mg) having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C(OCC)C.[CH:17]1([Mg]Br)[CH2:19][CH2:18]1>O1CCCC1>[CH:17]1([C:7]2([OH:11])[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)[CH2:19][CH2:18]1
Reactant: Br[Mg]C1CC1
Reactant: O=C1CCc2cc(F)ccc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(C2CC2)CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.00 g (13.3 mmol) of 5-fluoro-1-indanone were introduced into 50 ml of diethyl ether at RT, 40 ml (20.0 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were added, and the mixture was stirred at RT overnight. The reaction mixture was added to a saturated, ice-cold aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 2.22 g (87% of theory) of the title compound which were reacted without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[C:5]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH3:14])(=[O:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:5]([N:8]1[CH2:13][CH2:12][N:11]([CH2:2][CH2:3][OH:4])[CH2:10][C@H:9]1[CH3:14])(=[O:7])[CH3:6]
Reactant: CC(=O)N1CCNC[C@H]1C
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)N1CCN(CCO)C[C@H]1C
Temperature: 80 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
2-Bromoethanol (7.34 mL, 103.38 mmol) was added to a stirred mixture of (R)-1-acetyl-2-methylpiperazine (2.94 g, 20.68 mmol) and potassium carbonate (8.57 g, 62.03 mmol) in THF (75 mL). The resulting mixture was stirred at 80° C. for 18 hours before, then filtered and evaporated. The residue was purified by ion exchange chromatography, using an SCX column and eluting with 2M ammonia in methanol. Pure fractions were evaporated to dryness to give (R)-2-(4-acetyl-3-methylpiperazin-1-yl)ethanol (3.74 g, 97%) as a yellow oil.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[N:9]1[CH:10]=[CH:11][N:12]2[C:17]=1[CH:16]=[C:15]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22])[CH:14]=[N:13]2>CN(C=O)C>[I:1][C:11]1[N:12]2[N:13]=[CH:14][C:15]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:17]2=[N:9][CH:10]=1
Reactant: COC(=O)c1cccc(-c2cnn3ccnc3c2)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2cnn3c(I)cnc3c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 50.1 %

Procedure:
N-Iodosuccinimide (280 mg, 1.3 mmol) was added to a mixture of methyl 3-imidazo[1,2-b]pyridazin-7-ylbenzoate (160.0 mg, 0.6318 mmol) in DMF (2 mL) and then the reaction was stirred at r.t. for 6 h. The precipitate formed was filtered and washed with ether to provide the desired product (0.12 g). LCMS (M+H)+: m/z=380.0
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C)CCN(C)C.C([Li])(CC)C.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]=[O:32]>C(OCC)C>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]([CH:12]1[CH2:11][CH2:10][CH2:9][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[OH:32]
Reactant: O=Cc1ccco1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC1C(O)c1ccco1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
N-Boc-pyrrolidine (5.0 g) is dissolved in diethyl ether (60 mL) and the solution is cooled to −78° C. N,N,N′,N′-Tetramethylethylenediamine (TMEDA) (4.4 mL) is added to the mixture followed by sec-butyl lithium (27.0 mL, 1.3 M in cyclohexane) maintaining the temperature below −60° C. After 2 h, 2-furaldehyde (2.9 mL) is added and the mixture is stirred at −70° C. for an additional 30 min. The reaction mixture is allowed to warm to room temperature and is then quenched with water (25 mL) and poured into EtOAc (200 mL). The separated organic layer is washed with saturated aq. ammonium chloride (3×50 mL) followed by brine (50 mL), dried (MgSO4), and concentrated The crude product is purified by column chromatography (heptane/EtOAc, 8/1; 5/1) to afford 4.97 g of 2-furyl(N-Boc-pyrrolidin-2-yl)methanol as a mixture of diastereomers. The resulting 2-furyl(N-Boc-pyrrolidin-2-yl)methanol (4.43 g) is dissolved in dichloromethane (200 mL) and trifluoroacetic acid (30 mL) is added. The mixture is poured into a 1 M solution of sodium hydroxide. The organic layer is separated and washed with saturated aq. sodium bicarbonate (2×100 mL). The aqueous layers are extracted with dichloromethane (4×50 mL) and the combined organic layers are concentrated. The crude product is purified by column chromatography (CH2Cl2/methanol/NH4OH, 95/5/1; 90/10/1). The resulting oil is distilled in a Kugelrohr apparatus (0.175-200° C., 0.2 Torr) to afford 0.20 g of the title compound as a mixture of diastereomers. Physical characteristics. MS (ESI+) m/z 168 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH3:7])[CH2:5][OH:6])[CH3:2].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[CH2:1]([O:3][CH:4]([CH3:7])[CH2:5][O:6][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15])[CH3:2]
Reactant: CCOC(C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(C)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
10 g of 2-ethoxypropanol was dissolved in 59 ml of pyridine and the solution was cooled to below 5° C. To the solution under stirring was added 22 g of p-toluenesulfonic acid chloride. After that, the mixture was stirred for 5 hours at room temperature and left standing overnight. Cold water was added thereto, and the mixture was subjected to extraction with ether. The ether extract was washed with water, followed by distilling-off of the ether to obtain 24 g of p-toluenesulfonic acid 2-ethoxypropyl ester.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[Br:12][CH:13](Br)[CH3:14]>O.CCOC(C)=O>[Br:12][CH2:13][CH2:14][O:11][C:6]1[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([Cl:10])[CH:7]=1
Reactant: CC(Br)Br
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1cc(Cl)cc(OCCBr)c1
Temperature: 25 °C

Procedure:
To a solution of NaOH (2.45 g, 61.3 mmol) in water (20 mL) was added 3,5-dichlorophenol (5 g, 30.7 mmol). The solution was heated at reflux for 1 h and was cooled to room temperature. Dibromoethane (11.52 g, 61.3 mmol) was added and the reaction was heated at reflux for 24 h. The cooled solution was diluted with EtOAc and the organic solution was washed sequentially with HCl (1N, 1×), water (1×), and brine (1×). The organic solution was dried (MgSO4), filtered, and concentrated. Purification by flash chromatography (hexanes to 5% EtOAc in hexanes ) provided the title compound (3.79 9). 1H NMR (400 MHz, CDCl3) δ6.98 (m, 1H), 6.82 (m, 2H), 4.25 (t, 2H), 3.61 (t, 2H).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[C:6]([C@@H:14]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].[CH3:30][S:31][C:32](=[N:35][C:36]#[N:37])SC.C(OCC)(=O)C>C(O)C>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C@@H:14]([C:22]2[CH:23]=[CH:24][C:25]([NH:26][C:32](=[N:35][C:36]#[N:37])[S:31][CH3:30])=[CH:27][CH:28]=2)[CH2:15][C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:12])[F:13]
Reactant: Nc1ccc([C@@H](Cc2ccncc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Reactant: CSC(=NC#N)SC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSC(=NC#N)Nc1ccc([C@@H](Cc2ccncc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Yield: 54.1 %

Procedure:
To a solution of 4-[1-(R)-(3,4 bis(difluoromethoxy)phenyl)-2-(4-pyridinyl)ethyl]aniline (1.8 g, 4.4 mmol) in ethanol (20 ml) at room temperature was added dimethylcyanodithioimidocarbonate (1.3 g, 8.9 mmol). The mixture was heated at 70° for 72 h, cooled and the solvent removed in vacuo to give a yellow foam. The foam was subjected to flash chromatography (SiO2 ; eluant ethyl acetate) to give the title compound as a yellow foam (1.2 g). 1Hnmr (300 MHz, CDCl3) δ 2.46 (3H, s), 3.30 (2H, d, J 7.98 Hz), 4.23 (1H, t, J 7.84 Hz), 6.46 (1H, t, J 73.58 Hz), 6.48 (1H, t, J 73.51 Hz), 6.90 (2H, d, J 6.0 Hz), 7.02 (1H, d, J 8.38 Hz), 7.06 (1H, br), 7.16 (1H, d, J 3.0 Hz), 7.16 (1H, d, J 3.0 z), 7.18-7.25 (3H, c), 8.10 (1H, br) and 8.40 (2H, d, J 6.03 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:24])=O>CN(C=O)C.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:24])=[O:17])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(OCc2ccccc2)ccc1CC(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Using a similar procedure to that described in the portion of Example 17 that is concerned with the preparation of starting materials, 2-(4-benzyloxy-2-methoxyphenyl)acetic acid (0.1 g) was reacted with oxalyl chloride (0.093 ml) and DMF (3 drops) in methylene chloride (5 ml). The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated to give 2-(4-benzyloxy-2-methoxyphenyl)acetyl chloride. A mixture of the material so obtained, 3-amino-4,5-dimethylisoxazole (0.062 g), diisopropylethylamine (0.065 ml), 4-dimethylaminopyridine (0.005 g) and methylene chloride (5 ml) was stirred at ambient temperature for 14 hours. The resultant mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained N-(4,5-dimethylisoxazol-3-yl)-2-(4-benzyloxy-2-methoxyphenyl)acetamide; 1H NMR: (DMSOd6) 1.77 (s, 3H), 2.28 (s, 3H), 3.55 (s, 2H), 3.74 (s, 3H), 5.09 (s, 2H), 6.54 (m, 1H), 6.63 (d, 1H), 7.09 (d, 1H), 7.33 (m, 1H), 7.39 (m, 2H), 7.45 (m, 2H), 10.15 (br s, 1H); Mass Spectrum: M+H+ 367.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[CH:10][O:9][CH:8]=2)=[CH:3][CH:2]=1.BrC1C=CC(C2C=CC([C:31]#[N:32])=CC=2)=CC=1.O1C=CC(B(O)O)=C1>CO>[O:9]1[CH:10]=[CH:11][C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:12]3[CH:17]=[CH:16][C:15]([C:31]#[N:32])=[CH:14][CH:13]=3)=[CH:2][CH:3]=2)=[CH:8]1
Reactant: N#Cc1ccc(-c2ccc(Br)cc2)cc1
Reactant: c1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Agent: OB(O)c1ccoc1
Solvent: CO
Product: N#Cc1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Yield: 53 %

Procedure:
As described in Example 1(a) for the preparation of 3-biphenyl-4-yl-furan, crude 4′-bromo-biphenyl-4-carbonitrile (200 mg, 0.775 mmol) and 3-furanboronic acid (see Thompson, W. J.; Gaudino, G. J. Org. Chem. 1984, 49, 5237-5243; 105 mg, 0.937 mmol) in MeOH (2 mL) were coupled to give a yellow solid, which was purified via preparative TLC. Elution with EtOAc:benzene (1:99) provided 100 mg (53%) of 4′-furan-3-yl-biphenyl-4-carbonitrile as a grey powder, mp 199-203° C. 1H NMR (CDCl3): δ 7.81 (bs, 1H), 7.72 (d, 4H, J=1.9 Hz), 7.61 (s, 4H), 7.51 (bs, 1H), 6.75 (s, 1H). IR (KBr): 2225, 1604, 1503, 1396, 1162, 1102, 1058 cm−1. Anal. Calculated for C17H11NO•0.3 EtOAc•0.2 C6H6: C, 80.78; H, 5.05; N, 5.01. Found: C, 80.96; H, 4.88; N, 5.00.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH:14]([CH3:16])[C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1.O>CN1CCCC1=O>[CH3:1][N:2]1[CH2:15][CH:14]([CH3:16])[C:5]2[N:6]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:26][CH:25]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3C
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)C(C)CN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2,3,4,5-tetrahydro-2,4,8-trimethyl-1H-pyrido[4,3-b]indole (200 mg, 0.934 mmol) in N-methyl-2-pyrolidone (2.5 mL) was added powdered KOH (463 mg, 8.27 mmol) and allow to stir for 10 min at RT. 2-Trifluoromethyl-5-vinyl pyridine (323 mg, 1.87 mmol) was added and stirred further for 12 h at RT. The reaction was monitored by TLC. After completion of reaction, water (10 mL) was added and the mixture filtered. Water was added to the filtrate and the product extracted with EtOAc (50 mL). The organic layer was dried over sodium sulfate, evaporated in vacuum and purified by HPLC to obtain the product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.C([O-])(=O)C.[Na+]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[N+:24]([C:23]1[C:18]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: Nc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1cccnc1Nc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Temperature: 116 °C
Yield: 23 %

Procedure:
(R)-5-Amino-3-(pyrrolidin-2-ylmethyl)indole and 2-chloro-3-nitropyridine. Sodium acetate was used as base, acetic was used as solvent, and the reaction was heated at reflux (116° C.) for 2 hours. Column chromatography afforded the title compound (23%) as a dark red foam: 1H NMR (CDCl3) δ10.05 (br s, 1H), 9.23 (br s, 1H), 8.49 (dd, J=1.8 and 8.3 Hz, 1H), 8.39 (1.8 and 4.5 Hz, 1H), 7.70 (d, J=1.7 Hz, 1H) 7.33-7.22 (m, 2H), 6.98 (s, 1H), 6.73 (dd, J=4.5 and 8.3 Hz, 1H), 3.46-3.34 (m, 1H), 310-2.97 (m, 1H), 2.97-2.78 (m, 3H), 1.99-1.64 (m, 3H), 1.56-1.42 (m, 1H); 13C NMR (CDCl3) δ155.7, 151.5, 135.5, 134.5, 129.2, 128.1, 127.8, 123.8, 119.4, 114.3, 113.0, 111.6, 59.5, 45.7, 31.3, 30.6, 24.7; FAB LRMS (m/z, relative intensity) 338 (6,[MH+ ]), 309 (12), 155 (49), 135 (38), 119 (100). Anal. calcd. for C18H19N5O2. 0.67 C2H4O2 [acetic acid]: C, 61.53; H, 5.79; N, 18.56. Found: C, 61.57; H, 5.74; N, 18.82.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:12])[C:9]=1[CH2:10]Br)=[O:4].[CH2:13]([O:15][C:16](=[O:30])[CH2:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH3:29])C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:12])[C:9]=1[CH2:10][N:18]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH3:29])[CH2:17][C:16]([O:15][CH3:13])=[O:30])=[O:4]
Reactant: COC(=O)c1scc(Br)c1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(Br)csc1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
4-Bromo-3-bromomethyl-thiophene-2-carboxylic acid methyl ester (2.28 g, 7.31 mmol), example 31-b, was dissolved in 18 mL of dry N,N-dimethylformamide. N-(2,4-dimethoxy-benzyl)glycine ethyl ester (1.75 g, 7.31 mmol) and potassium carbonate (1.11 g, 8.04 mmol) were added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic fraction was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-60% ethyl acetate in hexanes to produce 3.18 g of a tan oil. MS: (+) m/z 494.1, 496.1 (M+Na+, 79Br/81Br).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][C@@H:9]([O:11]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:8][N:7]1[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])=[O:5])[CH3:2].[C:32]([O-])(=[O:34])[CH3:33].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][C@H:9]([O:11][C:32](=[O:34])[CH3:33])[CH2:8][N:7]1[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:23])=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1S(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H]1C[C@H](OC(C)=O)CN1S(=O)(=O)c1ccc(C)cc1
Temperature: 60 °C

Procedure:
To a stirred solution of 1-(toluene-4-sulfonyl)-4-(toluene-4-sulfonyloxy)-pyrrolidine-2-carboxylic acid ethyl ester (2) (1 g, 2.14 mmol) in dry DMF (25 mL) is added potassium acetate (0.314 g, 3.21 mmol) in one portion. The reaction mixture is then heated at 60° C. for 4 h. Water (50 mL) is added to the reaction mixture and extracted with ethyl acetate (2×75 mL), combined organic layer are washed with water (2×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give the crude compound. Crude compound is purified by column chromatography over silica gel (100-200 mesh) using 15% ethyl acetate-hexane as eluent to give compound (3).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([CH2:17][CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:16].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]3([CH2:17][CH3:18])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: CCC1(CCCCCCl)C(=O)Nc2ccccc21
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: CCC1(CCCCCN2CCN(c3ccc(Cl)cc3)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 from 3-(5-chloropentyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(4-chlorophenyl)-piperazine.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].N12CCCN=C1CCCCC2.Br[CH2:21][C:22](=[O:25])[CH2:23][CH3:24]>C1C=CC=CC=1>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([C:1]#[N:2])[CH2:21][C:22](=[O:25])[CH2:23][CH3:24])[CH3:8]
Reactant: CCC(=O)CBr
Reactant: CCOC(=O)CC#N
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(C#N)CC(=O)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a 5° C. solution containing 27.8 g (246 mmol) of ethyl cyanoacetate and 38.2 g (251 mmol) of 1,8-diazabicyclo[5.4.0]undec-7ene in 420 mL of benzene was added over 30 minutes a solution of 1-bromo-2-butanone in 70 mL of benzene. The ice bath was removed and the reaction stirred for 1 hour at ambient temperature. At this time, the solids were removed by filtration and washed with 100 mL of methyl tert-butyl ether. The filtrate and the wash were combined and concentrated. The crude product was purified by short path distillation (0.2 torr, 140° C.) to provide 40.0 g (88.9%) of 2-cyano-4-oxohexanoic acid ethyl ester as a colorless oil. nmr (500 MHz, CDCl3) δ1.09 (t, J=7.3 Hz, 3H), 1.31 (t, J=7.1 Hz, 3H), 2.50 (q, J=7.3 Hz, 2H), 2.96 (dd, J=5.5, 18.0 Hz, 1H), 3.16 (dd, J=7.2, 18.0 Hz, 1H), 3.96 (dd, J=5.5, 7.2 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H).