Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].Br[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1>N1C=CC=CC=1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([NH:2][NH2:3])=[N:6][CH:7]=1
Reactant: Brc1ccc(Br)nc1
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: NNc1ccc(Br)cn1

Procedure:
Hydrazine monohydrate (10 mL) was added to 2,5-dibromopyridine (10.0 g) in pyridine (100 mL) at room temperature, and the resultant mixture was refluxed under heat for 13 hours, and then cooled in air. The reaction solvent was removed under reduced pressure, and the residue was partitioned by use of aqueous 0.5N sodium hydroxide and chloroform. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give 5-bromo-2-hydrazinopyridine as a solid (7.61 g, 96%).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[NH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22]>>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([NH:17][C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: N#Cc1cccc(N)c1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: N#Cc1cccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)c1
Yield: 16 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and 3-aminobenzonitrile (38 mg, 0.33 mmol) to provide 233 (11 mg, 16% yield) as a white solid. LC-MS (M+H=313, obsd.=313).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:8](=[O:11])[C:9]=1[OH:10])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C=O)C>O>[C:1]([C:4]1[O:5][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:8](=[O:11])[C:9]=1[O:10][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1oc(-c2ccccc2)cc(=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1oc(-c2ccccc2)cc(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-acetyl-3-hydroxy-6-phenyl-4H-pyran-4-one (0.53 g), potassium carbonate (0.40 g), benzyl bromide (0.27 mL) and DMF (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.18 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=1.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][O:12][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:7][C:6]=2[CH:13]=1
Reactant: Oc1ccccc1
Reactant: OC[C@H]1COc2ccc(Br)cc2O1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)O[C@@H](COc1ccccc1)CO2
Temperature: 0 °C
Yield: 49.1 %

Procedure:
A mixture of [(2S)-7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (2.26 g, 9.20 mmol), phenol (0.87 g, 9.2 mmol), triphenylphosphine (2.42 g, 9.20 mmol) and THF (80 mL) is cooled in a 0° C. bath under N2. Diethylazodicarboxylate (1.50 ml, 9.5 mmol) is added, and the mixture is allowed to warm to rt overnight. The mixture is adsorbed onto SiO2 and chromatographed (Biotage 40S+SIM, (1:19) EtOAc:hexane). The product fractions are pooled and concentrated to afford 1.45 g (49%) of (2S)-7-bromo-2-(phenoxymethyl)-2,3-dihydro-1,4-benzodioxine as a clear oil. A mixture of this oil (14, 0.472 g, 1.47 mmol), (R)-3-aminoquinuclidine (0.557 g, 4.41 mmol), palladium acetate (0.083 g, 0.37 mmol), 1,3-bis(diphenylphosphino)propane (0.153 g, 0.370 mmol), and toluene (20 ml) are stirred under CO (g) in a 97° C. oil bath. The mixture is allowed to cool to rt and after 1.5 h is concentrated. The residue is partitioned between NaOH (aq) and EtOAc. The organic layer is separated, washed with brine, dried (MgSO4), filtered, and concentrated. The residue is chromatographed (Biotage 40 S, (1:10:190) NH4OH—MeOH—CHCl3). The product fractions are pooled and concentrated affording the product as a foam. The foam is taken up in EtOH, treated with fumaric acid (1.0 eq) and water (1 drop), and partially concentrated. Et2O is added and the resulting solid filtered and dried to provide 0.310 g (53%) of Example 11 as a monohydrate solid: 1H NMR (400 MHz, CD3OD) δ 7.49, 7.43, 7.25-7.35, 6.90-7.05, 6.70, 4.55-4.65, 4.45-4.55, 4.35-4.45, 4.20-4.35, 3.75-3.85, 3.20-3.50, 2.30-2.40, 2.15-2.30, 2.00-2.15, 1.85-2.00.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=O.C([O-])(O)=O.[Na+].[OH-].[Na+].[CH3:24][N:25]([CH3:28])[CH:26]=O>>[CH3:24][N:25]([CH3:28])[CH:26]=[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[F:6])[CH:14]=[O:16]
Reactant: O=C(O)Cc1ccccc1F
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)c1ccccc1F
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A flask containing phosphorus oxychloride (3.25 mL, 34.9 mmol) is cooled to ca. 10° C., and dimethylformamide (3.25 mL) is added dropwise. After stirring for 30 min, the resulting mixture is treated dropwise with a solution of 2-fluorophenylacetic acid (1.79 g, 11.6 mmol) in dimethylformamide (6 mL). This solution is heated to 70° C. for 18 h, then cooled and poured into ice. After being allowed to melt, the mixture is neutralized with solid NaHCO3, and then made basic with 50% aq. NaOH solution. After stirring for 1 h, the mixture is extracted twice with diethyl ether (100 mL), and the ether extracts are washed with brine, combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford 3-dimethylamino-2-(2-fluorophenyl)-acrolein (1.72 g, 8.92 mmol, 77%) as a yellow-brown oil. TLC RF 0.30 (ethyl acetate). 1H NMR (300 MHz, CDCl3): δ 9.08 (1H, s), 7.29-7.19 (2H, m), 7.14-7.01 (2H, m), 6.91 (1H, s), 2.88 (6H, br). MS (ES+): m/e 216 (18), 195 (23), 194 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:6]=1.[NH2:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[CH2:21]2)[CH:17]=[CH:16][C:15]=1[N+:33]([O-:35])=[O:34].C(N(C(C)C)CC)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([NH:13][C:14]3[C:15]([N+:33]([O-:35])=[O:34])=[CH:16][CH:17]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:27])[CH2:21]4)[N:19]=3)=[O:12])[CH2:8][CH2:9]2)[CH:6]=1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Reactant: O=C(O)C1(n2cc(Cl)cn2)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C([C@@H]1CCCN(c2ccc([N+](=O)[O-])c(NC(=O)C3(n4cc(Cl)cn4)CC3)n2)C1)N1CCCC1
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
Into a 1-L Atlas jacketed reactor were added 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarboxylic acid (49.08 g, 263.02 mmol), (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (70 g, 219.19 mmol), 4-dimethylaminopyridine (5.41 g, 43.84 mmol), toluene (600 mL) and diisopropylethylamine (95.56 mL, 547.96 mmol). The reaction mixture was heated to 45° C. and stirred for 10 min until most of the solids were dissolved. 1-Propanephosphonic acid cyclic anhydride (195.70 mL, 328.78 mmol, 50% solution in ethyl acetate) was added and the temperature was increased to 110° C. The reaction mixture was stirred for 19 h before adding more 1-propanephosphonic acid cyclic anhydride solution (25 mL). The mixture was stirred at 110° C. for 5 h. The mixture was concentrated to a low volume via distillation with jacket temperature at 80° C. A mixture of ethanol:water (1:1, 1000 mL) was added to keep the temperature around 70° C. Once the addition was complete, the mixture was cooled to 15° C. over a period of 2 h and left granulating for 18 h. The solids were filtered and rinsed with a mixture of ethanol:water (1:1, 750 mL) and dried in a vacuum oven at 40° C. with a nitrogen bleed for 18 h to afford (R)-1-(4-chloro-1H-pyrazol-1-yl)-N-(3-nitro-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-2-yl)cyclopropanecarboxamide (72 g). 1H NMR (500 MHz, CDCl3) δ 1.50-1.66 (m, 4H), 1.82-2.05 (m, 11H), 2.53-2.61 (m, 1H), 3.00-3.20 (m, 2H), 3.34-3.42 (m, 1H), 3.49 (t, 2H), 6.32 (d, 1H), 7.61 (s, 1H), 7.68 (s, 1H), 8.21 (d, 1H), 11.01 (s, 1H); MS (ES+) (M+H) 488; HPLC retention time: 7.520 min (Method: Column: Halo C18, 4.6×150 mm, 2.7 μm; Mobile Phase B: 0.1 M phosphoric acid (H3PO4) in water; Mobile Phase D: acetonitrile; Gradient: 80%-10% Mobile Phase B until 7.00 min; hold until 10.00 min; rapid ramp of 80% Mobile Phase B until 10.1 min; equilibrate until 12.1 min; Flow: 0.8 mL/min; Column Temperature: 30° C.; DAD1A, Sig=254 nm).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13]O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:34]I.N1C=CN=C1>C1COCC1>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13][I:34])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c(CCO)coc12
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc2c(CCI)coc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(7-methoxy-1-benzofuran-3-yl)ethanol (960 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. The reaction mixture was extracted with chloroform, washed well with 5% Na2S2O3 solution and the organic layer was dried over anhydrous MgSO4. It was filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexane. The product, namely 2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide, was obtained as brown liquid. Yield: 1.3 g (86%); 302 (M+H).
Reaction SMILES: C[S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]#[N:10].[Br:11]Br>ClC1C=CC=CC=1>[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[S:2][Br:11])#[N:10]
Reactant: CSc1ccccc1C#N
Reactant: BrBr
Solvent: Clc1ccccc1
Product: N#Cc1ccccc1SBr
Temperature: 100 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
74.5 g (0.500 mol) of 2-cyanophenyl methyl sulfide and 250 g of chlorobenzene were placed in a 500 ml four-neck flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser and 96.0 g (0.600 mol) of bromine was added dropwise thereto at about 100° C. over five hours while stirring. The excess bromine was removed with an aqueous sodium carbonate solution, followed by distillation under reduced pressure to obtain 90.4 g of 2-cyanobenzenesulfenyl bromide. The yield starting from 2-cyanophenyl methyl sulfide was 84.5%.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([CH2:22][CH2:23][C:24]=2Br)[CH:20]([NH:26][C:27](=[O:36])[CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:19]3=[O:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:38]([O:49]CCCC)([O:44][CH2:45][CH2:46][CH2:47][CH3:48])[O:39][CH2:40][CH2:41][CH2:42][CH3:43]>C1(C)C=CC=CC=1.[Ni](Cl)Cl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([CH2:22][CH2:23][C:24]=2[P:38]([O:39][CH2:40][CH2:41][CH2:42][CH3:43])([O:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:49])[CH:20]([NH:26][C:27](=[O:36])[CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:19]3=[O:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Br)CCC12
Reactant: CCCCOP(OCCCC)OCCCC
Agent: Cl[Ni]Cl
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(OCCCC)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)C2CC1
Yield: 24 %

Procedure:
A solution of 3-bromo-7-[(phenoxyacetyl)amino]-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (diphenylmethyl)ester (2 g, 3.6 mmol) in toluene (50 mL) was added tri-n-butyl phosphite (15 mL) and nickel(II)chloride (50 mg, 039 mmol). The reaction was brought to reflux under nitrogen. Each hour, the reaction was cooled and an additional portion of nickel(II)chloride (50 mg, 0.39 mmol) was added. This process was continued for a total of six hours. The reaction was concentrated in vacuo and the residue purified by flash chromatography on silica gel (25%-50% ethyl acetate/hexanes) to provide 7-[(Phenoxyacetyl)amino]-8-oxo-3-(dibutoxyphosphinyl)-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid (diphenylmethyl)ester (588 mg, 24%):
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[S:23](Cl)([Cl:26])(=[O:25])=[O:24].N1C=CC=CC=1>C(Cl)Cl>[S:23]([Cl:26])([O:8][C:7]1[CH:6]=[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])[C:4]([F:22])=[CH:3][C:2]=1[Cl:1])(=[O:25])=[O:24]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OS(=O)(=O)Cl)c(Cl)cc2F)c1=O

Procedure:
A solution of 10.16 g of 3-(4-chloro-2-fluoro-5 -hydroxyphenyl)-1-methyl-6 -trifluoromethyl-2,4 (1H,3H)-pyrimidinedione and 20.20 g of sulphuryl chloride in 100 ml of methylene chloride is treated with a solution of 3.56 g of pyridine in 10 ml of methylene chloride while stirring and cooling during 5 minutes. The temperature rises to 20° C. The reaction mixture is stirred at 20°-25° C. for 15 minutes, subsequently poured on to ice and stirred vigorously. The organic phase is washed throughly with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from diethyl ether/n-hexane. There is obtained 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorophenyl chlorosulphate m.p. 133°-135° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:11][S:12][C:13]2[NH:14][C:15]3[CH:21]=[C:20]4[O:22][CH2:23][O:24][C:19]4=[CH:18][C:16]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[N+]([O-])=O.[CH3:25][OH:26].C[O-].[Na+]>C(O)(=O)C>[CH3:25][O:26][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:11][S:12][C:13]2[NH:14][C:15]3[CH:21]=[C:20]4[O:22][CH2:23][O:24][C:19]4=[CH:18][C:16]=3[N:17]=2)[C:2]=1[CH3:1]
Reactant: Cc1c([N+](=O)[O-])ccnc1CSc1nc2cc3c(cc2[nH]1)OCO3
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)OCO4)c1C

Procedure:
A solution of 500 mg (1.45 mmol) of 6-[[(3-methyl-4-nitro-2-pyridyl)methyl]thio]-5H-1,3-dioxolo[4,5-f]-benzimidazole in 20 ml of abs. methanol is treated with 300 mg of sodium methylate, whereupon the mixture is boiled at reflux under argon for 18 hours. The reaction mixture is buffered by means of glacial acetic acid and concentrated in vacuo. The residue is treated with methylene chloride/sodium bicarbonate solution, whereupon the organic solution is dried and concentrated. By recrystallization from ethyl acetate there is obtained 6-[[(4-methoxy-3-methyl-2-pyridyl)methyl)thio)-5H-1,3-dioxolo[4,5-f]benzimidazole of melting point 215°-220°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([NH2:10])[CH:5]=1.Br[C:12]1[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16]([Br:18])[CH:17]=1>>[Br:18][C:16]1[CH:17]=[C:12]([NH:10][C:6]2[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[N:8]([CH3:9])[N:7]=2)[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: COCc1cc(N)nn1C
Product: COCc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Yield: 71.4 %

Procedure:
Following Example 148a, 1.7 g of 176b and 3.2 g of 3,5-dibromo-1-methylpyridin-2(1H)-one were reacted to give 176c as a yellow solid (2.8 g, 70%). MS: [M+H]+ 327. 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J=2.5, 1H), 7.38 (s, 1H), 6.88 (d, J=2.5, 1H), 5.86 (s, 1H), 4.41 (s, 2H), 3.82 (s, 3H), 3.58 (s, 3H), 3.36 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[C:33]([NH:37][C:38](=[O:46])[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([CH3:36])([CH3:35])[CH3:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:43]3[CH2:42][CH2:41][N:40]([CH2:39][C:38]([NH:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:46])[CH2:45][CH2:44]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)NC(=O)CN1CCNCC1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)(C)C)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N-tert-butyl-2-piperazin-1-yl-acetamide dihydrochloride to give 2-{4-[(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-tert-butyl-acetamide in an analogous manner as described in example 1. LR-MS: 642.3 [(M+H)+]
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[OH:7][CH2:8][CH2:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14].N1C=CC=CC=1>C(OCC)C>[Br:1][CH:2]([CH3:6])[C:3]([O:7][CH2:8][CH2:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[O:4]
Reactant: CC(Br)C(=O)Br
Reactant: CCOC(=O)NCCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)NCCOC(=O)C(C)Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 32.4 g of 2-bromopropionyl bromide in 70 ml of diethyl ether is added dropwise within one hour while cooling with ice to a solution, cooled to 0° C., of ethyl 2-hyroxyethylcarbamate and 13.1 g of pyridine in 80 ml of diethyl ether. The reaction mixture is then stirred at room temperature for 45 minutes. For the working-up, the mxture is filtered under suction through Celite and the filtrate is poured into water. The aqeuous phase is extracted twice with diethyl ether, and the combined organic phases are washed twice with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulphate and evaporated to dryness. There is obtained ethyl 2-(2-bromopropionyloxy)-ethylcarbamate as a colourless oil which either can be used in the reaction without further purification or can be purified further by chromatography on silica gel with n-hexane/diethyl ether (1:1); nD20 1.4770.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N:12][O:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[N:12][O:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2conn2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(-c2conn2)cc1
Temperature: 75 °C

Procedure:
A mixture of 4-nitrophenyloxadiazole (2.87 g, 0.015 mol, prepared according to Lin et al., J. Org. Chem., 1979, 44, 4160) and SnCl2.2H2O (16.92 g, 0.075 mol) in 75 mL of ethyl acetate was heated at 75° C. for 30 minutes. The yellow reaction mixture was cooled to room temperature, poured into ice-water and the pH was made slightly basic (pH 7-8) by the addition of 5% NaHCO3. The reaction mixture was then extracted with ethyl acetate, dried over MgSO4 and concentrated in vacuo. The remaining yellow solid was triturated with hexane, collected and dried to yield 2.07 g of the title A compound, m.p. 97°-99° C. TLC, silica gel, EtOAc/hexanes (2:1), Rf =0.55; M.S. (M+H)+ at 162, M.W. 161. This compound was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]1([C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13]1)[CH2:7]2)([O-])=O>CCOC(C)=O.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]1([C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13]1)[CH2:7]2
Reactant: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CC1(C2)NC(=O)NC1=O
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a suspension of (±)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione (1.77 g, 7.16 mmol) in EtOAc (100 μL) and MeOH (100 mL) was added 10% Pd/C (400 mg) and the reaction stirred vigorously under hydrogen (ca. 1 atm). After 1 h, the catalyst was filtered off and the filtrate was concentrated to yield 1.50 g (97%) of the title compound as a pale brown solid. MS: m/z=218 (M+1).
Reaction SMILES: COCC[CH:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10].[C:11]([O:14][C:15](=O)[CH3:16])(=[O:13])[CH3:12]>>[C:6]([O:7][CH2:8][CH2:9][CH:12]1[CH2:16][CH2:15][O:14][C:11]1=[O:13])(=[O:10])[CH3:5]
Reactant: COCCC1CCOC1=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCCC1CCOC1=O
Temperature: 120 °C
Reaction time: 69 h
Yield: 61 %

Procedure:
In a stirred vessel, a mixture of 20 g of 3-(2'-methoxyethyl)-dihydro-2(3H)furanone, 100 g of acetic anhydride, and 10 of Nafion is heated to 120° C. Following a period of 69 h, the reaction is terminated (conversion: 100%) and the catalyst is separated by filtration. Following purification by distillation, there is obtained 61% of 3-(2'-acetoxyethyl)-dihydro-2(3H)furanone.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([CH3:15])[CH3:14].C(O)(C(F)(F)F)=O>>[CH:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:18][CH:17]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 65.1 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (5.0 g, 31.2 mmol), 4-isopropylbenzaldehyde (5.08 g, 1.1 equiv.) and TFA (4.8 mL, 2 equiv.) to give the title compound (5.9 g, 67%) as white crystals after recrystallization from iPr2O.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[F:12][C:13]1[C:18]([CH:19]=[O:20])=[C:17]([F:21])[CH:16]=[CH:15][C:14]=1[NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24].[OH-].[K+].Cl>CO>[C:10]([C:8]1[CH:9]=[C:4]2[C:3]([CH:19]([OH:20])[C:18]3[C:13]([F:12])=[C:14]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH:15]=[CH:16][C:17]=3[F:21])=[CH:2][NH:1][C:5]2=[N:6][CH:7]=1)#[N:11]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Reactant: N#Cc1cnc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(C#N)cc23)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (13, 301 mg, 2.10 mmol), propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (12, 1.11 g, 4.20 mmol) and potassium hydroxide (354 mg, 6.31 mmol) were combined in a vial with 4.2 mL of methanol. The reaction was stirred for 3 hours at room temperature. The reaction solution was neutralized with 0.1 N aqueous hydrochloric acid and extracted 3× with ethyl acetate. The organic layers were combined and washed with brine, then dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. This was allowed to stir over the weekend at room temperature, then extracted with ethyl acetate and water. The organic layer was washed with brine and then dried over magnesium sulfate, filtered, and the solvents were removed from the filtrate under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired compound (14, 315 mg). MS(ESI) [M−H+]−=405.3.