Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[O:8][CH2:7]2)(O)=O.S(N)([NH2:29])(=O)=O.S(Cl)(Cl)=O.[OH-].[NH4+]>S1(CCCC1)(=O)=O.CCCCCCC.O>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)([CH2:13][CH2:14][CH2:15][N:16]([CH3:17])[CH3:18])[O:8][CH2:7]2)#[N:29]
Reactant: NS(N)(=O)=O
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C(=O)O)ccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 130 °C
Reaction time: 0.25 h

Procedure:
5-Carboxy-1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-1,3-dihydro-isobenzofuran (5 g, 0.015 mole) and sulfamide (1.65 g, 0.017 mole) were dissolved in sulfolane (15 mL). Thionylchloride (2.25 g, 0.019 mole) was added at room temperature and the temperature of the reaction mixture was raised to 130° C. for 2 hours. The reaction mixture was allowed to cool to 75° C. and water (25 mL) was added. The temperature was held at 75° C. for 15 min, and then the reaction mixture was cooled to room temperature. pH was ajusted to 9 with ammonium hydroxide and then n-heptane (75 mL) was added. The temperature was raised to 70° C. and the hot n-heptane layer was isolated from which the title compound crystallised on cooling. Yield 3.77 g. Purity (HPLC peak area)>97%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14]O)C1C=CC=CC=1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N:32]1(C(OC(C)(C)C)=O)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.C(Cl)(Cl)Cl>[CH3:1][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1
Reactant: OCC1COCCN1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1CCOCC1CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4-Benzylmorpholin-3-yl)methanol (3.00 g, 22.9 mmol) described in Journal of Chemical Society, Perkin Transactions 1, p. 2577 (1985) was dissolved in tetrahydrofuran (5 mL), and the solution was mixed with triethylamine (6.30 mL, 49.2 mmol) and methanesulfonic anhydride (3.20 g, 18.5 mmol), followed by stirring at room temperature for two hours. After checking the completion of the reaction by thin layer chromatography, the reaction mixture was mixed with chloroform (50 mL) and a saturated aqueous sodium bicarbonate solution (50 mL), followed by separation. The organic layer was washed with brine (100 mL), was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting pale yellow oil was dissolved in dioxane (50 mL), and the solution was mixed with tert-butyl 1-piperazinecarboxylate (3.44 g, 18.5 mmol) and sodium carbonate (19.6 g, 185 mmol), followed by stirring at 80° C. for eighteen hours. After standing to cool, the reaction mixture was mixed with chloroform (50 mL) and water (50 mL), followed by separation. The organic layer was washed with brine (100 mL), was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting brown oil was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and thereby yielded tert-butyl 4-(4-benzylmorpholin-3-ylmethyl)piperazinecarboxylate (2.79 g, 60%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:13][CH2:14][C:15](O)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(OCC)(=O)C.[OH-].[Na+]>CCOCC.O>[CH:7]1([CH2:13][CH2:14][CH2:15][OH:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(O)CCC1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OCCCC1CCCCC1

Procedure:
Lithium aluminum hydride (24.2 g, 0.64 mole) was slurried into 300 ml of dry ether (distilled from benzophenone ketyl, generated in situ from sodium and benzophenone). The slurry was cooled in an ice-water bath and a solution of 100 g (0.64 mole) of 3-cyclohexylpropionic acid (Bielstein 9:[2]13) in 250 ml of dry ether was slowly added. The resultant mixture was heated to reflux for 1 hr and then cooled in an ice-water bath. Ethyl acetate (100 ml) was slowly added to the mixture. This addition was followed by the addition of 24.2 ml of water, 24.2 ml of 15% aqueous sodium hydroxide solution and 72.6 ml of water. The mixture was filtered and the solvent was removed in vacuo. Distillation of this mixture at reduced pressure resulted in 71.6 g (78.7%) of pure 3-cyclohexylpropan-1-ol having the following physical characteristics:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1)=O)(C)(C)C.Cl.O1CCOCC1>>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([N:21]([CH:23]([CH3:24])[CH3:25])[CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(c1ccc(NC(=O)OC(C)(C)C)cc1)N(C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C(c1ccc(N)cc1)N(C)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 26 (1.19 g, 3.40 mmol) and 4M hydrogen chloride in 1,4-dioxane (15.0 mL, 60 mmol), and the mixture was stirred at room temperature for 4 h. After this time, the reaction mixture was concentrated under reduced pressure, and the resulting residue was partitioned between 10% aqueous potassium carbonate (100 mL) and methylene chloride (75 mL). The layers were separated, and the aqueous phase was extracted with methylene chloride (2×75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 27 in 81% yield (878 mg) as an orange solid: mp 70-71° C.; 1H NMR (500 MHz, DMSO-d6) δ 7.02 (d, 2H, J=7.5 Hz), 6.49 (d, 2H, J=7.5 Hz), 5.07 (bs, 2H), 4.07-3.97 (m, 3H), 2.81 (septet, 1H, J=6.5 Hz), 1.99 (s, 3H), 1.11 (t, 3H, J=7.0 Hz), 0.92 (d, 3H, J=6.5 Hz), 0.85 (d, 3H, J=6.5 Hz); MS (ESI+) m/z 251 (M+H).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2C=CC(F)=C[CH:38]=2)=S)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:16]2=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:19][N:15]2[N:14]=[CH:13][N:12]=1.Cl.FC1C=C(C(C(NC2C=CC(F)=CC=2)=O)C(N)=O)C=CC=1[O:53]C1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1>>[CH:36]1([C:35]([NH:34][C:32]([NH:31][C:6]2[CH:7]=[CH:8][C:9]([O:10][C:11]3[C:16]4=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]5[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]5)=[CH:19][N:15]4[N:14]=[CH:13][N:12]=3)=[C:4]([F:3])[CH:5]=2)=[O:53])=[O:44])[CH2:37][CH2:38]1
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)NC(=O)C4CC4)cc3F)c12

Procedure:
Prepared in a similar manner as Example 264 using Compound B of Example 45 and Compound A of Example 280 (20.3 mg, 64%). 1H NMR (CD3OD) δ 10.85 (s, 1H), 7.70 (s, 1H), 7.76–7.72 (m, 2H), 7.22–7.14 (m, 2H), 4.14 (t, 2H, J=5.5 Hz), 2.94 (t, 2H, J=5.5 Hz), 2.89–2.60 (m, 4H), 2.78 (s, 3H), 2.34 (s, 4H), 1.70–1.67 (m, 1H), 0.99–0.95 (m, 2H), 0.91–0.86 (m, 2H); MS(ESI+) m/z 512.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.C(=O)(O)[O-].[Na+].[I-].[Na+].[CH3:20][N:21]([CH2:25][CH2:26]Cl)[CH2:22][CH2:23]Cl.Cl.[OH-].[NH4+].C1C=CC2C(=CC=CC=2O)C=1>C(#N)C.CO.C(Cl)Cl>[CH3:20][N:21]1[CH2:25][CH2:26][N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]3)[CH2:23][CH2:22]1
Reactant: Nc1cccc2ccc(O)cc12
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: Oc1cccc2ccccc12
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2cccc3ccc(O)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 8-amino-2-naphthol (3.28 g, 20 mmol, Aldrich Chem, Co.) in 100 mL of acetonitrile was added sodium bicarbonate (7.42 g, 88 mmol), sodium iodide (6.72 g, 44 mmol) and mechlorethamine hydrochloride (4.32 g, 22 mmol). Under nitrogen, the reaction was heated to reflux and stirred for another 2 hr. The reaction mixture was then allowed to cool to room temperature and was stirred overnight. A thin layer chromatography (tlc) using methylene chloride:methanol:conc. ammonium hydroxide (90:10:1) showed the more polar product (Rf 0.25) with only a trace of the starting naphthol. Silica gel (4.5 g) was added and the reaction mixture was concentrated in vacuo to a dry purple solid. This was added to a column of silica gel (ca. 400 g) and eluted with 2 L volumes of CH2Cl2, CH2Cl2 :CH3OH (40:1), CH2Cl2 :CH3OH:conc. NH4OH (20:1:0.1) and finally 4 L of CH2Cl2 :CH3OH:conc. NH4OH (10:1:0.1). The appropriate fractions were combined to yield a purple-black solid, 5.26 g, mp 184-185° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([NH:16][C@H:17]([C:19]([OH:21])=[O:20])[CH3:18])[CH2:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Na+].[Na+]>[H][H].C(O)C.O>[CH2:1]([O:3][C:4]([C@@H:6]([NH:16][C@H:17]([C:19]([OH:21])=[O:20])[CH3:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)N[C@@H](C)C(=O)O
Reactant: [H][H]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Temperature: 20 °C
Yield: 67.6 %

Procedure:
N-(1-ethoxycarbonyl-3-oxo-3-phenylpropyl)-L-alanine [(1S/1R)=9.0] (10.0 g, 34 mmoles) was added to 105 ml of 7% (w/w) water-containing ethanol containing 1.9 N sulfuric acid. Thereto 50% (w/w) water-containing 5% Pd--C (5.0 g) was added and the catalytic reduction was carried out in hydrogen atmosphere (atmospheric pressure) under the conditions of an inner temperature of about 20° C. and an agitation power of a range from 0.5 to 1 kW/m3 (amount of sulfuric acid based on substrate: 6 equivalents). Supply of hydrogen was stopped at the time when hydrogen is absorbed in 90% and somewhat more of the required amount. And then, the atmosphere was rapidly replaced with nitrogen to stop the reaction. Pd--C was rapidly removed by filtration and the Pd--C cake was conscientiously washed with 10 ml of 7% (w/w) water-containing ethanol and 5 ml of water. After 30 ml of water was added to the resulting filtrate, the filtrate was neutralized (pH 4.5) by slowly adding dropwise an aqueous 30% (w/w) sodium hydroxide solution. The filtrate was concentrated at the inner temperature of a range from 40° to 60° C. under reduced pressure, and then concentrated under reduced pressure with appropriately adding water to obtain slurry with replacing with water. The content of ethanol in the slurry was 3% (w/w), the content of sodium sulfate was 9% (w/w) and the pH was 5.0. After cooling to an inner temperature of 20° C., the crystal was filtered and washed with water in a 2-fold amount of the cake. The resulting crystal was vacuum-dried (30 mmHg to 0.1 mmHg) at a range from 40° to 60° C. to obtain N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine (6.3 g, 23 mmoles). The yield was 75%. HPLC purity: 99.3% (w/w), the content of N-(1(R)-ethoxycarbonyl-3-phenylpropyl)-L-alanine: not detected, the content of N-(1-ethoxycarbonyl-3-cyclohexylpropyl)-L-alanine: 0.1% (w/w), the content of N-(1-carboxy-3-phenylpropyl)-L-alanine: less than 0.1% (w/w), residue on ignition: 0.1% 35 (w/w).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][C:5]=1[CH3:15])[CH3:2].[OH-].[Na+].Cl>O.CO>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[CH3:15])[CH3:2]
Reactant: CCOC(=O)c1ccc(OCC)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1ccc(C(=O)O)cc1C
Temperature: 0 °C
Yield: 64 %

Procedure:
The crude ethyl 4-ethoxy-3-methyl-benzoate was suspended in a solution of NaOH (10.5 g, 263 mmol) in water (50 mL) and methanol (25 mL). The reaction mixture was refluxed for 1 h. The reaction mixture was cooled to 0° C., acidified with 12 M HCl (24.7 mL, 296 mmol) and the resulting solid filtered. The solid was slurried with acetonitrile and filtered to provide 4-ethoxy-3-methyl-benzoic acid (760 mg, 4.22 mmol, 64%) as a light pink solid. ESI-MS m/z calc. 180.07864. found 181.3 (M+1)+; Retention time: 1.31 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 7.77 (dd, J=8.5, 2.2 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 4.11 (q, J=7.0 Hz, 2H), 2.17 (s, 3H), 1.36 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:4][C:5]3[N:10]4[CH:11]=[CH:12][N:13]=[C:9]4[C:8](=[O:14])[NH:7][C:6]=3[C:15]=2[CH:16]=[CH:17][CH:18]=1.S(=O)(=O)(O)O.[N+:24]([O-])([O-:26])=[O:25].[K+]>>[N+:24]([C:18]1[CH:17]=[CH:16][C:15]2[C:6]3[NH:7][C:8](=[O:14])[C:9]4[N:10]([CH:11]=[CH:12][N:13]=4)[C:5]=3[CH2:4][C:3]=2[C:2]=1[Br:1])([O-:26])=[O:25]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1c(Br)cccc1-2
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2c(n3ccnc13)Cc1c-2ccc([N+](=O)[O-])c1Br
Temperature: 20 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
1 g of 9-bromo-5H, 10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one is added to 6 ml of concentrated sulphuric acid (20N) at a temperature close to 0° C. 0.3 g of potassium nitrate is then added in two portions to this solution while maintaining the temperature between 0° and 5° C. The reaction medium is stirred for 18 hours at 20° C., then poured into 50 ml of ice-cold water. The insoluble matter is filtered, washed with 50 ml of ethyl acetate and dried under reduced pressure (15 mmHg; 2 kPa) at 50° C. 0.77 g of 8-nitro-9-bromo-5H, 10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one is thus obtained which melts above 260° C. (analysis: % calculated C: 44.98, H: 2.03, Br: 23.02, N: 16.14, % found C: 45.40, H: 2.20, Br: 21.30, N: 15.70).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:28]=O)=[CH:20][CH:19]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[NH4+]>ClCCCl.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][N:13]([CH2:28][C:21]4[C:22]5[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:18]=[CH:19][CH:20]=4)[CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccnc2ccccc12)CC3
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.7 %

Procedure:
A mixture of 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one (1.0 g, 4.3 mmol), 4-quinolinecarboxaldehyde (0.68 g, 4.3 mmol), and glacial acetic acid (1.75 mL, 30.6 mmol) in 20 mL of 1,2-dichloroethane is treated in small portions with sodium triacetoxyborohydride (1.3 g, 6.1 mmol). The mixture is stirred at room temperature for 24 hours. Water (100 mL) is slowly added, followed by concentrated ammonium hydroxide until slight basicity. The mixture is extracted with dichloromethane, and the combined organic layers are washed with brine, dried (anhydrous sodium sulfate), and evaporated. Purification of the residue by flash chromatography (silica gel, 3% methanol in dichloromethane elution) gives 0.70 g (42%) of product; mp 186°-188° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1.Br[CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:10]([CH2:20][C:21]#[N:22])[C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCN1C(=O)COc2nc(Br)c(-c3ccccc3)cc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
A mixture of 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0.4 g, 1.311 mmol), 2-bromoacetonitrile (0.472 g, 3.93 mmol) and potassium carbonate (0.544 g, 3.93 mmol) in DMF (4 ml) was stirred at 50° C. for 2 h. The reaction mixture was diluted with water (20 ml) and extracted with dichloromethane (3×20 ml). The combined organic phase was washed with water, brine, dried over sodium sulfate and concentrated to give crude product which was purified by column chromatography (biotage 25 g) eluted with 0-50% ethyl acetate/cyclohexane to afford product (0.19 g) 1H NMR (500 MHz, CDCl3) 7.45-7.50 (m, 3H), 7.4-7.43 (m, 2H), 7.31 (s, 1H), 4.93 (s, 2H), 4.83 (s, 2H).
Reaction SMILES: C1(S(C2(SC)[CH2:15][C@@H:14]3[C@@:12]([C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:18][CH:17]=4)([CH2:13]3)[CH2:11]2)(=O)=O)C=CC=CC=1.[CH3:28][OH:29].Cl>C(OCC)(=O)C.CCCCCC>[C:16]1([C@@:12]23[CH2:13][C@@H:14]2[CH2:15][C:28](=[O:29])[CH2:11]3)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CO
Reactant: CSC1(S(=O)(=O)c2ccccc2)C[C@H]2C[C@@]2(c2cccc3ccccc23)C1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1C[C@H]2C[C@@]2(c2cccc3ccccc23)C1
Yield: 99 %

Procedure:
(1R,5R)-3-Benzenesulfonyl-1-(1-naphthyl)-3-methylsulfanyl-bicyclo[3.1.0]hexane (620 mg, 1.6 mmol), methanol (4 mL) and concentrated hydrochloric acid (0.7 mL) were heated to reflux for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane (20:80)) The reaction mixture was concentrated under reduced pressure to remove methanol. The pH of the reaction mass was adjusted to 8-9 with saturated sodium bicarbonate solution. The aqueous layer was extracted with diethyl ether (50 mL). The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 458 mg of crude oil, which was purified by preparative HPLC to yield 135 mg (39%) of 99% pure product. 1H NMR δ(300 MHz,CDCl3) 0.76-0.79 (1H,t, J=4 Hz), 1.38 (1H,m), 2.01 (1H,m), 2.49-2.56 (1H,d, J=10Hz), 2.75 (2H,d,J=6 Hz), 3.05-3.15 (2H,dd,J=10 Hz), 7.40-7.45 (1H,m), 7.50-7.56 (3H,m), 7.76-7.79 (1H,d,J=9 Hz), 7.88-7.90 (1H,m), 8.13-8.15 (2H,d ,J=6 Hz). 13CNMR(CDCl3)δ: 218.25, 139.12, 134.01, 128.96, 127.80, 126.77, 126.17, 125.78, 125.33, 124.0, 48.18, 42.46, 27.80, 20.62, 20.05.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[N+:17]([O-])([OH:19])=[O:18]>>[CH3:1][C:2]1[NH:3][C:4]([N+:17]([O-:19])=[O:18])=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: Cc1ncc([N+](=O)[O-])[nH]1
Yield: 60 %

Procedure:
Into a glass bottle of 750 ml, provided with a reflux condenser, 50 g of 2-methylimidazole was placed and while constantly stirring and cooling, 10 ml of sulphuric acid of 1.84 density were carefully and gradually introduced in such a way, that the temperature did not exceed 120° (2-methylimidazole is a free base and its transformation into the sulphate of 2-methylimidazole is a highly exothermic reaction). Then there was slowly introduced 20 ml of sulphuric acid and after lowering the temperature to about 50°, 100 ml of nitric acid with a density of 1.50 was poured in, and, if a too violent course of the reaction in the first stage was detected, the reaction could be inhibited by addition of several ml of nitric acid of 1.50 density. Then, after several minutes, as the intensity of the reaction and of the exothermic effect began to diminish sulphuric acid was added up to exhaustion of the entire quantity of 50 ml. After the sulphuric acid was added, the reflux condenser was removed and the temperature raised to 130°-150°. The solution remained for complete cooling and in a known manner, by means of neutralization with ammonia water, 4.5 g of 2-methyl-5-nitroimidazole were isolated corresponding to a yield of about 60% of theoretical.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][NH:17][C:16]=2[N:15]=1)[CH3:2].C1C=CC(O[C:40](OC2C=CC=CC=2)=[N:41][C:42]#[N:43])=CC=1.O.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[N:7]1[CH2:8][CH2:9][N:10]([CH2:11][CH2:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[CH2:20][CH2:19][CH2:18][NH:17][C:16]=3[N:15]=2)[C:40]1=[N:41][C:42]#[N:43])[CH3:2]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CCOC(=O)C[C@H](NCCNCCCc1ccc2c(n1)NCCC2)c1ccc(OC)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](c1ccc(OC)nc1)N1CCN(CCCc2ccc3c(n2)NCCC3)C1=NC#N
Temperature: 75 °C

Procedure:
A solution of the diamine 1-2 (120 mg, 0.27 mmol), diphenyl cyanocarbonimidate (65 mg, 0.27 mmol) and K2C03 (94 mg, 0.68 mmol) in EtOAc (10 mL) and water (5 mL) was stirred at room temperature for 16 hours then heated to 75° C. for 6 hours. After cooling, the mixture was poured into saturated Na2CO3, extracted with EtOAc and washed successively with water and brine. The EtOAc layer was dried (MgSO4) and concentrated in vacuo to give 1-3 an oil which was used as such in the next step.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]1=[O:10].Br[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.CNCCNC.[I-].[K+]>O1CCOCC1.[Cu]I>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH2:3][C:2]2=[O:10])=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=C1Cc2cccnc2N1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: [I-]
Solvent: C1COCCO1
Product: O=C1Cc2cccnc2N1c1ccc([N+](=O)[O-])cc1
Temperature: 95 °C
Yield: 25.2 %

Procedure:
A mixture of 1H-pyrrolo[2,3-b]pyridin-2(3H)-one (431 mg), 1-bromo-4-nitrobenzene (778 mg), copper(I) iodide (122 mg), N1,N2-dimethylethane-1,2-diamine (113 mg) and potassium iodide (1.36 g) in 1,4-dioxane (10 mL) was sparged with argon for 5 min then heated overnight at 95° C. After this time, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (100 mL), filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, heptane to 1:1 ethyl acetate/heptane) to afford 1-(4-nitrophenyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (207 mg) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][NH2:17])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]\[C:29]([OH:31])=[O:30]>C(#N)C.CO.C(OCC)C>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]\[C:29]([OH:31])=[O:30].[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][NH:17][CH2:2][CH2:3][S:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:13]
Reactant: CCN(CC)CCN
Reactant: O=S(CCCl)c1ccccc1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: CCOCC
Product: CCN(CC)CCNCCS(=O)c1ccccc1
Yield: 50.3 %

Procedure:
A mixture of 20.0 g (0.106 mole) of [(2-chloroethyl)sulfinyl]benzene, 30.0 g (0.259 mole) of N,N-diethylethylenediamine and excess sodium carbonate in 600 ml of acetonitrile was refluxed for 16 hr. The reaction mixture solution was filtered, and the solvent was removed in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over sodium sulfate and the solvent was removed in vacuo to give an oil. This was dissolved in methanol, and a solution of 2 equivalents of maleic acid in methanol was added. Diethyl ether was added and a whie solid precipitated to give 26.7 g (50.3%) of title compound, a white crystalline solid, mp 111°-112.5° C.