Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[CH2:2]([NH2:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21])([O:14]C)=[O:13].[OH-].[Na+]>CCOCC>[CH2:2]([NH:11][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][C:12]([OH:14])=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCN
Reactant: COC(=O)CCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCNC(=O)CCCCC(=O)O

Procedure:
A two liter beaker fitted with a mechanical stirrer, ice bath, and pH electrode, was charged with 700 mL of water and 89.4 g (0.624 mol) of nonylamine in 200 mL of ether. To this stirred mixture was added dropwise over a 30 minute period a solution of the above 5-carbomethoxyvaleryl chloride in 100 mL of ether. Concurrent with addition of the ether solution was added 50% sodium hydroxide solution at a rate such as to keep the pH of the aqueous layer between 10 and 12. Following addition of the acid chloride and sodium hydroxide the reaction mixture was added to a two L separatory funnel and extracted with 300 mL methylene chloride. The methylene chloride layer was separated, washed with 300 mL saturated sodium chloride solution, and dried over magnesium sulfate. Removal of the methylene chloride on a rotary evaporator yielded a yellow oil which solidified upon standing. Recrystallization from hexane afforded the methylester of 6-nonylamino-6-oxocaproic acid as colorless crystals, mp 56°-57° C., weight 155.1 g. Upon cooling to -15° C. the filtrate deposited an additional 11.0 of product. Total yield was 166.1 g (93%).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[NH:17]1[CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18]1>C1(C)C(C)=CC=CC=1>[NH2:14][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]2[O:4][C:3]([CH2:2][N:17]3[CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18]3)([CH3:16])[CH2:7][C:6]=2[C:8]=1[CH3:15]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Reactant: CCOC(=O)C1CCNCC1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1CCN(CC2(C)Cc3c(C)c(N)c(C)c(C)c3O2)CC1
Temperature: 180 °C
Reaction time: 15 h
Yield: 27.2 %

Procedure:
In an autoclave, a mixture of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (8.4 g), ethyl isonipecotate (14 g), and xylene (20 mL) was stirred under nitrogen gas at 180° C. for 15 hours. The supernatant was taken from the reaction mixture and washed with water, saturated aqueous NaHCO3, and saturated aqueous NaCl, dried over MgSO4, treated with activated carbon, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5:1 to 2:1) and crystallized from hexane to provide 2.9 g of the title compound. Yield 27%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.ClCCl>[CH3:14][S:11]([C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[O:5][C:22](=[O:24])[NH:1][C:2]=2[CH:10]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc2c(=O)oc(=O)[nH]c2c1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-amino-4-methanesulfonyl-benzoic acid (1.00 g, 4.64 mmol) in acetonitrile (15 mL) at 55° C. were simultaneously added pyridine (0.75 mL, 9.3 mmol) and a solution of triphosgene (0.455 g, 1.53 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at 55° C. for 2 hours and the solvent was removed using a rotary evaporator. The residue was diluted with water (50 mL) and the precipitate was filtered, and air dried to provide 7-methanesulfonyl-1H-benzo[d][1,3]oxazine-2,4-dione. Yield: 0.98 g (82%).
Reaction SMILES: C([O:8][C@H:9](C)[C:10]([NH:12][C@H:13]1[CH2:17][C@@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([N:42]2C[CH2:45][C@@H:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH2:43]2)=[N:22][C:23]=3[NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:15]([OH:57])[C@@H:14]1[OH:58])=[O:11])C1C=CC=CC=1.[NH2:60][C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)[C@H](OCC4C=CC=CC=4)C)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1>>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][NH:27][C:23]2[N:22]=[C:21]([N:42]3[CH:43]=[C:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH:45]=[N:60]3)[N:20]=[C:19]3[C:24]=2[N:25]=[CH:26][N:18]3[C@@H:16]2[CH2:17][C@H:13]([NH:12][C:10](=[O:11])[CH2:9][OH:8])[C@@H:14]([OH:58])[C@H:15]2[OH:57])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(NC(=O)Nc5cccnc5)cn4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to (R)-2-benzyloxy-N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 181, step 5), by substituting N-{(1S,2R,3S,4R)-4-[2-(4-amino-pyrazol-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZP) for (R)—N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4).
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=[C:5]([NH2:16])[C:4]=2[N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C@H:26]2[CH2:31]N[CH2:29][CH2:28][NH:27]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C@@H:26]2[NH:27][CH2:28][CH2:29][N:16]([C:5]3[C:4]4[N:3]=[C:2]([CH3:1])[S:11][C:10]=4[NH:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[N:6]=3)[CH2:31]2)=[CH:22][CH:23]=1
Reactant: Cc1nc2c(s1)Nc1ccccc1N=C2N
Reactant: Fc1ccc(CC[C@H]2CNCCN2)cc1
Product: Cc1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccc(F)cc2)C1
Yield: 38.3 %

Procedure:
By a similar method to the method of Example 460, using 2-methyl4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.21 g, 5.25 mmol) and (S)-2-[2-(4-fluoro-phenyl)-ethyl]-piperazine (1.09 g, 5.25 mmol) to give 0.848 g of the title compound as a tan solid: mass spectrum (ion spray): m/z=422 (M+1); Analysis for C23H24FN5S(0.3 H2O): calcd: C, 64.70; H, 5.81; N, 16.40; found: C, 64.97; H, 5.86; N, 16.15.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([C:9]1([CH3:30])[CH2:14][CH2:13][C:12]2[C:15]([CH3:29])=[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]([CH3:20])=[C:18]([CH3:19])[C:11]=2[O:10]1)C(OC)=O.[OH-].[K+].C(O)CO.O.CCOCC>O>[CH3:30][C:9]1([CH2:4][C:3]([OH:31])=[O:2])[CH2:14][CH2:13][C:12]2[C:15]([CH3:29])=[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]([CH3:20])=[C:18]([CH3:19])[C:11]=2[O:10]1
Reactant: COC(=O)C(C(=O)OC)C1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: OCCO
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CC(=O)O)O2

Procedure:
A mixture of 0.43 g (1 mmole) of rac-3,4-dihydro-2,5,7,8-tetramethyl-6-(phenylmethoxy)-2H-1-benzopyran-2-ylpropanedioic acid dimethyl ester, 0.56 g (10 mmoles) of potassium hydroxide, and 25 ml of 9:1 ethylene glycol-water is stirred and refluxed for 8 hr. The mixture is cooled, diluted with water, and extracted with ether (the ether extract is discarded). The aqueous, alkaline solution is acidified with 3NHCl and the acid product isolated by ether extraction. The ether extracts are combined, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. Recrystallization of the residue from aqueous ethanol gives rac-3,4-dihydro-2,5,7,8-tetramethyl-6-(phenylmethoxy)-2H-1-benzopyran-2-acetic acid which can be converted to Vitamin E by the procedures in Helv. Chim Acta 61, 837 (1978); Helv. Chim. Acta 59, 290(1976) and Helv. Chim. Acta 64, 1158 (1981).
Reaction SMILES: CC(CC)[O-].CC(CC)[O-].CC(CC)[O-].[Al+3].C1(O)CCCCC1.[CH3:24][C:25]1[CH:26]=[CH:27][C:28]2[CH:29]=[C:30]3[C:43]([C:44](=O)[C:45]=2[CH:46]=1)=[CH:42][C:41]1[C:32]([C:33](=O)[C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[C:36]([CH3:48])[CH:35]=2)=[CH:31]3.Cl>C1COCC1.CC(C)=O>[CH3:24][C:25]1[CH:26]=[CH:27][C:28]2[C:45](=[CH:44][C:43]3[C:30]([CH:29]=2)=[CH:31][C:32]2[C:41](=[CH:40][C:39]4[C:34]([CH:33]=2)=[CH:35][C:36]([CH3:48])=[CH:37][CH:38]=4)[CH:42]=3)[CH:46]=1
Reactant: Cc1ccc2c(c1)C(=O)c1cc3c(cc1=C2)C(=O)c1cc(C)ccc1C=3
Agent: CCC(C)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: OC1CCCCC1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc2cc3cc4cc5cc(C)ccc5cc4cc3cc2c1
Temperature: 145 °C

Procedure:
To a 500 mL three necked round bottom flask with a thermometer, and a distillation head was added 32.76 grams of aluminum tri(sec-butoxide) and 200 mLs of cyclohexanol. To this was added 9 grams 3,10-Dimethylpentacene-5,12-dione. The reaction mixture was heated to 145° C. At 140° C., 8.7 grams of a distillate was collected. The reaction mixture was heated at 140° C. for 43 hours and cooled to room temperature. A solid was isolated by centrifugation. The supernate liquid was poured off and the solid was slurried with 140 mLs of 1N HCl and isolated on a Buchner funnel. The solid was slurried three times with 100 mLs each 1N HCl and the solvent was poured off each time. The solid was slurried three times with 100 mLs of acetone and isolated by filtration. The solid was slurried three times with 100 mLs of THF and isolated by filtration. The residue was air dried to give 2,9-dimethylpentacene.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][S:7][C@@H:6]([C:9]([SH:12])([CH3:11])[CH3:10])[CH2:5]1)([OH:3])=[O:2].C(=O)(O)[O-].[Na+].[CH2:18](O)[CH3:19]>S(=O)(=O)(O)O>[CH2:18]([O:2][C:1]([C@@H:4]1[CH2:8][S:7][C@@H:6]([C:9]([SH:12])([CH3:10])[CH3:11])[CH2:5]1)=[O:3])[CH3:19]
Reactant: CC(C)(S)[C@H]1C[C@H](C(=O)O)CS1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)[C@@H]1CS[C@@H](C(C)(C)S)C1
Reaction time: 1.5 h

Procedure:
To a stirred solution of trans-4-carboxy-2-(1-mercapto-1-methylethyl)tetrahydrothiophene (compound No. 8-1, 50 mg) in ethanol (3 ml), one drop of concentrated sulfuric acid was added under nitrogen atmosphere and the mixture was stirred for 1.5 hours. After cooling, the reaction mixture was week alkalized with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give 53 mg of the titled compound (compound No. 12-1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Br:11]Br>CC(O)=O>[Br:11][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[C:9]=1[F:10]
Reactant: COc1c(N)cccc1F
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1c(N)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxy-3-fluoroaniline (Compound 147I, 7.70 g, 54.6 mmol) in AcOH (45.0 mL) was added a solution of bromine (6.98 g, 43.6 mmol) in AcOH (45.0 mL) dropwise. The reaction mixture was stirred at rt for 30 minutes. The resulting solid was filtered and washed with acetic acid to give the HBr salt of the desired product. The solid was dissolved in water (15 mL), basified by addition of KOH, and extracted with EtOAc (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a white solid. The crude material was purified by silica gel chromatography on an ISCO combi-flash Rf system using Heptane/EtOAc (100:0→70:30) as eluent to yield the desired product as a white solid, 6.536 mg (54% yield). 1H NMR (CDCl3, 400 MHz): δ=3.93 (d, J=1.52 Hz, 3 H), 6.42 (dd, J=8.84, 1.77 Hz, 1 H), 7.01 (dd, J=8.72, 6.95 Hz, 1 H). MS (ES+): m/z 221.98 [MH+] (TOF, polar).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:19]=[C:20]([NH2:25])[C:21]([NH2:24])=[CH:22][CH:23]=4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1.[N:26]#[C:27]Br.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:23]=[CH:22][C:21]5[N:24]=[C:27]([NH2:26])[NH:25][C:20]=5[CH:19]=4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Sc2nnc3ccc(-c4ccc(F)cc4)nn23)cc1N
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2[nH]1

Procedure:
A mixture of 4-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}benzene-1,2-diamine and of 42 mg of cyanogen bromide in 10 cm3 of ethanol is brought to reflux for 3 hours. The resulting reaction mixture is then run into a 2.5N aqueous solution of sodium hydroxide and the mixture obtained is subsequently extracted with a 90/10 mixture of ethyl acetate and methanol. The organic phases are combined then dried over magnesium sulphate and then evaporated. A yellow powder is recovered, and is chromatographed on Biotage Quad 12/25 (KP-SIL, 60 A; 32-63 μM), elution being carried out with a gradient of dichloromethane and then dichloromethane/eluent B: 95/5, 92.5/7.5, 90/10, 87.5/12.5, 85/15 (eluent B=dichloromethane/methanol/aqueous ammonia 38/17/2). 43.2 mg of 6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1H-benzimidazol-2-amine are thus obtained in the form of a whitish powder, the characteristics of which are as follows:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[C:13](Br)=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].B[C:27]1[CH:31]=[CH:30][N:29]([Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH:28]=1.ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.O>[C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([C:27]3[CH:31]=[CH:30][N:29]([Si:32]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[CH:33]([CH3:34])[CH3:35])[CH:28]=3)=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Bc1ccn([Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: CC(C)(C)OC(=O)n1c(=O)n(Cc2ccccc2)c2cccc(Br)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2cccc3c2n(C(=O)OC(C)(C)C)c(=O)n3Cc2ccccc2)c1
Temperature: 85 °C
Yield: 77.1 %

Procedure:
To 10 mL of a 9:1 mixture of dimethoxyethane/water was added 3-benzyl-7-bromo-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (0.719 g, 1.783 mmol), 3-boranyl-1-triisopropylsilanyl-1H-pyrrole (0.476 g, 1.783 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (69.7 mg, 0.089 mmol), and cesium carbonate (0.697 g, 2.139 mmol.) The resulting suspension was vacuum-purged with argon and heated to 85° C. for 1 hour. The reaction mixture was added to 100 mL of 1:1 water/ethyl acetate and the organic layer was separated. The combined organic fractions were washed with 100 mL each of water and brine and dried over sodium sulfate. Concentration in vacuo gave a crude solid which was purified by flash chromatography (0 to 10% gradient ethyl acetate in hexanes) to give 0.750 g of 3-benzyl-2-oxo-7-(1-triisopropylsilanyl-1H-pyrrol-3-yl)-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester as a white solid. MS: 446 (M−BOC+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[NH2:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:25][CH2:24][CH2:23][C:22]([NH:21][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])([CH3:27])[CH3:26]
Reactant: CC(C)(N)CCO
Reactant: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(CCO)Nc1cc(C(=O)OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 11.4 %

Procedure:
A stirred solution of benzyl 3-fluoro-4-nitrobenzoate (2.67 g, 9.69 mmol) and 3-amino-3-methylbutan-1-ol (1.00 g, 9.69 mmol) in acetonitrile (20 mL) containing potassium carbonate (1.34 g, 9.69 mmol) is heated to 80° C. for 16 h. The solvent is evaporated, water (100 mL) is added, and the mixture is extracted with EtOAc (3×100 mL). The combined organic layers are dried (MgSO4), concentrated and purified by flash chromatography in heptanes/EtOAc to afford the title compound (395 mg, 1.10 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]=[CH:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[N:16][N+:17]([O-:19])=[O:18])[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C.O>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:13]2[CH2:14][CH2:15][N:11]([CH:10]=[N:9][C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)[C:12]2=[N:16][N+:17]([O-:19])=[O:18])=[CH:23][N:22]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: Cc1ccc(N=CN2CCNC2=N[N+](=O)[O-])cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(N=CN2CCN(Cc3ccc(Cl)nc3)C2=N[N+](=O)[O-])cc1C
Temperature: 70 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
A mixture of 71,0 g of 1-(3,4-dimethylphenyliminomethyl)-2-nitroiminoimidazolidine, 48.5 g of 2-chloro-5-chloromethylpyridine, 50.0 g of potassium carbonate and 200 g of dimethylsulfoxide was agitated at 70° C. for 1 hour. After cooling to room temperature, about 800 ml of water and about 200 ml of ethyl acetate were added to the reaction mixture, followed by agitation, separation into settled crystals and a filtrate, washing with water, drying and recrystallization of a combination of the crystals with those obtained by concentration to about 1/5 from about 400 ml of acetonitrile to give 41 g of 1-(2-chloropyridine-5-ylmethyl)-2-nitroimino-3-(3,4-dimethylphenyliminomethyl)imidazolidine.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:12][N:13]1[C:17]([C:18](=[O:20])[NH2:19])=[CH:16][C:15]([C:21]([O:23][CH3:24])=[O:22])=[CH:14]1>>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]2[NH:19][C:18](=[O:20])[C:17]3=[CH:16][C:15]([C:21]([O:23][CH3:24])=[O:22])=[CH:14][N:13]3[N:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1cc(C(N)=O)n(N)c1
Product: COC(=O)c1cc2c(=O)[nH]c(-c3ccc([N+](=O)[O-])cc3)nn2c1
Yield: 72 %

Procedure:
According to the general preparation method described in example 5 above, p-nitrobenzaldehyde reacts with compound 3 to give compound Ma as light yellow solid in 72.0% yield. m.p.>300° C. 1H NMR (300 MHz, DMSO-d6): δ 12.52 (s, 1H), 8.38 (d, J=8.5 Hz, 2H), 8.22 (s, 1H), 8.21 (d, J=8.5 Hz, 2H), 7.26 (s, 1H), 3.80 (s, 3H). LRMS (EI) m/z (%): 314 (M+, 85), 283 (100). HRMS calcd. C14H10N4O5: 314.0651. found: 314.0659.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.[CH3:29][N:30]([CH3:34])[CH2:31][C:32]#[CH:33].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:33]#[C:32][CH2:31][N:30]([CH3:34])[CH3:29])=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC#Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.6 %

Procedure:
A solution of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 486 mg, 1.0 mmol) and 1-dimethylamino-2-propyne (830 mg, 10.0 mmol) in toluene (6 ml) was treated with N,N-diisopropylethylamine (1.5 ml), copper(I) iodide (19.2 mg, 0.10 mmol), and dichlorobis(triphenylphosphine)palladium(II) (36.0 mg, 0.05 mmol). The resulting reaction mixture was stirred at 25° C. for 24 h. At this time, the reaction mixture was concentrated in vacuo. The residue was extracted into methylene chloride from water. The combined organic layers were dried and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 4/1 ethyl acetate/methanol) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-prop-1-ynyl)-pyrazin-2-yl]-propionamide (360 mg, 74%) as a pale brown solid: (ES)+-HRMS m/e calcd for C24H29ClN4O3S (M+H)+ 489.1722, found 489.1725.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[S:12][C:13]2[CH:36]=[C:35]([O:37]C)[CH:34]=[CH:33][C:14]=2[C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:20][CH:19]=1)=[O:17].C(S)C.[Cl-].[Al+3].[Cl-].[Cl-].CO>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[S:12][C:13]2[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:14]=2[C:15]=1[C:16]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[CH:22][CH:23]=1)=[O:17]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc4ccccc4c3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Solvent: CCS
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc3ccccc3c2)sc2cc(O)ccc12
Yield: 98.1 %

Procedure:
By the method described in Example 2, the product of Example 3 (1.35 g, 2.59 mmol), ethanethiol (0.56 mL, 7.69 mmol), and aluminum chloride (2.07 g, 15.52 mmol) were reacted in anhydrous methylene chloride (50 mL) to give, after chromatography (silica gel, 5% methanol in methylene chloride) 1.29 g (98%) of the title product as a yellow foam; 1H NMR (300 MHz, CDCl3) δ1.46 (m, 2H), 1.66 (M, 4H), 2.58 (m, 4H), 2.77 (t, J=5.5 Hz, 2H), 4.04 (t, J=5.5 Hz, 2H), 6.54 (d, J=8.9 Hz, 2H), 6.75 (dd, J=2.2 Hz, 8.8 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 7.39-7.46 (m, 4H) 7.64 (d, J=8.6 Hz, 1H), 7.69-7.76 (m, 4H), 7.86 (d, J=1.5 Hz, 1H); 13C NMR (75 MHz, DMSO--d6) δ23.3, 24.9, 53.7, 56.4, 65.3, 106.7, 114.0, 115.0, 123.2, 125.4, 126.3, 126.3, 126.9, 127.0, 127.5, 127.9, 129.1, 130.0, 131.1, 131.2, 131.7, 131.8, 132.1, 138.9, 139.4, 155.4, 162.4, 191.9; MS (FD) m/e 508 (MH+), 507 (M+); Anal. calc'd. for C32H29NO3S: C, 75.71; H, 5.76; N, 2.76. Found: C, 75.86; H, 5.82; N, 2.75.