Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[O-]S([O-])(=O)=O.[Mg+2].[CH:18](=O)[CH2:19][CH2:20][CH3:21].CCN(CC)CC.[BH4-].[Na+]>CO.C1COCC1>[CH2:18]([NH:6][C@@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([O:3][CH3:2])=[O:11])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC=O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCN[C@@H](CC(C)C)C(=O)OC
Yield: 27.1 %

Procedure:
Synthesized according to the general procedure as described in Example 1a using L-leucine methyl ester hydrochloride (1.5 gm, 8.25 mmol), THF (25 mL), MgSO4 (1.68 gm, 14.02 mmol), butyraldehyde (1.45 mL, 16.5 mmol), Et3N (1.14 mL, 8.25 mmol), sodium borohydride (625 mg, 16.5 mmol), and methanol (25 mL) to give 11j (450 mg, 27%) in FIG. 2. 1H NMR (500 MHz, CDCl3): δ 0.86-0.98 (9H, m), 1.24-1.52 (7H, m), 1.64-1.74 (1H, heptet), 2.4-2.48 (1H, m), 2.52-2.6 (1H, m), 3.27 (1H, t, J=7.33 Hz), 3.71 (3H, s). ESI-MS: 224.1 (M+23).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[CH:11]=2)[NH:6][N:5]=1>CO>[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=2)[NH:6][N:5]=1
Reactant: COC(=O)c1ccc2[nH]nc(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1n[nH]c2ccc(C(=O)O)cc12
Temperature: 70 °C
Reaction time: 6 h

Procedure:
Aqueous 5N NaOH (4 ml, 20.00 mmol) was added to a stirred solution of methyl 3-methyl-1H-indazole-5-carboxylate (1.02 g, 5.36 mmol) in MeOH (10 ml) and the mixture was stirred at 70° C. for 6 h. The mixture was cooled, and the solvent was evaporated under reduced pressure. The mixture was diluted with H2O, and aqueous 5N HCl (4 ml) was added to the mixture with stirring, the resulted precipitate was filtered and dried over at 50° C. overnight to give intended compound as a brown solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([OH:15])=[O:14])[CH:7]=[CH:6]2.[OH-].[NH4+].Cl>Br.O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([OH:15])=[O:14])[CH:7]=[CH:6]2
Reactant: COc1ccc2nc(C(=O)O)ccc2c1
Agent: Br
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: O=C(O)c1ccc2cc(O)ccc2n1
Temperature: 125 °C

Procedure:
6-Methoxy-quinoline-2-carboxylic acid (4 g, 0.019 mol) was suspended in hydrobromic acid 48% in water (80 ml) and the mixture was heated at 125° C. overnight. After cooling to 0° C. ammonium hydroxide was added until the pH was 6-7 followed by addition of HCl until the pH was 3-4 and the compound precipitated. The solid was filtrated, washed with water and dried under vacuum to yield 3.5 g (0.0185 mol, 97% of theory) of the title compound as a yellow solid MS (m/e)=190.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=1.C(OC(=O)C)(=O)C.[OH-].[Na+]>[Cl-].[Zn+2].[Cl-].ClCCl>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:11]/[C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C)nc1
Reactant: CSc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(/C=C/c2ccc(SC)cc2)nc1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A mixture of 4-(methylsulfanyl)benzaldehyde (250 mg, 1.52 mmol), methyl 6-methylnicotinate (230 mg, 1.52 mmol), acetic anhydride (310 mg, 3.04 mmol) and a catalytic amount of zinc chloride was heated under reflux for 12 h. The reaction mixture was allowed to cool to room temperature before crushed ice was added followed by sodium hydroxide solution 10% (dropwise with stirring) until the mixture was basic (pH 8). Dichloromethane was added and the layers separated. The combined organic layers were collected, dried (MgSO4) and concentrated under reduced pressure to give the crude product as brown solid. The crude mixture was purified by column chromatography (ethyl acetate/n-hexane, 1:1, RF=0.80), followed by recrystallization from methanol to give the sub-title compound as pale yellow crystals (251 mg, 58%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=[C:7]([Cl:15])[CH:6]=1>CC#N>[Cl:15][C:7]1[CH:6]=[C:5]([N:2]([CH3:3])[CH3:1])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1
Reactant: CNC
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Solvent: CC#N
Product: COC(=O)c1cnc(Cl)cc1N(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
Dimethylamine (1.23 mL, 9.71 mmol) was slowly added to a stirred solution of methyl 4,6-dichloronicotinate (0.40 g, 1.94 mmol) in MeCN (6 mL) at room temperature. The solution was stirred at room temperature for 18 hours then concentrated in vacuo onto silica gel. Gradient chromatography, eluting with 5% EtOAc:c-Hex over 5 column volume and 5-50% over 15 column volume, gave methyl 6-chloro-4-(dimethylamino)nicotinate (335 mg, 1.56 mmol, 80% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([C:13]2[C:14]([C:19]([OH:21])=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=2)=O)[N:4]=1.S(Cl)([Cl:24])=O>C(Cl)(Cl)(Cl)Cl>[Cl:24][C:11]1([C:5]2[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=2)[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[C:19](=[O:20])[O:21]1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(OC)nc(C(=O)c2cccnc2C(=O)O)n1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(OC)nc(C2(Cl)OC(=O)c3ncccc32)n1
Temperature: 70 °C

Procedure:
45.53 g of 3-[(4,6-dimethoxy-2-pyrimidinyl)carbonyl]-2-pyridinecarboxylic acid are suspended in 700 ml of carbon tetrachloride and 186.4 g of thionyl chloride added with stirring. The suspension is heated to 70° C. for 4 hrs and the reaction mixture then cooled to RT and the excess thionyl chloride and carbon tetrachloride evaporated off to give the title compound as a tan solid m.p. 146°-148° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:18]2[C:19]([C:25]([C:27]3[CH:28]=[N:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=3)=[O:26])=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)COC)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>Cl.O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:18]2[C:19]([C:25]([C:27]3[CH:28]=[N:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=3)=[O:26])=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccc(C#N)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccc(C#N)nc2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 33.3 %

Procedure:
4-tert-Butyl-N-[5-chloro-2-(6-cyano-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-benzenesulfonamide (15 mg, 0.030 mmol) was dissolved in 4N HCl (500 μL) and dioxane (1 mL). The reaction was then stirred at 90° C. for 12 hours. The solvent was removed under reduced pressure and the crude solid was purified by preparatory TLC (1:4 EtOAc/hexanes) to give 5 mg (0.01 mmol, 40% yield) of the desired product as a white solid. MS calc'd for C22H20ClN4O3S (MH+): expected 455.1, found 455.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[CH2:10]([N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:28]([C:30]1[CH:31]=[N:32][CH:33]=CC=1)#[N:29].B(O)(O)C1C=CC=C(F)C=1>ClCCl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:33]2[N:29]=[CH:28][C:30]([C:21]3[NH:17][C:18]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[N:19][CH:20]=3)=[CH:31][N:32]=2)[CH:2]=1.[CH2:10]([N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1cccnc1
Reactant: N#Cc1cccnc1
Agent: OB(O)c1cccc(F)c1
Agent: c1ccc(Cn2ccnc2-c2cccnc2)cc1
Solvent: ClCCl
Solvent: CO
Product: c1cncc(-c2ncc(-c3cnc(-c4cccnc4)[nH]3)cn2)c1

Procedure:
The title compound was prepared by the method described in Example 1, except that (i) commercially available 3-pyridyl boronic acid was used instead of benzene boronic acid in Step A, and (ii) 3-(1-benzyl-1H-imidazol-2-yl)pyridine was used instead of 1-benzyl-2-phenyl-1H-imidazole in Step C. 3-(1-Benzyl-1H-imidazol-2-yl)pyridine was prepared by the method described in Example 8, Steps A and B except the commercially available 3-cyanopyridine was used instead of 3-fluorobenzonitrile; Rf 0.35 with 92.5:7.5 v/v dichloromethane-methanol; melting point 299° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.52 (s, 1H), 9.35 (s, 2H), 9.21 (s, 1H), 8.72-8.65 (m, 2H), 8.60-8.56 (m, 1H), 8.37-8.32 (m, 1H), 8.15 (s, 1H), 7.58-7.50 (m, 2H); LC/MS (ESI+) m/z 301.1 (M+1); H-PGDS FPBA IC50: 1.3 μM.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH:8]([CH3:10])[CH3:9])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]=1.[CH3:15][Si:16]([CH3:21])([CH3:20])[C:17]#[C:18][CH3:19]>>[CH:8]([N:7]1[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]=[C:3]1[CH2:2][CH2:19][C:18]#[C:17][Si:16]([CH3:21])([CH3:20])[CH3:15])([CH3:10])[CH3:9]
Reactant: CC#C[Si](C)(C)C
Reactant: CC(C)n1c(CCl)nc2ccccc21
Product: CC(C)n1c(CCC#C[Si](C)(C)C)nc2ccccc21
Yield: 99.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(D), from of 2-(chloromethyl)-1-isopropyl-1H-benzo[d]imidazole (500 mg, 2.4 mmol) and trimethyl(prop-1-ynyl)silane (323 mg, 2.88 mmol). 1-isopropyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (680 mg, Yield: 100%) was obtained as a brown oil which was used in the next step without any purification.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]1(=[O:15])[O:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+]>C1COCC1.O>[C:3]1([S:9][CH2:13][CH2:12][CH2:11][C:10]([OH:15])=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCCO1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCSc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 10.4 g, 0.26 mol) in anhydrous THF (400 mL) at ambient temperature is added thiophenol (26 g, 0.23 mol) dropwise via syringe. The resulting white suspension is stirred for 30 minutes under a nitrogen atmosphere then γ-butyrolactone (22.4 g, 0.26 mol) is added. The mixture is warmed to gentle reflux and stirred for 6 hours after which it became a solid mass and is allowed to cool to room temperature and stand overnight. The mixture is dissolved in water (1200 mL) containing 1 N NaOH (100 mL) and is extracted with diethyl ether (2×500 mL). The aqueous layer is acidified with 1N HCl and extracted with diethyl ether (3×500 mL). The organic extracts are washed with brine (300 mL) then dried over MgSO4, filtered and concentrated to afford a white solid which is chromatographed on silica gel (pet-ether/EtOAc, 19:1→9:1) to afford 4-phenylsulfanylbutanoic acid (36.6 g, 79%) as a white solid. TLC analysis [pet-ether/EtOAc, 1:1, Rf (thiophenol)=0.90, Rf (acid)=0.50]. m.p. 73-74° C.; 1H NMR (300 MHz, CDCl3) δ 1.95 (quint, J=7.1 Hz, 2H), 2.52 (t, J=7.2 Hz, 2H), 2.97 (t, J=7.1 Hz, 2H), 7.1-7.3 (m, 5H) ppm. Mass spectrum (EI) m/z 196 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:11])([CH3:10])[C:8]#[N:9])=[C:4]([F:14])[CH:3]=1.Cl.[CH2:16]([OH:18])[CH3:17]>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:11])([CH3:10])[C:8](=[NH:9])[O:18][CH2:16][CH3:17])=[C:4]([F:14])[CH:3]=1
Reactant: CC(C)(C#N)Oc1ccc(Cl)cc1F
Reactant: CCO
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)C(C)(C)Oc1ccc(Cl)cc1F
Reaction time: 48 h

Procedure:
Through a cooled solution of Example 53D (7.2 g, 33.7 mmol) in ethanol (75 mL) and dichloromethane (30 mL) was bubbled HCl gas at 0° C. for 30 minutes. The reaction was kept in a refrigerator for 24-72 hours (checked by LCMS). The reaction mixture was then concentrated and the residue was triturated with diethyl ether. The titled compound was collected by filtration.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+:27]([C:30]1[CH:67]=[CH:66][C:33]([CH2:34][O:35][C:36]([N:38]2[CH2:43][CH2:42][CH:41]([S:44][C:45]3[N:46]=[CH:47][N:48]4[CH:52]=[C:51]([Sn](CCCC)(CCCC)CCCC)[S:50][C:49]=34)[CH2:40][CH2:39]2)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:51]3[S:50][C:49]4=[C:45]([S:44][CH:41]5[CH2:40][CH2:39][N:38]([C:36]([O:35][CH2:34][C:33]6[CH:66]=[CH:67][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=6)=[O:37])[CH2:43][CH2:42]5)[N:46]=[CH:47][N:48]4[CH:52]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SC3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SC5CCN(C(=O)OCc6ccc([N+](=O)[O-])cc6)CC5)c4s3)[C@H](C)[C@H]12
Yield: 52.1 %

Procedure:
The procedure of Example 1a) was repeated, except that 410 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 881 mg of 7-[1-(4-nitrobenzyloxycarbonyl)piperidin-4-yl]thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 450 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[1-(4-nitrobenzyloxycarbonyl)piperidin-4-yl]thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: Cl[C:2]1[N:10]2[CH:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[C:20]2[C:21]([CH3:26])=[N:22][O:23][C:24]=2[CH3:25])[N:3]=1.Cl.[NH:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1>CO>[CH3:26][C:21]1[C:20]([C:7]2[C:8]3[O:13][CH2:12][CH:11]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[N:10]4[C:2]([N:28]5[CH2:31][CH:30]([OH:32])[CH2:29]5)=[N:3][C:4]([C:9]=34)=[CH:5][CH:6]=2)=[C:24]([CH3:25])[O:23][N:22]=1
Reactant: OC1CNC1
Reactant: Cc1noc(C)c1-c1ccc2nc(Cl)n3c2c1OCC3c1cccnc1
Agent: Cl
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2nc(N3CC(O)C3)n3c2c1OCC3c1cccnc1

Procedure:
The title compound was prepared by methods analogous to Example 157, substituting 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine, azetidin-3-ol hydrochloride and extending the reaction time to 60 min. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound as a racemic mixture (16 mg, 23%). LCMS calc. for C22H22N5O3 (M+H)+: m/z=404.2. found: 404.2. The isomers were separated by prep chiral column chromatography using the following conditions: Column: phenomenex Lux Cellulose C-2 5 μm, 21, 2×250 mm, Mobile phase: 45% EtOH/Hexanes, gradient condition: isocratic at 18 mL/min, Loading: 2.0 mg in 900 μL, run time: 24 min, peak time: 12.0, 14.0, 16.0 and 21.0 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH:5]=[CH:6][CH:7]=1.O>C(O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH2:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnccc1Nc1cccc(Cl)c1
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: Nc1cnccc1Nc1cccc(Cl)c1
Yield: 88.5 %

Procedure:
The product of Step 1 (325 mg, 1.302 mmol), was dissolved in ethanol (20 ml), and treated with iron powder (727 mg, 13.017 mmol), 20 drops of 37%. hydrochloric add and water (2 ml), and refluxed for 1 hour. The reaction was then filtered hot, and the filtrate evaporated in vacuo. The residue was dissolved in ethyl acetate then washed with saturated sodium bicarbonate solution, water, and brine, separated, dried over anhydrous sodium sulfate and evaporated in vacuo to afford the title compound (253 mg, 88%). MS (ES+), m/e 220/222 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][N:33]=[CH:34][C:29]=1[C:25]1[CH:24]=[C:23]([C:22]2[CH2:21][C:20](=[O:36])[NH:19][C:9]3[CH:10]=[C:11]([N:14]4[CH:18]=[CH:17][CH:16]=[CH:15]4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1NC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cnccn3)c2)=Nc2ccc(-n3cccc3)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-4-pyrrol-1-yl-phenyl}-carbamic acid tert-butyl ester (Example M100) (0.37 g, 0.74 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (170 mg, 60%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH:20]=[CH:21][CH:22]=O.C([O-])(=O)C.[NH4+]>C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][C:15]2[N:19]=[CH:20][CH:21]=[CH:22][C:14]=2[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC=CC=O
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Product: O=C(NC1CCc2ncccc2C1)OCc1ccccc1
Temperature: 115 °C
Reaction time: 72 h
Yield: 10.6 %

Procedure:
A mixture of 4-benzyloxycarbonylaminocyclohexanone (13.75 g, 55.6 mmol), 3-aminopropenal (5.57 g, 78.4 mmol), and ammonium acetate (0.14 g, 1.78 mmol) in triethylamine (85 mL) was stirred at 115° C. under nitrogen for 3 d. The reaction mixture was then partitioned between chloroform and water. The organic layer was separated, washed sequentially with water, saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum to yield a residue. The residue was subjected to silica gel chromatography (eluted with 5% methanol in methylene chloride) to obtain the title compound (1.67 g, 10.5%) as a brown oil. 3C NMR (400 MHz, CDCl3) δ 155.6, 147.5, 137.2, 136.4, 129.2, 128.5, 128.1, 121.2, 66.7, 46.2, 35.2, 30.1, 28.7. 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J=4.4 Hz, 1H), 7.27 (m, 6H), 6.98 (dd, J=4.8, 7.5 Hz, 1H), 5.03 (s, 2H), 4.85 (br s, 1H), 4.00 (br s, 1H), 3.06 (d, J=16.3 Hz, 1H), 2.97 (t, J=6.6 Hz, 2H), 2.62 (dd, J=7.9, 16.0 Hz, 1H), 2.08 (d, J=8.4 Hz, 1H), 1.82 (m, 1H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[C:25]1[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=1.C(O)C>CS(C)=O>[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[C:25]1[CH2:26][CH2:27][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:29][CH:30]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Cc1cccc2c(C3=CCNCC3)c[nH]c12
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cccc2c(C3=CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c12

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.389 g, 2.05 mmol) and 7-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole ( 0.400 g, 1.87 mmol) using ethanol as reaction solvent. Yield 0.292 g (39%) as an orange foam. mp 155-158° C. FDMS m/e 401 (M+ of free base). α[D]589=+5.9 (c=1.05, dimethylsulfoxide).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>ClCCl.C(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)c([N+](=O)[O-])c1)OCc1ccccc1
Yield: 90.5 %

Procedure:
Two equal batches of 4-chloro-3-nitroaniline (20.0 g each, 0.116 mol) were dissolved separately in freshly distilled dichloromethane (over P2O5) (150 mL each) and dry triethylamine (1.1 eq. each, 18 mL, 0.128 mol) under a drierite drying tube. Each of the reaction mixtures was chilled in an ice bath and benzyl chloroformate (50 mL each, 0.348 mol) was slowly added. The resulting solutions were heated to reflux for 4 days, and then they were combined and concentrated. The residue was further concentrated in vacuo using a kugelrohr apparatus (0.1 mm Hg, 60° C.) to give a thick oil. The oily material was dissolved in chloroform (300 mL) and washed with brine (100 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified on a silica gel column, using a 2.5% methanol/chloroform as a solvent. A total yield of 32.2 g (46% yield) of N-benzyloxycarbonyl-4-chloro-3-nitroaniline was isolated as a yellow oil that solidified upon refrigeration. Rf320.61 (20% ethyl acetate/hexane). IR (neat) 3424, 3100, 3060, 3025, 2918, 2865, 1603, 1528, 1493, 1448, 1395, 1351, 1231, 1204, 1146, 1071, 1027, 960, 894, 841, 805, 734, 694. 1H-NMR (500 MHz, CDCl3) 7.28 (t, 9.0, 2H), 7.24 (s br, 1H), 7.22 (t, 9.0, 1H), 7.16 (d, 8.0, 1H), 7.13 (d, 9.0, 2H), 6.98 (d, 3.0, 1H), 6.73 (dd, 3.0, 8.0, 1H), 4.60 (s, 2H).
Reaction SMILES: [SH2:1].[C:2]([O:6][C:7](=[O:19])[CH:8]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])[N+:9]#[C-:10])([CH3:5])([CH3:4])[CH3:3]>O1CCCC1.[Cu]>[C:2]([O:6][C:7](=[O:19])[CH:8]([NH:9][CH:10]=[S:1])[P:11]([O:13][CH2:14][CH3:15])([O:16][CH2:17][CH3:18])=[O:12])([CH3:4])([CH3:3])[CH3:5]
Reactant: S
Reactant: [C-]#[N+]C(C(=O)OC(C)(C)C)P(=O)(OCC)OCC
Agent: [Cu]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(NC=S)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Dry hydrogen sulphide gas is passed for 10 minutes into a solution, cooled to 0° C., of 277 mg (1 mmol) of diethylphosphono-isocyanoacetic acid tert.-butyl ester in 5 ml of dry tetrahydrofurane (filtered through aluminum oxide). After adding a few crystals of copper-II acetylacetonate, the reaction vessel is closed and left to stand overnight at room temperature. The reaction mixture is filtered and the filtrate is evaporated in vacuo. The residue is chromatographed on silica gel thick layer plates with toluene/ethyl acetate, 1:1, and gives thioformamido-diethylphosphonoacetic acid tert.-butyl ester in the form of a colorless oil: IR spectrum (in methylene chloride): characteristic bands at 3:13; 3.35; 5.75; 7.01; 8.10; 8.70 and 9.75μ.