Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N=C=O)CCCCC[N:7]=[C:8]=[O:9].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=CC=CC=1.C1(C)C=CC(S(OC)(=O)=O)=CC=1>>[C:13]([OH:20])(=[O:9])[CH:14]=[CH2:19].[NH2:7][C:8]([O:20][CH2:13][CH3:14])=[O:9]
Reactant: O=C=NCCCCCCN=C=O
Reactant: O=C(Cl)c1ccccc1
Agent: COS(=O)(=O)c1ccc(C)cc1
Product: C=CC(=O)O
Product: CCOC(N)=O
Reaction time: 3 h

Procedure:
1300 g of HDI (hexamethylene diisocyanate), 1.3 g of benzoyl chloride and 1.3 g of methyl para-toluenesulfonate are initially charged in a 41 four-neck flask while stirring. Within 3 hours, 1456 g of a difunctional polypropylene glycol polyether having a number-average molecular weight of 2000 g/mol are added at 80° C., and the mixture is stirred at the same temperature for a further 1 hour. Subsequently, the excess HDI was distilled off by thin-film distillation at 130° C. and 0.1 torr. The resulting prepolymer has an NCO content of 3.23% and a viscosity of 1650 mPas (25° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH2:3]1.I[C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.C(N(CC)CC)C>[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.C(Cl)Cl>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)N(c1ccccc1)CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)N(c2ccccc2)CCC3(C)C)cc1
Temperature: 40 °C

Procedure:
To a mixture of 0.020 g (0.08 mmol) of 4,4-dimethyl-1,2,3,4-tetrahydro-N-phenyl-7-ethynylquinoline (Compound 8) and 0.51 g (1.8 mmol) of ethyl 4-iodobenzoate were added 1.5 g (2.0 mL, 14 mmol) of triethylamine, 6.2 mg(0.03 mmol) of copper(I)iodide, and 12 mg (0.02 mmol) of bis(triphenylphosphine)palladium(II) chloride, consecutively. The resulting mixture was heated at 40° C. for 5.5 hours. The reaction was cooled, methylene chloride was added, and the reaction mixture was adsorbed onto silica gel. The mixture was purified by flash chromatography (5% ethyl acetate in hexanes) to give the title compound as a yellow oil. PNMR (300 MHz, CDCl3) d 1.36 (6 H, s), 1.39 (3 H, t, J=7.2 Hz), 1.86 (2 H, t, J=6.0 Hz), 3.64 (2 H, t, J=6.0 Hz), 4.36 (2 H, q, J=7.2 Hz), 6.87 (1 H, d, J=1.6 Hz), 6.91 (1 H, dd, J=7.9, 1.6 Hz), 7.14 (1 H, t, J=7.3 Hz), 7.25 (1 H, d, J=7.9 Hz), 7.25 (2 H, d, J=7.3 Hz), 7.39 (2 H, t, J=7.3 Hz), 7.48 (2 H, d, J=8.5 Hz), 7.97 (2 H, d, J=8.5 Hz).
Reaction SMILES: C(N(C(C)C)CC)(C)C.O=[C:11]1[CH2:17][C@H:16]2[N:13]([C:14](=[O:35])[C@H:15]2[C:18]([CH3:34])([O:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH3:19])[C@H:12]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:64][C:65]1[O:69][C:68]([SH:70])=[N:67][N:66]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:19][C:18]([C@@H:15]1[C:14](=[O:35])[N:13]2[C@@H:16]1[CH2:17][C:11]([S:70][C:68]1[O:69][C:65]([CH3:64])=[N:66][N:67]=1)=[C:12]2[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=1)=[O:37])([O:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:34]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: Cc1nnc(S)o1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nnc(SC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@@H](C(C)(C)OC(=O)OCc4ccc([N+](=O)[O-])cc4)[C@H]3C2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
A solution of N,N-diisopropyl-N-ethylamine (0.135 ml) in methylene chloride (1.21 ml) was added to a solution of 4-nitrobenzyl (2R, 5R, 6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (350 mg) and 4-(N,N-dimethylamino)pyridine (7.9 mg) in methylene chloride (17.5 ml) at -30° C. A solution of trifluoromethanesulfonic anhydride (0.114 ml) in methylene chloride (1.02 ml) was added to the mixture and stirring was continued at the same temperature for 30 minutes. A solution of N,N-diisopropyl-N-ethylamine (0.563 ml) in methylene chloride (5.06 ml) and 5-methyl-1,3,4-oxadiazole-2-thiol (225 mg) were then added thereto, and the reaction mixture was stirred at -30° C. for 30 minutes and allowed to warm to ambient temperature over a period of an hour. After stirring at ambient temperature for 4 hours, the mixture was allowed to stand at 5° C. for 14 hours. After the solvent was removed by evaporation, the residue was dissolved in ethyl acetate (20 ml). The organic solution was washed in turn with water and a saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on deactivated silica gel with 10% water (7 g), eluting with a mixture of benzene and acetone (20:1 to 10:1) to give 4-nitrobenzyl (5R, 6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (290 mg) as an oil.
Reaction SMILES: [CH:1]1[C:6]([C@@H:7](O)[C@H:8]([NH:11]C(C(Cl)Cl)=O)[CH2:9][OH:10])=[CH:5]C=C([N+]([O-])=O)C=1.CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@@](OC)(C)C2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@](O)(C)C[C@@H](C)C(=[O:28])[C@H](C)[C@@H](O)[C@@]1(O)C.C[C@]1(O)[C@@H]2C(=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C2)C(=O)C2C(O)=CC=CC1=2>>[NH2:11][C@H:8]([C:9]([OH:10])=[O:28])[CH2:7][CH:6]([CH3:5])[CH3:1]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: O=C(N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1)C(Cl)Cl
Agent: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)cccc4[C@@](C)(O)[C@H]3C[C@@H]12
Product: CC(C)C[C@H](N)C(=O)O
Reaction time: 48 h

Procedure:
Table 3 shows the enzymatic formation of pepstatins from L-leucine and other reactants. In this experiment a medium containing 1.0% glucose, 1.0% starch, 0.75% polypeptone, 0.75% Ehrlich meat extracts, 0.3% NaCl, 0.01% MgSO4.7H2O, 0.1% KH2PO4 and 0.1% metal ions solution (the same composition as described in Experiment 1), pH 7.2, was prepared and sterilized at 120° for 15 min. A pepstatin-producing strain Streptomyces testaceus MC144-Cl (ATCC 21469) was added to a 50 ml portion of the medium in a 500 ml flask. The flask was shaken on a rotary shaker (220 r.p.m.) at 28° for 48 hrs. The cells were harvested, washed with cold sterile water three times, and suspended in M/15 phosphate buffer solution, pH 7.0. 100ml flasks containing 20ml of a reaction mixture consisting of L-leucine and other reactants as indicated in Table 3, the cell suspension (final concentration = 10mg/ml as dry matter), and 10 mcg/ml of chloroamphenicol were shaken on a rotary shaker at 28° for 20 hrs. Chloramphenicol is added to prevent contamination and growth of the cells during the reaction because the strains employed in these experiments were sensitive to antibiotics such as chloramphenicol, erythromycin or tetracyclin. The results shown in Table 3 indicate that significant amounts of pepstatins were formed by the aerobic reaction of L-leucine and the cells, and that the amounts of the product were increased by the addition of amino acids such as L-valine, L-lysine, L-aspartic acid, or L-alanine, of sugars such as glucose, of organic acids such as malic acid, or of alcohols such as glycerine. Similar results (Table 4) were obtained when the reaction was carried out with the organic acids related to the Krebs cycle such as citric acid, succinic acid, pyruvic acid, glutamic acid, or alpha-ketoglutaric acid in place of malic acid in the present experiment; the glucose could also be replaced by sucrose, invert sugar, molasses, or starch hydrolysate.
Reaction SMILES: C([O:5][C:6](=[O:51])[CH2:7][N:8]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[O:37][C:36]=3[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:44]([C:36]1[O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:35]=1[C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:27]=[CH:28][C:23]([S:20]([N:8]([CH2:7][C:6]([OH:51])=[O:5])[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)(=[O:22])=[O:21])=[CH:24][CH:25]=2)=[CH:30][CH:31]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc(C(F)(F)F)c1)S(=O)(=O)c1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN(Cc1cccc(C(F)(F)F)c1)S(=O)(=O)c1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tert-Butyl-{[4′-(2-benzylbenzofuran-3-yl)biphenyl-4-sulfonyl]-(3-trifluoromethyl-benzyl)amino}acetate (90 mg) was dissolved in methylene chloride (4 mL). TFA (1 mL) was added and the reaction mixture was stirred at room temperature for 16 h, and then concentrated in vacuo. Purification by flash column chromatography (5% methanol in methylene chloride) afforded the title compound as an off white solid (45 mg).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:21]4=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]4[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:21]4=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]4[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc2c(cnn2-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc2c(cnn2-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c1
Reaction time: 15 h
Yield: 13.8 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.1 g, 208 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(5-methyl-pyrazolo[3,4-b]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (10 mg, 14%). MS (M+H)+=350; 1H NMR (DMSO-d6) δ: 9.08 (s, 1H), 8.54 (d, J=1.8 Hz, 1H), 8.50 (s, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 8.21 (dd, J=2.0, 0.8 Hz, 1H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]([NH2:11])[CH:7]([C:8]([OH:10])=[O:9])[CH:2]1[CH:3]=[CH:4]2.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>O.O1CCOCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:11][CH:6]2[CH:5]3[CH2:1][CH:2]([CH:3]=[CH:4]3)[CH:7]2[C:8]([OH:10])=[O:9])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC1C2C=CC(C2)C1C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1C2C=CC(C2)C1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 12 h
Yield: 98 %

Procedure:
To a solution of 3-exo-aminobicyclo[2.2.1]hept-5-ene-2-exo-carboxylic acid (4.60 g, 0.03 mol) and 4-benzyloxy-benzenesulfonyl chloride (8.49 g, 0.03 mol) in water-dioxane (30 mL−30 mL) was added triethylamine (8.38 mL, 0.06 mol) at room temperature. The mixture was stirred for 12 h. The solution was concentrated and the residue was dissolved in water (30 mL). The aqueous solution was extracted with ether (50 mL) and the aqueous layer was acidified with 1 N HCI. The white precipitate was collected and dried to give 3-(4-benzyloxy-benzenesulfonylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (98% yield). Mp=201-203° C. (white solid).
Reaction SMILES: ClC1C=CC(O[CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=CC=1.Cl.N[C@@H](CCN1CC([C:41](=[O:50])[C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([F:49])[CH:43]=2)C1)CO>>[Cl:48][C:45]1[CH:46]=[CH:47][C:42]([C:41]([CH:7]2[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:10]2)=[O:50])=[CH:43][C:44]=1[F:49]
Reactant: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)n(C)n1
Reactant: N[C@H](CO)CCN1CC(C(=O)c2ccc(Cl)c(F)c2)C1
Agent: Cl
Product: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(C(=O)c3ccc(Cl)c(F)c3)C2)n(C)n1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea in Example 88 except using (S)-2-amino-4-[3-(4-chloro-3-fluoro-benzoyl)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1.[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17]Cl.O>CN(C=O)C>[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17][N:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2cccnc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.1 %

Procedure:
To a suspension of sodium hydride (934 mg, 0.0358 mol) in DMF (57 mL) was added dropwise under N2, a solution of 1H-pyrrolo[2,3-b]pyridine (3.00 g, 0.0254 mol) in DMF (20 mL). The mixture was stirred at r.t. for 45 min. then cooled to 0° C. and treated dropwise with [2-(trimethylsilyl)ethoxy]methyl chloride (6.32 mL, 0.0357 mol). The mixture was stirred at rt for 12 h. then poured into water (10 mL), stirred for 30 min. and extracted with Et2O (4×10 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude product which was chromatographed over silica gel eluting with hexane→1:9 Et2O:hexane to afford 6 g desired product.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]([C:14]2[CH:27]=[CH:26][C:25]3[C:16](=[CH:17][C:18]4[C:19]([CH3:31])([CH3:30])[CH2:20][CH2:21][C:22]([CH3:29])([CH3:28])[C:23]=4[CH:24]=3)[CH:15]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].I[CH3:33].O>CN(C=O)C>[CH3:33][O:3][C:4]1[CH:13]=[C:12]([C:14]2[CH:27]=[CH:26][C:25]3[C:16](=[CH:17][C:18]4[C:19]([CH3:31])([CH3:30])[CH2:20][CH2:21][C:22]([CH3:29])([CH3:28])[C:23]=4[CH:24]=3)[CH:15]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(-c2ccc3cc4c(cc3c2)C(C)(C)CCC4(C)C)cc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc3cc4c(cc3c2)C(C)(C)CCC4(C)C)cc1OC

Procedure:
130 mg (4.2 mmol) of sodium hydride (80% in oil) and 20 ml of DMF were introduced into a three-necked flask, a solution of 1.6 g (4.2 mmol) of methyl 2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthryl)benzoate in 50 ml of DMF was added dropwise and the mixture was stirred until gaseous emission ceased. 340 μl (5.5 mmol) of iodomethane were then added and the mixture was stirred at room temperature for two hours. The reaction medium was poured into water, extracted with ethyl ether, the organic phase decanted, dried over magnesium sulfate and evaporated. 1.6 g (96%) of the expected compound was recovered in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1.Cl.[NH2:15][OH:16].C(=O)(O)[O-].[Na+]>CO.CCOC(C)=O.O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[NH:12])[NH:15][OH:16])=[CH:7][CH:6]=1
Reactant: NO
Reactant: COC(=O)Cc1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C(=N)NO)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 95.7 %

Procedure:
(4-Cyano-phenyl)-acetic acid methylester (1.054 g, 6.02 mmol), hydroxylamine hydrochloride (0.690 g, 9.93 mmol) and sodium bicarbonate (0.834 g, 9.93 mmol) were dissolved in MeOH (12.03 mL) at RT. The mixture was stirred at 60° C. for 5 h, diluted with EtOAc (200 mL) and 40 ml water added. The aqueous layer was extracted with EtOAc (100 mL). The combined organic phases were washed with brine (40 mL) and dried over sodium sulfate. Solvent was removed to yield 1.2 g (5.76 mmol) of yellow oil, which was dried on high vacuum over night. The crude mixture was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH2:16][CH2:17][CH2:18]O)[C:13]2[C:20]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][CH:22]=[C:23]([Cl:24])[C:12]=2[N:11]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2=[N:11][C:12]3[C:23]([Cl:24])=[CH:22][CH:21]=[C:20]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:13]=3[N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(C)cc3Br)n(CCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(C)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 4-[2-[(2-bromo-4-methylphenyl)amino]-4-chloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butan-1-ol (Reference Example 54; 1.02 g, 2.13 mmol) in pyridine (2.5 mL) was added methanesulfonyl chloride (824 μL, 10.65 mmol) at 0° C. The reaction mixture was stirred at room temperature for 0.5 hr. The reaction mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude mesylate (MS Calcd.: 555; Found: 556 (M+H)) was subjected for the next step without further purification. To the crude material in N,N-dimethylformamide (2.0 mL) was added potassium carbonate (588.8 mg, 4.26 mmol). The reaction mixture was stirred at 80° C. for 12 hr. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-20% ethyl acetate/n-hexane gradient mixture. The resulting solid was washed with n-hexane to give the title compound as a colorless powder (810.1 mg, 1.77 mmol, 83% (2 steps)).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2[C:12]([F:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Si](C)(C)C)=[CH:19][C:18]=1[F:27])=[O:5])[CH3:2].[I:28]Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2[C:12]([F:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:28])=[CH:19][C:18]=1[F:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc2c(F)cncc2c1Nc1ccc([Si](C)(C)C)cc1F
Reactant: ClI
Solvent: ClCCl
Product: CCOC(=O)c1sc2c(F)cncc2c1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a cooled (0° C.) solution of 7-fluoro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (330 mg, 0.81 mmol) in DCM (10 mL) was added iodine monochloride (1M in DCM, 1.6 mL, 1.6 mmol) dropwise. On complete addition the mixture was allowed to stir at 0° C. for 1 hour then quenched by the addition of saturated sodium thiosulphate solution (10 mL). The mixture was stirred vigorously for 10 min and partitioned between ethyl acetate and water. The organic layer was separated and washed with a saturated solution of sodium hydrogenocarbonate followed by brine, dried over sodium sulphate, filtered and concentrated to give the title compound as a yellow solid (358 mg, 54%). LCMS (method B): RT=4.72 min, M+H+=461.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[O:10])=[CH:4][CH:3]=1.[CH2:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)[CH3:21].C([O-])([O-])=O.[Na+].[Na+]>COCOC.O>[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[O:10])=[CH:4][CH:3]=2)=[CH:24][CH:23]=1)[CH3:21]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: O=C(Cc1ccc(Cl)nc1)NCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCOC
Solvent: O
Product: CCc1ccc(-c2ccc(CC(=O)NCc3cccc(F)c3)cn2)cc1
Temperature: 25 °C

Procedure:
2-(6-Chloro-pyridin-3-yl)-N-(3-fluoro-benzyl)-acetamide and (0.125 gm, 0.5 mmole), 4-ethylbenzeneboronic acid (0.083 gm, 0.55 mmole) was dissolved in dimethoxymethane (DME), Na2CO3 (0.11 gm, 1 mmole) in 5 ml of water was added to the DME solution, the solution was then degassed for 30 min (Ar through the solution and vacuum applied for the first 5 min), Palladiumtetrakistriphenylphosphine (0.029 gm, 0.025 mmole) was added, degassed for additional 15 min, refluxed for 24 hr. The reaction was allowed to cool to room temperature, filtered, solid washed with ethyl acetate; the organic layer was dried, evaporated. The residue was chromatographed using ethyl acetate/hexane 3:2. The product is white solid (0.08 gm, 47%). H1-NMR INOVA-500 (DMSO d6) δ 1.228 (t, J=7.5 Hz, 3H), 2.669 (q, J=7.5 Hz, 2H), 3.590 (s, 2H), 4.321 (d, J=6 Hz, 2H), 7.053-7.113 (m, 3H), 7.324-7.375 (m, 3H), 7.766 (dd, J=9.0, 2.0 Hz, 1H), 7.887 (d, J=8.5 Hz, 1H), 7.994 (d, J=8.0 Hz, 2H), 8.548 (s, 1H), 8.696 (t, J=5.5 Hz, 1H). MS (m/z) 349.3 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[C:24]([O-])(=O)C.[Na+].C=O>>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:2]2[NH:1][C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=2)[CH2:20][CH2:19]1
Reactant: CC(=O)[O-]
Reactant: COc1ccccc1N1CCNCC1
Reactant: c1cnc2[nH]ccc2c1
Agent: C=O
Agent: [Na+]
Product: COc1ccccc1N1CCN(Cc2cc3cccnc3[nH]2)CC1

Procedure:
1H-pyrrolo[2,3-b]pyridine (47 mg, 0.40 mmol), 1-(2-methoxyphenyl)piperazine (65 mg, 0.48 mmol), sodium acetate (72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were processed as described in Example 18 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.97 (m, 4H) 3.68 (m, 4H) 3.72 (s, 3H) 4.05 (s, 2H) 5.60 (m, 1H) 6.60 (m, 1H), 6.89 (m, 2H) 7.08 (ddd, J=21.36, 7.80, 4.75 Hz, 1H) 7.52 (m, 2H) 8.07 (m, 2H) (ESI) m/z 323 (M+H)+.