Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][CH:11]([O:14][CH2:15][CH3:16])[C:12]#[CH:13])[CH3:9].[Br:17][C:18]1[CH:23]=[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:21](I)=[CH:20][N:19]=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.CN(C=O)C>[Br:17][C:18]1[N:19]=[CH:20][C:21]2[CH:13]=[C:12]([CH:11]([O:14][CH2:15][CH3:16])[O:10][CH2:8][CH3:9])[N:24]([S:25]([CH3:28])(=[O:27])=[O:26])[C:22]=2[CH:23]=1
Reactant: CS(=O)(=O)Nc1cc(Br)ncc1I
Reactant: C#CC(OCC)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(OCC)c1cc2cnc(Br)cc2n1S(C)(=O)=O
Temperature: 60 °C
Yield: 51 %

Procedure:
To DMF (3.4 mL) containing triethylamine (0.64 mL, 0.46 g 4.5 mmole) was added propargylaldehyde diethyl acetal (183 uL, 163 mg, 1.27 mmole) and N-(2-bromo-5-iodopyridin-4-yl)methanesulfonamide, (Preparation 8, 400 mg 1.06 mmole) followed by copper(I) iodide (7.1 mg, 0.037 mmole). The reaction was placed under nitrogen. Bis(triphenylphosphine)palladium dichloride (26.1 mg, 0.037 mmole) was added and the reaction was flushed again with nitrogen, then heated at 60° C. for 2 hours. The reaction was cooled and added to water (35 mL) containing a sodium bicarbonate solution (3 mL). The reaction was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water containing sodium bicarbonate solution (3×10 mL), brine and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 100% dichloromethane to 5% ethyl acetate in dichloromethane to 10% ethyl acetate in dichloromethane to give the title compound (207 mg, 51%). 1H-NMR (CDCl3, 500 MHz): δ 1.32 (t, J=6.94 Hz, 6H), 3.38 (s, 3H), 3.75 (m, 2H), 3.84 (m, 2H), 5.86 (d, J=0.95 Hz, 1H), 6.94 (t, J=0.95 Hz, 1H), 8.14 (t, J=0.95 Hz, 1H), 8.67 (d, J=0.95 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH:18]=2)=[O:13])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([CH:12]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH:18]=2)[OH:13])[CH2:10][CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)c2cc3ccccc3o2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(C(O)c2cc3ccccc3o2)CC1

Procedure:
Alternatively, the starting bromobenzofuran may be reacted with magnesium metal under standard conditions to prepare the corresponding Grignard reagent, benzofurylmagnesium bromide. This Grignard reagent is then reacted with the Weinreb amide, N-methyl N-methoxy 1-(tert-butoxycarbonylamino)cyclopropane-1-carboxamide, to provide 1-(tert-butoxycarbonylamino)-1-(benzofurylcarbonyl)cyclopropane. This ketone is then reduced under standard conditions, typically with sodium borohydride in methanol or ethanol, to provide 1-(tert-butoxycarbonylamino)-1-(benzofuryl(hydroxymethyl))cyclopropane. This alcohol is then converted to the corresponding acetate and reduced to the corresponding methylene by treatment with samarium iodide as previously described. The resulting 1-(tert-butoxycarbon-yl)-1-(benzofurylmethyl)cyclopropane is treated with acid under standard conditions to provide the compounds of the present invention. If necessary or desired, the Weinreb amide may be reduced by reaction with lithium aluminum hydride to provide the corresponding aldehyde essentially as described by Fehrentz and Castro (Synthesis, 676 (1983)). This aldehyde is then reacted with the Grignard reagent previously described to prepare 1-(tert-butoxycarbonylamino)-1-(benzofuryl(hydroxymethyl))cyclopropane, which is then subjected to the reaction conditions previously described to prepare the compounds of the present invention. The requisite Weinreb amide, N-methyl N-methoxy 1-(tert-butoxycarbonylamino)cyclopropane-1-carboxamide, may be prepared from the commercially available 1-amino-1-carboxycyclopropane by standard methods well known in the art.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]1[CH2:8][C@H:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([CH3:23])[CH3:22])[N:13]=2)=[O:11])[CH2:6][N:5]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>>[C:31]([NH:1][CH2:2][CH2:3][C@@H:4]1[CH2:8][C@H:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([CH3:23])[CH3:22])[N:13]=2)=[O:11])[CH2:6][N:5]1[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])(=[O:35])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CCN)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Product: CC(C)C(=O)NCC[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Step 3 of Example 17 from tert-butyl (2R,4S)-2-(2-aminoethyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidine-1-carboxylate (Step 2 of Example 19) and isobutyryl chloride.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:20][C:21]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH3:29][S:30]([OH:33])(=[O:32])=[O:31]>CO>[CH3:29][S:30]([OH:33])(=[O:32])=[O:31].[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=4)=[CH:20][C:21]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ccccn4)cc3C)c(C)nc12
Agent: CS(=O)(=O)O
Solvent: CO
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccc(C)n4)cc3C)c(C)nc12
Yield: 200 %

Procedure:
To a solution of 8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-5-pyridin-2-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine (0.55 g, 1.36 mmol) and MeOH (6 mL) is added methane sulfonic acid (0.088 mL, 1.36 mmol). After one hour the solution is concentrated and the solution is treated with Darco-60® for 1 hour, filtered and concentrated to furnish the title compound (0.68 g, 1.36 mmol, >99%). 1H NMR (CDCl3: CD3OD 95:5) δ 0.85 (t, J=7.4 Hz, 6H), 1.67-1.91 (m, 4H), 1.96 (s, 3H), 1.97 (s, 3H), 2.20 (s, 3H), 2.61 (s, 3H), 2.90 (s, 3H), 3.17-3.29 (m, 1H), 7.33 (s, 1H), 7.64 (d, J=7.4 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 8.18 (s, 1H), 8.34 (t, J=7.9 Hz, 1H), 9.95 (bs, 1H). LC/MS (m/z): calcd. for C25H32N4O2S2 (M+H)+: 405.6; found: 405.6.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:8][C:7]1[C:2]2[N:1]=[C:20]([CH3:21])[C:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:24][CH:23]=3)=[C:17]([CH3:18])[C:3]=2[C:4]([OH:9])=[CH:5][CH:6]=1
Reactant: Nc1cc(O)ccc1Cl
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 170 °C

Procedure:
A mixture of 3-amino-4-chlorophenol (2.2 g), 3-(4-chlorobenzyl)pentane-2,4-dione (3.4 g) and toluene-4-sulfonic acid (few crystals) was heated at 170° C. under nitrogen for 10 hours. The mixture was cooled to room temperature and purification by column chromatography on silica gel, eluting with a mixture of methanol and dichloromethane (1:19 by volume), followed by trituration with diethyl ether gave title compound as a pale brown solid, 0.41 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([OH:19])=O)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27]O)=[NH:26])=[CH:23][N:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]4[O:19][N:27]=[C:25]([C:24]5[CH:29]=[CH:30][C:21]([NH2:20])=[N:22][CH:23]=5)[N:26]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc2ccc(-c3ccc(Cl)cc3)cn12
Reactant: N=C(NO)c1ccc(N)nc1
Product: Nc1ccc(-c2noc(-c3cnc4ccc(-c5ccc(Cl)cc5)cn34)n2)cn1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.36) (136 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate) and further purification by crystallization (MeOH/diethyl ether) as a white solid (34 mg, 17%). MS (ISP) 389.3 [(M+H)+]; mp 273° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:11][C:12]([NH:14][C:15]1[C:16]([S:24][CH3:25])=[N:17][C:18]([CH3:23])=[CH:19][C:20]=1[S:21][CH3:22])=[O:13].[SH:26][C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>O>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[S:26][CH2:11][C:12]([NH:14][C:15]1[C:16]([S:24][CH3:25])=[N:17][C:18]([CH3:23])=[CH:19][C:20]=1[S:21][CH3:22])=[O:13]
Reactant: Sc1nc2ccccc2o1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CSc1cc(C)nc(SC)c1NC(=O)CSc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
Potassium carbonate (46 mg, 0.33 mmol) was added to an acetonitrile (5 ml) solution of this amide (96 mg, 0.3 mmol) and 2-mercaptobenzoxazole (45 mg, 0.3 mmol), and the mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 10 g, eluent—hexane:acetone=5:2) to obtain 88 mg (yield 75%) of the desired compound as a colorless crystal.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:22]1[N:23]([CH2:30][C:31]2([CH3:34])[CH2:33][O:32]2)[CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[N:26]=1.[H-].[Na+]>CN(C=O)C.O>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:33][C:31]3([CH3:34])[O:32][C:22]4=[N:26][C:25]([N+:27]([O-:29])=[O:28])=[CH:24][N:23]4[CH2:30]3)=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Br)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OCC3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 60 °C
Yield: 88.7 %

Procedure:
tert-Butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate (1.5 g, 5.4 mmol) and 2-bromo-1-(2-methyl-oxiranylmethyl)-4-nitro-1H-imidazole (1.96 g, 7.5 mmol) are dissolved in DMF (100 ml) and sodium hydride (0.39 g, 9.7 mmol, 60% in mineral oil) is added at room temperature. Once gas evolution ceases the mixture is heated to 60° C. for 1 h. The mixture is cooled, diluted with water and extracted with ethyl acetate. The combined extracts are purified by silica gel chromatography (1% methanol in methylene chloride) to give 2.2 g (88%) of the product as a tan solid. ESI MS m/z 482 (M+Na+); 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 6.87 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 4.48 (d, 10 Hz, 1H), 4.18 (d, J=10.4 Hz, 1H), 4.02 (t, J=9.2 Hz, 1H), 4.0-3.55 (m, 4H), 3.05-2.99 (m, 4H), 1.77 (s, 2H), 1.57 (s, 9H), 1.47 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:37]([NH:44][CH2:45][CH2:46]N)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[CH2:37]([NH:44][CH2:45][CH2:46][NH:18][C:16]([C:15]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]=1[O:6][C:5]1[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=1)=[O:17])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NCCNCc1ccccc1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)NCCNCc3ccccc3)cc21
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring at for 18 hours, the reaction was treated with N1-benzyl-ethane-1,2-diamine (1 equivalent). After an additional 18 hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to MeOH/CH2Cl2 to provide compound 11g-5 as an oil in 100% yield.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]([O:12]CC)=[O:11])[NH:7][C:8]=1[CH3:9]>CO>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]([OH:12])=[O:11])[NH:7][C:8]=1[CH3:9]
Reactant: CCOC(=O)c1cc(Cl)c(C)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]c(C(=O)O)cc1Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Lithium hydroxide (2 M, 4 ml) was warmed to 50° C. and a solution of ethyl 4-chloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 7; 0.30 g, 1.60 mmol) in MeOH was added to it. The reaction was heated to 80° C. and stirred for two hours. The MeOH was removed and the aqueous solution was cooled to 0° C. and acidified with 30% HCl. The precipitated product (0.23 g, 92%) was filtered and dried. MS (ES): 160 (M+1) for C6H6ClNO2; NMR (CDCl3): 2.25 (s, 3H), 6.85 (s, 1H), 8.98 (brs, 1H).
Reaction SMILES: CS(O[C@@H:6]1[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(=O)=O.[C-:42]#[N:43].[Na+]>CN(C=O)C>[C:30]([O:29][C:27]([NH:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[N:9]1[CH2:10][C@H:11]([CH3:12])[C@H:6]([C:42]#[N:43])[C@H:7]([NH:34][C:35](=[O:36])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])[CH2:8]1)=[O:28])([CH3:31])([CH3:33])[CH3:32]
Reactant: [C-]#N
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1C#N
Temperature: 80 °C
Reaction time: 6 h
Yield: 5 %

Procedure:
To a solution of (3R,4R,5S)-1-(3-(bis(tert-butoxycarbonyl)amino)pyridin-4-yl)-3-(tert-butoxycarbonylamino)-5-methylpiperidin-4-yl methanesulfonate (1.0 equiv.) in DMF (0.10 M) was added NaCN (5.0 equiv.). The mixture was stirred at 80° C. for 6 hrs and partitioned between EtOAc and H2O. The organic layer was washed NaCl(sat), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield tert-butyl ((3S,4S,5R)-1-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-4-cyano-5-methylpiperidin-3-yl)carbamate in 5% yield. LC/MS (m/z)=432.2 (MH+), Rt=0.73 min.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C)C=O>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]/[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(/C=C/N(C)C)c([N+](=O)[O-])c1
Temperature: 130 °C
Yield: 97.6 %

Procedure:
A solution of methyl 4-methyl-3-nitrobenzoate (4.46 g) in N,N-dimethylformamide (23 ml) was treated with N,N-dimethylformamide dimethyl acetal (8.18 g) and heated at 130° C. for 2 hours. The solvent was evaporated and the residue was triturated with ether to give methyl E-4-(2-dimethylaminovinyl)3-nitrobenzoate (5.58 g, 98%) as a red powder; NMR (80 MHz, CDCl3) 2.98[s, 6H, N(CH3)2 ], 5.90(d, 1H, CHN), 7.14(d, 1H, CHCHN), 7.45(d, 1H, H5 -Ar), 7.90(dd, 1H, H6 -Ar), 8.47(d, 1H, H2 -Ar).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][P:5]([CH2:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:8])[O:6][CH3:7].[CH2:17]1[C@@H]2OC(C[C@@H]2[C@@H](CO)[C@@H]1O)=O.C(O)(=O)C>C1COCC1>[CH3:3][O:4][P:5]([CH2:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:17])[CH3:15])(=[O:8])[O:6][CH3:7]
Reactant: O=C1C[C@@H]2[C@@H](CO)[C@H](O)C[C@@H]2O1
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCCC(C)C)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the suspension of sodium hydride (NaH) (60%, 250 mg) in THF (40 ml) was added dropwise dimethyl(2-oxoheptyl)phosphonate, and the reaction solution was stirred for 30 min. A THF solution (40 ml) of the aldehyde (2) previously prepared by Collins oxidization of (−)-Corey lactone (1) (2 g) was added. Reaction was maintained at room temperature overnight, and then acetic acid was added. After the usual work-up, an α,β-unsaturated ketone (3) was obtained. Yield: 1.95 g (50%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C:8]#[N:9].[BH4-].[Na+].O>C(O)C.[Ni](Cl)Cl>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH2:8][NH2:9]
Reactant: Cc1ccsc1CC#N
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccsc1CCN
Temperature: 25 °C
Yield: 49.5 %

Procedure:
Nickel chloride (0.95 g, 0.73 mmol) was slowly added dropwise to the solution of 2-(3-methylthiophen-2-yl) acetonitrile obtained in step (45-2) (0.10 g 0.73 mmol) in ethanol (3 mL). To a reaction mixture was added portion wise sodium borohydride (0.83 g, 2.19 mmol), and was stirred at room temperature. Water (30 mL) was sequentially added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography (dichloro methane:methanol=8:2), to obtain the title compound (51 mg, 50%).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][N:22]3[CH2:23][CH2:24][N:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=4)[CH2:20][CH2:21]3)[C:7]=2[CH:8]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Clc1ccc2scc(CBr)c2c1
Product: Clc1ccc2scc(CN3CCN(c4ccccn4)CC3)c2c1

Procedure:
3-(Bromomethyl)-5-chloro-1-benzothiophene and 1-(2-pyridinyl)piperazine were processed as described in Example 2 to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) δ 3.15 (m, 2H), 3.49 (m, 6H), 3.75 (s, 2H), 6.61 (dd, 1H, J=7.5,4.5 Hz), 6.80 (d, 1H, J=8.7 Hz), 7.40 (dd, 1H, J=8.7,1.5), 7.52 (m, 1H), 7.70 (s, 1H), 8.00 (d, 1H, J=8.7 Hz), 8.08 (m, 2H). MS (DCI/NH3) m/z 344.0 (M+H)+. Anal. Calcd for C18H18N3SCl: C, 62.87; H, 5.28; N, 12.22. Found: C, 62.71; H, 5.23; N, 12.26.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:22]([O:14][C:13](=[O:15])[C@@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 98.6 %

Procedure:
N-Tert-butoxycarbonyl-D-valine (70 g, 0.32 mol) and cesium carbonate (200.2 g, 0.615 mol) were stirred in dry dimethylformamide (550 mL). Benzyl bromide (40.32 mL, 0.336 mol) was added and the reaction mixture was stirred overnight. The material was concentrated on the roto-evaporator and the residue was dissolved in methylene chloride (200 mL) and the methylene chloride layer was washed with water and brine, dried over magnesium sulfate and concentrated to give N-tert-butoxycarbonyl-D-valine benzyl ester (97 g) as a viscous oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1.O=C1CCC(=O)N1[O:41][C:42](=O)[CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][NH:81][C:82](=[O:92])[CH2:83][CH2:84][N:85]1[C:89](=[O:90])[CH:88]=[CH:87][C:86]1=[O:91].CCN(C(C)C)C(C)C>>[Cl:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:32])[C:25]=1[C:24]([NH:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@H:12]([NH:11][C:9]([C:4]2([CH2:3][CH2:2][NH:1][C:42](=[O:41])[CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][NH:81][C:82](=[O:92])[CH2:83][CH2:84][N:85]3[C:89](=[O:90])[CH:88]=[CH:87][C:86]3=[O:91])[CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:10])[C:13]([OH:15])=[O:14])=[CH:22][CH:21]=1)=[O:33]
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Reactant: NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCN1C(=O)C=CC1=O)NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-[[1-(2-aminoethyl)cyclopentanecarbonyl]amino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid (100 mg, 0.2 mmol), 3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)propionylamino]-ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (176 mg, 0.2 mmol), and DIPEA (258 mg, 191 uL, 2.0 mmol), and after HPLC purification, resulted in a white solid (28 mg, 11%). ES(+)-HRMS m/e calcd. for C58H85Cl2N5O20 (M+H)+ 1242.5238, obsd. 1242.5248.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:37])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[C:16]([Cl:37])=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(OC)cc2)c1OC(C)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccc(OC)cc2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 124(b) from 4-acetoxy-7-cyano-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and NCS in MeCN. The title compound, ESI MS (m/z): 428 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([NH2:13])[CH3:12]>C1(C)C(C)=CC=CC=1>[CH2:11]([NH:13][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCN
Solvent: Cc1ccccc1C
Product: CCNc1ncccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 110.8 %

Procedure:
A stirred mixture of 2-chloro-3-nitropyridine (8.60 g, 0.054 mol), ethylamine (5.37 g, 0.12 mol), and xylene (10 ml) was heated at 100° C. in a sealed tube for three hours. After cooling, the solvent was removed in vacuo, and water was added to the residue. The product was extracted with methylene chloride, dried (sodium sulfate), and concentrated in vacuo to give 10.0 g of the title compound as a yellow oil, suitable for use in the next reaction.