Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@@H:7]2[C@@H:11]([OH:12])[CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:8]2)=O)[CH2:3][CH2:2]1.O.C(N(CC)CC)C>O1CCCC1>[CH:1]1([NH:4][CH2:5][C@@H:7]2[C@@H:11]([OH:12])[CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1C[C@H](CNC2CC2)[C@@H](O)C1
Yield: 99 %

Procedure:
364 g of benzyl (3S,4R)-3-(N-cyclopropyl)carbamoyl-4-hydroxypyrrolidine-1-carboxylate (1.20 mol) was suspended in 1.46 L of dehydrated tetrahydrofuran. While this suspension was stirred, 3.07 L of a 1.17 M tetrahydrofuran solution of borane-tetrahydrofuran complex in (3.59 mol) was added dropwise at an internal temperature of 20 to 43° C. The mixture was stirred at an internal temperature of 41 to 46° C. for 8 hours. Subsequently, the mixture was allowed to cool under stirring and then cooled in an ice bath while kept stirred. 364 mL of water was then added dropwise at an internal temperature of 15 to 25° C. Subsequently, 726 g of triethylamine was added dropwise at an internal temperature of 16 to 18° C. The mixture was then heated and stirred for 14 hours under reflux. Subsequently, the reaction mixture was allowed to cool under stirring and concentrated under reduced pressure. To the resulting residue, 1.09 L of water was added to dissolve the solid and the solution was extracted with 2.55 L of ethyl acetate. The organic layer was washed with 1.82 L of water and extracted with 1.50 L of 2 mol/L hydrochloric acid. A 2 mol/L sodium hydroxide solution (1.67 L) was then added to the aqueous layer under stirring until pH 12. The mixture was extracted with 2.55 L of ethyl acetate and the organic layer was washed with 1.82 L of 28% brine. To this layer, 255 g of anhydrous sodium sulfate was added and the mixture was stirred for 1 hour. The resulting solid was separated by filtration and washed with 0.55 L of ethyl acetate. The filtrate and the wash were combined and concentrated under reduced pressure to give 345 g of a crude product of the title compound as a faint yellow oil. This product was used in the subsequent step without further purification.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]([C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:21]2=[O:24])=[CH:17][CH:16]=1)#[N:14].CI.Cl>CCCCCC.C1COCC1>[C:13]([C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][C:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH3:1])[C:21]2=[O:24])=[CH:17][CH:16]=1)#[N:14]
Reactant: CC(C)NC(C)C
Reactant: CCCCCCCCC1Cc2ccc(C#N)cc2C1=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: CCCCCCCCC1(C)Cc2ccc(C#N)cc2C1=O
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 339.2 %

Procedure:
In a 2 liter-reaction vessel, 1.6 g (1.15×10-1M) of diisopropylamine and 450 ml of dry THF were placed and cooled to -10 ° C. Under stirring, 72.8 ml (1.5 M) of a solution of n-butyllithium in hexane was added dropwise to the above mixture in 10 minutes and cooled to -70° C. A solution of 28.0g (1.04×10-1M) of 6-cyano-2-octyl-indanone in 150 ml of dry THF was then added dropwise in 30 minutes, followed by stirring for 2 hours while the reaction temperature was gradually restored to room temperature. After the reaction, the reaction mixture was cooled to -20° C., and 28.0 g (1.97×10-1M) of methyl iodide was added dropwise thereto in 10 minutes. After the addition, the resultant mixture was stirred for 18 hours while the reaction temperature was gradually restored to room temperature. After the reaction, 1N-HCl was added dropwise to the reaction mixture under cooling to decompose the reaction mixture. The organic layer was successively washed with water, sodium hydrogencarbonate and water, followed by drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: chloroform/n-hexane=1/1; 300 mesh silica gel: 50 times in weight) to obtain 15.2 g of 6-cyano-2-octyl-2-methyl-1-indanone (Yield: 52%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:6](=[O:7])[O:5][CH:4]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:26])[CH2:13][C:14]([OH:25])([CH3:24])[CH:15]([OH:23])[C:16]([CH3:22])=[CH:17][C:18]([O:20][CH3:21])=[O:19].[CH3:27]I>CCOC(C)=O.[Ag]=O>[CH3:27][O:1][CH2:2][CH:3]1[C:6](=[O:7])[O:5][CH:4]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:26])[CH2:13][C:14]([OH:25])([CH3:24])[CH:15]([OH:23])[C:16]([CH3:22])=[CH:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: CI
Reactant: COC(=O)C=C(C)C(O)C(C)(O)CC(C)CCCCC1OC(=O)C1CO
Agent: O=[Ag]
Solvent: CCOC(C)=O
Product: COCC1C(=O)OC1CCCCC(C)CC(C)(O)C(O)C(C)=CC(=O)OC
Temperature: 53 °C

Procedure:
10 mg of methyl 11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-4,5-dihydroxy-3,5,7-trimethyl-2-undecenoate in 2 ml of EtOAc was added 35 mg of silver oxide and 0.3 ml of methyl iodide. The mixture was heated at 53° C. overnight. The solution was filtered and concentrated by dryness. The product was purified by prep. TLC (EtOAc:Hexane=1:1) to afford methyl 11-(3-methoxymethyl-4-oxo-2-oxetanyl)-4,5-dihydroxy-3,5,7-trimethyl-2-undecenoate. ##STR26##
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30].O>C(#N)C>[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(C)CCNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (200 mg, 0.775 mmol) in acetonitrile (5 mL) was added potassium carbonate (214 mg, 1.55 mmol) and N,N-dimethylethylenediamine (82 mg, 0.93 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (240 mg, 95% yield) as orange crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1cnc2[nH]cc(I)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.9 %

Procedure:
Into a 250 mL round bottomed flask were added 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (8.00 g, 40.6 mmol) and 120 mL dry THF. The solution was cooled in an ice bath at 0° C. and NaH (2.40 g, 60.0 mmol) was added in three portions. After 20 min, p-toluenesulfonyl chloride (8.70 g, 45.63 mmol) was added, and the reaction mixture was allowed to warm to rt over 30 min. The reaction mixture was concentrated and hexanes was added to obtain a precipitate, which was collected and washed with ice cold 2M NaOH. The crude product was recrystallized from EtOAc/hexanes to afford 17.8 g (92%) of the title compound as a light tan powder. 1H-NMR (500 MHz, d6-DMSO) δ 8.49 (d, J=2.5 Hz, 1H), 8.21 (s, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.98 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 2.32 (s, 3H); MS: m/z 476.8/478.8 [MH+].
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:33][C:34]1[CH:46]=[CH:45][CH:44]=[CH:43][C:35]=1[O:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[C:47]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:52]=[CH:51][C:50]([NH:53][C:54]([C:56]2([C:59](O)=[O:60])[CH2:58][CH2:57]2)=[O:55])=[CH:49][CH:48]=1>CN(C=O)C.O>[C:47]1([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:52]=[CH:51][C:50]([NH:53][C:54]([C:56]2([C:59]([N:40]3[CH2:41][CH2:42][CH:37]([O:36][C:35]4[CH:43]=[CH:44][CH:45]=[CH:46][C:34]=4[Cl:33])[CH2:38][CH2:39]3)=[O:60])[CH2:58][CH2:57]2)=[O:55])=[CH:49][CH:48]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(-c3ccccc3)cc2)CC1
Reactant: Clc1ccccc1OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(-c2ccccc2)cc1)C1(C(=O)N2CCC(Oc3ccccc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
HOBt (57 mg, 0.42 mol) and DIPEA (137 mg, 1.06 mmole), EDCI.HCl (82 mg, 0.42 mol) followed by 4-(2-chloro-phenoxy)-piperidine hydrochloride (105 mg, 0.42 mol) were added to a stirred solution of 1-(biphenyl-4-ylcarbamoyl)-cyclopropanecarboxylic acid (100 mg, 0.35 mmol) in DMF (2.0 mL) and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with water. The product was extracted with ethylacetate and the organic layers were washed with brine and concentrated to afford 78 mg (46%) of 1-[4-(2-chloro-phenoxy)-piperidine-1-carbonyl]-cyclopropanecarboxylic acid biphenyl-4-ylamide. LCMS: 475.17 (M+1)+, 92.81%, 1H NMR (DMSO-d6): δ 9.8 (s, 1H), 7.8-7.5 (d, 2H), 7.7-7.6 (t, 4H), 7.5-7.4 (m, 3H), 7.4-7.2 (m, 3H), 7.0-6.9 (m, 1H), 4.7 (m, 1H), 3.8-3.6 (m, 2H), 3.5 (m, 2H), 2.0-1.8 (m, 2H), 1.7-1.6 (m, 2H), 1.4 (m, 2H), 1.3-1.2 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.C(N(CC)CC)C.Cl[C:26]([O:28][CH3:29])=[O:27].O>ClCCl>[Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][N:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12
Reactant: Cc1nccn2c(C3CCNCC3)nc(Br)c12
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)N1CCC(c2nc(Br)c3c(C)nccn23)CC1
Yield: 85.4 %

Procedure:
1-Bromo-8-methyl-3-(piperidin-4-yl)imidazo[1,5-a]pyrazine (0.169 mmol, 50 mg) was dissolved in dichloromethane (1 ml) and triethylamine (0.337 mmol, 47 μl) and methyl chloroformate (0.186 mmol, 14.40 μl) were added at 0° C. After stirring at room temperature for one hour water and dichloromethane were added. The organic layer was separated, dried (sodium sulfate) and concentrated in vacuo to give methyl 4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate (51 mg).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc(CBr)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-bromomethyl-3-nitrobenzoic acid (2.00 g, 7.69 mmol), benzyl alcohol (796 mL, 832 mg, 7.69 mmol) and 4-dimethylaminopyridine (9.4 mg, 77 μmol) in dichloromethane (5 mL) was added DCC (1.59 g, 7.71 mmol) and the mixture was stirred at ambient temperature for 3 h. The mixture was filtered and the solvent was removed under reduced pressure. The residue was purified by chromatography using a 0-30% gradient of heptane/ethyl acetate gave benzyl 4-bromomethyl-3-nitrobenzoate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])=[CH:4][CH:3]=1.[CH3:17][S:18][CH2:19][C:20]#[N:21].C(OCl)(C)(C)C>C(Cl)Cl>[NH2:15][C:10]1[C:9]([C:8](=[O:16])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[CH:19]([S:18][CH3:17])[C:20]#[N:21]
Reactant: Nc1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: CSCC#N
Agent: CC(C)(C)OCl
Solvent: ClCCl
Product: CSC(C#N)c1cccc(C(=O)c2ccc(Cl)cc2)c1N
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a solution of 46.3 g (0.2 mole) of 4'-chloro-2-aminobenzophenone and 17.4 g (0.2 mole) of methylthioacetonitrile in 1 liter of methylene dichloride at a temperature of -70° C. was added dropwise 22.2 g (0.21 mole) of tert. butyloxychloride at a rate to ensure that the reaction temperature did not exceed -65° C. The resulting solution was allowed to warm to ambient temperature, washed twice with water, dried over sodium sulphate, and concentrated to give a gum residue. The gum crystallized when it was triturated with diethyl ether. The solid was collected by filtration and recrystallized from 2-propanol to yield 43.0 g (68%) of the title compound as a tan solid, m.p. 122° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C@@H:7]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]([OH:11])[C@H:8]1[OH:9])=[O:5])[CH3:2].[N:18]([O-])=[O:19].[Na+]>O.C(O)(=O)C>[CH2:1]([N:3]([N:18]=[O:19])[C:4]([NH:6][C@@H:7]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]([OH:11])[C@H:8]1[OH:9])=[O:5])[CH3:2]
Reactant: CCNC(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCN(N=O)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 96.4 %

Procedure:
1-ethyl-3-(β-D-glucopyranosyl)urea (930 mg) was dissolved in a mixture of water (4.3 ml) and acetic acid (4.3 ml), and to the solution was added 370 mg (1.5 mol. equivalents) of sodium nitrite in small portions under stirring. The mixture was stirred overnight at ambient temperature to complete the nitrosation. The reaction mixture was then treated with 4 ml of a cation-exchange resin, Amberlite IR-120 (H+ form), to remove the sodium ion therefrom. The reaction mixture was subsequently freeze-dried, affording 1.0 g of the titled compound as an amorphous substance of pale yellow color. [α]D26 -2° (c 1.0, H2O). This substance gave a single spot at Rf 0.82 in a thin layer chromatography on silica gel using chloroform-methanol (3:2 by volume) as eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[Br:22][CH2:23][C:24](Br)=[O:25].[Na+].[Cl-]>C(Cl)Cl.C(OCC)(=O)C>[Br:22][CH2:23][C:24]([NH:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:25]
Reactant: O=C(Br)CBr
Reactant: Nc1ccoc1C(=O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CBr)Nc1ccoc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
3-Amino-2-benzoylfuran (4.93 g, 0.025 mol) was dissolved in s dry methylene chloride (50 mL). The solution was cooled to 0° C. under nitrogen and triethylamine (3.8 mL, 0.0275 mol) was added followed by bromoacetyl bromide (2.4 mL, 0.0275 mol). The mixture was stirred at 0° C. for five hours. Next another 10% of triethylamine and bromoacetyl bromide were added and the reaction was left over night. Ehtyl acetate (200 mL) and saturated NaCl (75 mL) were added. The ethyl acetate layer was separated, washed with saturated NaCl solution, dried over sodium sulfate, filtered and concentrated in vacuo. A tan solid was obtained in theoretical yield (7.7 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[CH2:24]([N:26]=[C:27]=[S:28])[CH3:25]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:3])[N:26]([CH2:24][CH3:25])[C:27]2=[S:28])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: CCN=C=S
Product: CCn1c(=O)c2cnc3c(OC)cccc3c2n(C2CCCC2)c1=S
Yield: 33.8 %

Procedure:
1-Cyclopentyl-3-ethyl-7-methoxy-2-thioxo-2,3-dihydro-1H-pyrimido[5,4-c]quinolin-4-one (12 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) (prepared as described in Example 1) and ethyl isothiocyanate (0.4 mmol) following a procedure similar to general procedure C. LCMS: m/z 356 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.50 (s, 1H), 7.74 (d, 1H), 7.53 (t, 1H), 7.21 (d, 1H), 5.03 (p, 1H), 4.09 (s, 3H), 4.07 (q, 2H), 2.42 (m, 2H), 2.08 (m, 4H), 1.64 (m, 2H) and 1.34 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]#[CH:11])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[N:12]([CH:15](O)[CH3:16])=[N+:13]=[N-:14].[O:18]=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>[O-]S([O-])(=O)=O.[Cu+2].CO>[N+:1]([C:4]1[N:5]([CH2:9][C:10]2[N:14]=[N:13][N:12]([CH2:15][CH2:16][OH:18])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: C#CCn1ccnc1[N+](=O)[O-]
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Reactant: CC(O)N=[N+]=[N-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1nccn1Cc1cn(CCO)nn1
Reaction time: 16 h
Yield: 76.3 %

Procedure:
To a round bottom flask was added nitropropyne 10 (150 mg, 0.99 mmol) and azido ethanol (86 mg, 0.99 mmol). To this flask was added CuSO4 (0.04M, 100 uL) and sodium ascorbate (0.1 M, 100 uL). After 16 hrs, the reaction was poured onto EtOAc and washed with NH4OH. The organics were combined and the residue was purified on a combiflash system using EtOAc:Hex as the eluent followed by DCM:MeOH to afford 180 mg (76.3% yield) of 11 as a clear colorless oil. Mass Spec (lo-res): Calc'd for C8H10N6O3: 238.08; found: 239.10 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[C:12]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][CH2:28][C:29](O)=[O:30])[CH:19]=2)=[CH:3]1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH2:48]([O:50][C:51](=[O:55])[C@H:52]([CH3:54])[NH2:53])C.C(N(CC)CC)C>O1CCCC1>[CH3:48][O:50][C:51](=[O:55])[C@H:52]([CH3:54])[NH:53][C:29](=[O:30])[CH2:28][CH2:27][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([C:12]2[C:13](=[O:17])[NH:14][C:15](=[O:16])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:19]1
Reactant: CCOC(=O)[C@H](C)N
Reactant: Cn1cc(C2=C(c3cn(CCC(=O)O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)NC(=O)CCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-[3-[4-(1-Methylindol-3-yl)-1H-pyrrole-2,5-dion-3-yl]-indol-1-yl)-propionic acid 272 mg (0.65 mmol) are dissolved in 3 mL anhydrous tetrahydrofuran and mixed with 145 mg (0.70 mmol) dicyclohexylcarbodiimide and a mixture of 90 mg (0.8 mmol) alanine ethyl ester hydrochloride and 85 mg triethylamine dissolved in 5 mL anhydrous tetrahydrofuran. The reaction mixture is stirred for 24 hours at ambient temperature, the solvent is then distilled off in a vacuum, the residue is taken up in 100 mL ethyl acetate, and the organic phase is washed with water. After drying over anhydrous sodium sulphate and distilling off the solvent in a vacuum, the crude product obtained is separated by thick layer chromatography (silica gel, dichloromethane/methanol=90:10%). The fraction with the RF of 0.31 is separated, the product is extracted and, after removal of the solvent in a vacuum, there are isolated 130 mg (40% of theory) of the desired product;
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:18][CH3:19])C(O)=O)=[CH:10][CH:9]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([S:37][CH2:38][CH3:39])=[C:25]([CH:36]=1)[CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:18][CH2:19][C:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([S:37][CH2:38][CH3:39])=[C:25]([CH:36]=2)[CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:3])=[CH:12][CH:13]=1
Reactant: CCSc1ccc(N)cc1CN(C)C(=O)OC(C)(C)C
Reactant: CCC(C(=O)O)c1ccc(Br)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCSc1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
Oxalyl chloride (0.180 mL, 2.06 mmol) was added dropwise to a suspension of 4-bromophenylbutanoic acid (0.250 g, 1.03 mmol) in DCM (3 mL) containing DMF (1 drop) at rt. After 4 h, the reaction mixture was concentrated in vacuo and coevaporated with toluene. The residue was dissolved in DCM (2 mL) and added dropwise to a solution of 17A (0.300 g, 1.01 mmol), DMAP (0.025 g, 0.2 mmol)and pyridine (1.0 mL, 12.3 mmol) in DCM (2 mL) at rt. The reaction mixture was stirred overnight at rt. The reaction mixture was concentrated in vacuo and the residue was triturated with water and then purified by silica gel chromatography (gradient from 0 to 20% ethyl acetate in hexanes) to give 17B (0.46 g, 88%) as a clear oil that solidified on standing. 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (t, J=7.03 Hz, 3 H) 1.33-1.58 (m, 9 H) 1.96-2.04 (m, 2 H) 2.33 (t, J=7.47 Hz, 2 H) 2.63 (t, J=7.47 Hz, 2 H) 2.63 (t, J=7.47 Hz, 2 H) 2.74-2.93 (m, 3 H) 4.56 (br. s., 2 H) 6.96-7.02 (m, 0.5 H) 7.05 (d, J=8.35 Hz, 2 H) 7.13 (br. s., 0.4 H) 7.28-7.36 (m, 0.8 H) 7.38 (d, J=8.35 Hz, 2 H) 7.60-7.72 (m, 0.4 H) 7.81-7.98 (m, 0.9 H) 8.33 (br. s., 1 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH2:58])[S:55][C:45]=2[C:46]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[N:47][CH:48]=1>C1COCC1>[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH:58][C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[O:9])[S:55][C:45]=2[C:46]([N:49]2[CH2:50][CH2:51][O:52][CH2:53][CH2:54]2)=[N:47][CH:48]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)C3CCOCC3)nc12

Procedure:
From tetrahydro-pyran-4-yl-carboxylic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 379 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[CH:11]1([N:14]2[C:18]([C:19]3[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=3)=[CH:17][N:16]=[CH:15]2)[CH2:13][CH2:12]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:25][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:18]3[N:14]([CH:11]4[CH2:13][CH2:12]4)[CH:15]=[N:16][CH:17]=3)[N:24]=2)=[O:10])[CH:3]=1
Reactant: Nc1cccc(-c2cncn2C2CC2)n1
Reactant: O=C(O)c1cc(Cl)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cncn2C2CC2)n1)c1cc(Cl)ccn1
Yield: 47.1 %

Procedure:
A solution of 4-chloro-pyridine-2-carboxylic acid (141 mg, 0.895 mmol), 6-(3-cyclopropyl-3H-imidazol-4-yl)-pyridin-2-ylamine (150 mg, 0.750 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (342 g, 0.899 mmol), and N-methylmorpholine (250 μL, 2.70 mmol) in N,N-dimethylformamide was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, the residue suspended in acetonitrile, and the solid isolated by filtration, washed with water (80 mL), acetonitrile (80 mL) and diethyl ether (80 mL), and dried under reduced pressure to afford 4-chloro-N-(6-(1-cyclopropyl-1H-imidazol-5-yl)pyridin-2-yl)picolinamide as a white powder (120 mg, 47% yield). M+1=340.1