Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[NH2:27][C:28]1[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[NH2:27][C:28]1[CH:33]=[C:32]([O:34][C:2]2[N:3]=[C:4]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=2[CH2:8][CH3:9])[CH:31]=[CH:30][N:29]=1
Reactant: Nc1cc(O)ccn1
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1ccnc(N)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
A mixture of 5-chloro-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (200 mg), 2-amino-4-pyridinol (118 mg), cesium carbonate (348 mg), and N-methylpyrrolidone (2 mL) was stirred at 120° C. for 3 hours. The reactant was purified by silica gel column chromatography (eluent; chloroform:methanol=95:5-80:20, NH2 type: eluent; chloroform:methanol=99:1-98:2) and then washed with ethyl acetate to obtain 5-[(2-aminopyridin-4-yl)oxy]-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (104 mg) as a yellow solid.
Reaction SMILES: [C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].COCCOC(N=NC(OCCOC)=O)=O>ClCCl.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: C[C@H](O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reaction time: 46 h

Procedure:
After (S)-1-phenylethyl alcohol (300 mg, 2.46 mmol), triphenylphosphine (772.5 mg, 2.95 mmol), 4-nitrobenzoic acid (494 mg, 2.95 mmol), and dichloromethane (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (693 mg, 2.95 mmol) dissolved in dichloromethane (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 46 hours. Water (10 mL) was added, and separation was carried out. Then, the aqueous layer was extracted using dichloromethane (10 mL, ×1). The resulting organic layer was collectively washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 5% ethyl acetate-hexane solution) to give (R)-1-(4-nitrobenzoyloxy)-1-phenylethane as a pale yellow liquid substance (496 mg, yield: 74%/(S)-1-phenylethyl alcohol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[OH:24])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:6]([OH:24])=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:8]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(-c2ccc(N)cc2)cc(C(C)(C)C)c1O
Reaction time: 16 h

Procedure:
A solution of 50 g. (0.152 mole) of 2,6-di(t-butyl)-4-(4'-nitrophenyl)phenol in 350 ml. of ethyl acetate is reduced with hydrogen gas at about 45 psig in a Paar apparatus using 10 percent palladium on charcoal as catalyst. The mixture is allowed to stand for about 16 hours, filtered, and the filtrate evaporated under vacuum. The residue is cooled, dissolved in ethanol and triturated with water. The resulting off-white solid is recrystallized from petroleum ether to provide 4-(4'-aminophenyl)-2,6-di(t-butyl)phenol, m.p. 113°-114.5° C.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.Cl.[C:18]([NH:22][NH2:23])([CH3:21])([CH3:20])[CH3:19]>C(O)C>[C:18]([N:22]1[C:8]([NH2:9])=[CH:7][C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])=[N:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(N)n(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 31.5 %

Procedure:
A solution of pivaloylacetonitrile (300 mg, 2 mmol, 1.0 equiv), triethylamine (1.16 mL, 8.3 mmol, 3.2 equiv), and tert-butylhydrazine hydrochloride (1.03 g, 8.3 mmol, 3.2 equiv) in 10 mL of ethanol was heated at 100° C. in a sealed tube. After 4 days, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified via automated flash chromatography (40 g SiO2, ethyl acetate to 20% methanol in ethyl acetate) to afford the product as an off-white solid (123 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C([Sn]([N:26]=[N+:27]=[N-:28])(CCCC)CCCC)CCC.[N-]=[N+]=[N-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]1[N:26]=[N:27][NH:28][N:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [N-]=[N+]=[N-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)c(-c2nn[nH]n2)c1
Yield: 127.7 %

Procedure:
137 mg (0.750 mmol, 1 eq.) of 2-chloro-5-nitrobenzonitrile are dissolved in 8 mL of toluene, and 411 μl (1.5 mmol, 2 eq.) of tributyl tin azide are added to the reaction mixture. Then the mixture is heated under reflux of the toluene for one night. As the reaction is incomplete, 205 μl (0.75 mmol, 1 eq.) of azide are again added and the mixture is stirred under reflux for a further 5 hours. The mixture is then concentrated and 10 mL of HCl 2 N in Et2O are added, the precipitate formed is filtered and washed with pentane and diethyl ether. 216 mg of product 10 are obtained (yield=64%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32].N1C=CC=CC=1>C(Cl)Cl>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)cc3ccoc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NS(=O)(=O)c3ccccc3Cl)cc3ccoc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
tert-Butyl 4-(5-amino-1-benzofuran-7-yl)piperazine-1-carboxylate (0.59 g, 1.87 mmol; Intermediate 10) was dissolved in DCM. 2-Chlorobenzenesulfonyl chloride (0.59 g, 2.8 mmol) was added followed by pyridine (0.45 mL, 5.6 mmol). The reaction mixture was stirred at room temperature overnight. Filtration through a silica plug afforded 0.66 g (72%) of the title product. HPLC purity 92%, RT=2.56 min (System A; 10-97% MeCN over 3 min). 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9H) 3.07-3.21 (m, 4H) 3.51-3.65 (m, 4H) 6.51 (d, J=2.0 Hz, 1H) 6.62 (d, J=2.3 Hz, 1H) 6.93 (d, J=2.0 Hz, 1H) 7.00 (s, 1H) 7.18-7.31 (m, 2H) 7.36-7.47 (m, 1H) 7.47-7.57 (m, 2H) 7.90 (dd, J=7.9, 1.6 Hz, 1H). MS (ESI+) m/z 492.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([NH:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][C:32]=2[N:33]2[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:34]2)=[O:25])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Reactant: Nc1cnccc1N1CCC[C@H](NC(=O)OCc2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)Nc1cnccc1N1CCC[C@H](NC(=O)OCc2ccccc2)C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (632.0 mg, 1.575 mmol), benzyl [(3S)-1-(3-aminopyridin-4-yl)piperidin-3-yl]carbamate (559.9 mg, 1.715 mmol) and HATU (1822 mg, 4.792 mmol), DMF (15.0 mL) was added, followed by DIPEA (1854 mg, 14.34 mmol). The reaction mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with brine (2×100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-10% MeOH in DCM) to afford the sub-title compound (912.7 mg, 82%). LCMS calc. for C36H34BrN6O5(M+H)+: m/z=709.2. found 709.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C@H:10]2[CH2:14][C@@H:13]([CH2:15][OH:16])[CH:12]=[CH:11]2)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].Cl.[CH2:18](OC(OCC)OCC)C>>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]2[C:2]=1[N:1]=[CH:18][N:9]2[C@H:10]1[CH2:14][C@@H:13]([CH2:15][OH:16])[CH:12]=[CH:11]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1c(Cl)ncnc1N[C@@H]1C=C[C@H](CO)C1
Agent: Cl
Product: OC[C@H]1C=C[C@@H](n2cnc3c(Cl)ncnc32)C1

Procedure:
(1R,cis)-4-[(5-Amino-6-chloro-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol (from part d of this example, 9.63 g, 40.0 mmol), triethylorthoformate (150 mL), and concentrated hydrochloric acid (14 mL) were stirred for 3 hours. Volatiles were evaporated and the residual solid was partitioned between chloroform (300 mL) and saturated aqueous sodium carbonate (100 mL). The aqueous layer was extracted with chloroform (2×100 mL). The combined chloroform layers were dried (sodium sulfate). Volatiles were evaporated under reduced pressure and the residual yellow glass was chromatographed on silica gel. Elution with ethyl acetate gave title compound as white needles from ethyl acetate (7.45 g, 74%), m.p. 121–124° C.; 1H-NMR (DMSO-d6) δ 8.81 (s, 1H), 8.64 (s, 1H), 6.24 and 6.21 (two m, 2H), 5.75 (m, 1H), 4.75 (t, J=5.4 Hz, 1H), 3.34 (m, 2H), 2.95 (m, 1H), 2.75 (m, 1H), 1.75 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])=[N:4][CH:5]=[C:6]([I:8])[CH:7]=1.N1C=CC=CC=1.[C:21](Cl)(Cl)=[O:22]>ClCCl>[F:1][C:2]1[C:3]([N:9]2[CH2:10][C:11]([CH3:14])([CH3:12])[O:13][C:21]2=[O:22])=[N:4][CH:5]=[C:6]([I:8])[CH:7]=1
Reactant: CC(C)(O)CNc1ncc(I)cc1F
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CN(c2ncc(I)cc2F)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
(580 mg, 1.87 mmol) 1-(3-Fluoro-5-iodopyridin-2-ylamino)-2-methylpropan-2-ol (Example 1, step 1) was dissolved in dichloromethane (10 ml) and pyridine (300 μl, 3.74 mmol, 2 equiv.) was added at room temperature. The mixture was cooled to 0-5° C. and phosgene (20% in toluene) (1.19 ml, 2.24 mmol, 1.2 equiv.) was added dropwise over a period of 15 min at 0-5° C. The mixture was stirred for 1 hour at 0-5° C. The reaction mixture was extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with a heptane:ethyl acetate gradient 100:0 to 50:50. The desired 3-(3-fluoro-5-iodopyridin-2-yl)-5,5-dimethyloxazolidin-2-one (500 mg, 1.49 mmol, 79.5% yield) was obtained as a white solid, MS: m/e=337.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:20][O:21][CH2:22]Cl.Cl>C(Cl)Cl>[CH3:20][O:21][CH2:22][O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: N#CCc1ccc(O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Ten grams of 4-hydroxybenzyl cyanide was dissolved in 80 ml of methylene chloride, followed by addition of 20 ml of diisopropylethylamine and 9.1 g of chloromethyl methyl ether at 0 C., and stirred overnight at room temperature. The reaction solution was poured into 2N hydrogen chloride, followed by extraction of methylene chloride and washing in saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate to obtain residue. The residue was subjected to chromatography on a silica gel column, which was then eluted with chloroform to produce 12.8 g of 4-methoxymethyloxybenzyl cyanide.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[C:14]([Cl:27])=[CH:15][C:16]([F:26])=[C:17]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:18]=2)=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[C:14]([Cl:27])=[CH:15][C:16]([F:26])=[C:17]([NH:19][C:20](=[O:25])[C:21]([F:22])([F:23])[F:24])[CH:18]=1)[N:10]=2
Reactant: Nc1ccc(Oc2cc(NC(=O)C(F)(F)F)c(F)cc2Cl)nc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3cc(NC(=O)C(F)(F)F)c(F)cc3Cl)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Potassium thiocyanate (5.98 g, 61.5 mmol) was dissolved in acetic acid (280 mL), N-{5-[(5-aminopyridin-2-yl)oxy]-4-chloro-2-fluorophenyl}-2,2,2-trifluoroacetamide (5.20 g, 14.9 mmol) was added thereto, and the mixture was stirred at room temperature for 30 min. To the solution was added dropwise a solution (40 mL) of bromine (2.54 g, 15.9 mmol) in acetic acid, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (500 mL), the solution was washed with saturated aqueous sodium hydrogen carbonate solution (200 mL×3) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The dried organic layer was concentrated under reduced pressure. The precipitate was collected by filtration to give the title compound (5.78 g, 96%) as a pale-yellow powder.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=2[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:4]=1)=O.[NH2:23][C:24]1([CH2:37][CH3:38])[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:33]([O:32][C:30]([N:27]1[CH2:26][CH2:25][C:24]([NH:23][CH2:1][C:3]2[C:11]3[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=3[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:4]=2)([CH2:37][CH3:38])[CH2:29][CH2:28]1)=[O:31])([CH3:34])([CH3:36])[CH3:35]
Reactant: CCC1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC(=O)c1ccnc2c1c(C=O)cn2C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCC1(NCc2cn(C(=O)OC(C)(C)C)c3nccc(C(=O)OC)c23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
1-tert-Butyl 4-methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (211 mg, 0.692 mmol) was dissolved in MeOH (10 mL) and tert-butyl 4-amino-4-ethylpiperidine-1-carboxylate (158 mg, 0.692 mmol) were added followed by 2 drops of acetic acid. The solution was allowed to stir at room temperature for 2 h. Then sodium cyanoborohydride (44 mg, 0.692 mmol) was added over the course of 6 h at room temperature. The solution was quenched with water and extracted with ethyl acetate. The organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (70% EtOAc/Hexanes) gave 127 mg of 1-tert-butyl 4-methyl 3-((1-(tert-butoxycarbonyl)-4-ethylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate. [M+H] found 417.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[I-].ClC1C=CC=C[N+]=1C.[CH2:31](O)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([CH2:13][C:14]([O:16][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccco1
Reactant: CCCCCCCCCCCCO
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccco1
Yield: 77.2 %

Procedure:
2.0 g of 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]acetic acid, 2.02 g of 2-chloro-1-methylpyridinium iodide, 1.47 g of laurylalcohol, 1.60 g of triethylamine and 60 ml of tetrahydrofuran are treated in the same manner as described in Example 27. 2.4 g of lauryl 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]acetate are obtained. Yield: 77.4%
Reaction SMILES: C1(=O)N([CH:6]([N:12]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]2=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])C(=O)C=C1.[C:21]([NH:24][C@H:25]([C:28]([OH:30])=[O:29])[CH2:26][SH:27])(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([NH:24][CH:25]([C:28]([OH:30])=[O:29])[CH2:26][S:27][C:6]([S:27][CH2:26][CH:25]([C:28]([OH:30])=[O:29])[NH:24][C:21](=[O:23])[CH3:22])([N:12]1[C:13](=[O:18])[CH2:14][CH2:15][C:16]1=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:23])[CH3:22]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: CCCCCC(N1C(=O)C=CC1=O)N1C(=O)C=CC1=O
Solvent: c1ccncc1
Product: CCCCCC(SCC(NC(C)=O)C(=O)O)(SCC(NC(C)=O)C(=O)O)N1C(=O)CCC1=O
Temperature: 40 °C
Reaction time: 24 h

Procedure:
Bis-maleimidohexane (0.05 g, 1.81×10−4 mol) and N-acetylcysteine (0.059 g, 3.62×10−4 mol) were dissolved in pyridine (1 ml). The reaction was stirred at 40° C. for 24 h. The solvent was removed in vacuo and the residue was dissolved in ethanol (5 ml) and the solvent removed in vacuo. This procedure was repeated 3 times more. The residue of the title compound weighed 0.1 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:22][C@@H:23]([CH3:29])[C:24]([NH:26][CH2:27][CH3:28])=[O:25]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]([OH:12])[CH2:13][NH:22][C@@H:23]([CH3:29])[C:24]([NH:26][CH2:27][CH3:28])=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reactant: CCNC(=O)[C@H](C)N
Product: CCNC(=O)[C@H](C)NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C

Procedure:
Following the general procedure of EXAMPLEs 4 and 14-164 and making non-critical variations and reacting tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3) with (2S)-2-amino-N-ethylpropanamide (VI), the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][NH:66][CH2:65][C:64]1=[O:69]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:66]1[CH2:67][CH2:68][NH:63][C:64](=[O:69])[CH2:65]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: O=C1CNCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCNC(=O)C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and piperazinone in DMSO at ambient temperature.
Reaction SMILES: [C@H:1]1([O:12][C@H:13]2[C@H:22]([OH:23])[C@@H:21]([CH2:24][O:25][C@H:26]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@@H:27]3[OH:28])[O:20][C@H:15]([O:16][CH2:17][CH2:18][NH2:19])[C@H:14]2[OH:37])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[CH2:38]([O:45][C:46](=[O:64])[C@@H:47]([NH:53][C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[CH2:48][CH2:49][C:50](O)=[O:51])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:57]([O:56][C:54]([NH:53][C@@H:47]([CH2:48][CH2:49][C:50]([NH:19][CH2:18][CH2:17][O:16][C@H:15]1[O:20][C@H:21]([CH2:24][O:25][C@H:26]2[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@@H:27]2[OH:28])[C@@H:22]([OH:23])[C@H:13]([O:12][C@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]2[OH:3])[C@@H:14]1[OH:37])=[O:51])[C:46]([O:45][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:64])=[O:55])[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-aminoethyl α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranoside (2.6 g, 4.75 mmol), and (S)-5-(benzyloxy)-4-{[(benzyloxy)carbonyl]amino}-5-oxopentanoic acid (2.0 g, 5.39 mmol) in DMF (36 mL) at 0° C. was added DMAP (580 mg, 4.75 mmol) and EDC (3.64 g, 19.00 mmol). The reaction mixture was allowed to gradually warm up to rt. After stirring for 16 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on C18 reverse phase silica gel (275 g), eluting with 10-55% AcCN in H2O to give the title compound. UPLC Method B: calculated for C40H56N2O21 900.34, observed m/e: 901.26 [M+1]; Rt=2.46 min.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:10])=[C:5]([Br:9])[C:6]=1[C:7]#[N:8].CC(C)([O-])C.[K+].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].O>O1CCCC1>[Br:10][C:4]1[N:3]([C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[C:2]([Br:1])=[C:6]([C:7]#[N:8])[C:5]=1[Br:9]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(Br)c(Br)n(C(=O)Oc2ccccc2)c1Br

Procedure:
A mixture of 7.0 g of 2,4,5-tribromopyrrole-3-carbonitrile and 2.9 g of potassium t-butoxide in tetrahydrofuran is treated with 13.8 g of phenyl chloroformate, heated at reflux temperature for 12 hours, cooled, poured into water and filtered. The solid filter cake is washed with water and dried in vacuo to afford the title compound. A sample is recrystallized from a mixture of ethyl acetate and methylcyclohexane to give colorless crystals, mp 128°-129° C.