Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[O:22][CH2:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=1[F:32].[CH:33]1([C:36]#[C:37][C:38]([O:40][CH3:41])=[O:39])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:33]1([C:36]2[C:37]([C:38]([O:40][CH3:41])=[O:39])=[C:20]3[CH:19]=[C:18]([CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]4[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=4[F:32])[N:15]3[N:14]=2)[CH2:35][CH2:34]1
Reactant: COC(=O)C#CC1CC1
Reactant: Cc1cc[n+](N)c(OCc2c(F)ccc(F)c2F)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(C2CC2)nn2c(OCc3c(F)ccc(F)c3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
1.45 g (3.00 mmol, purity 98%) of 1-amino-4-methyl-2-[(2,3,6-trifluorobenzyl)oxy]pyridinium 2,4,6-trimethylbenzenesulphonate from Example 155A were dissolved in 9.7 ml of DMF and admixed with 670 mg (5.40 mmol) of methyl 3-cyclopropylprop-2-ynoate. 747 mg (5.40 mmol) of potassium carbonate was added and the mixture was stirred at RT for 3 h. Subsequently, the mixture was poured onto 73 ml of water and stirred briefly, and the precipitated solids were filtered off, washed with water and dried. 462 mg of the title compound were obtained (33% of theory; 85% purity).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reaction time: 0.5 h
Yield: 35 %

Procedure:
2-bromopyridine (14.9 g, 93.1 mmol) in anhydrous THF (700 mL) was cooled to −78° C. under a stream of nitrogen gas, n-BuLi in hexane (54 mL) were added thereto and the mixture was stirred for 30 min. Tributyltin chloride (29 mL, 108 mmol) was added and the mixture was stirred, at −78° C. for 2 hours and afterwards at −20° C. for 3 hours. It was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried and the solvent was evaporated. The residue was purified by chromatography (petroleum ether/ethyl acetate=9/1) to give 2-(tributylstannyl)pyridine (12 g, yield 34%) as a yellow liquid, LC-MS (ESI) m/z: 370 (M+1)+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C1(C(O)=O)[C:9]2([CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:8]1>ClCCl.CN(C)C=O>[CH:1]1([C:2]([Cl:4])=[O:3])[C:9]2([CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:8]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CC12CCOCC2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CC12CCOCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
60.0 ml of oxalyl chloride are added to a solution of 98.73 g of 6-oxaspiro[2.5]-octane-1-carboxylic acid in 500 ml of dichloromethane at 0° C. One drop of N,N-dimethylformamide is added, and the reaction solution is stirred at room temperature for 1 hour. The reaction solution is then evaporated, and the crude product is employed directly for the next stage.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][C:34]([NH:37][C:38]([NH:40][CH:41]([CH3:43])[CH3:42])=[O:39])([CH3:36])[CH3:35])[C:31]([CH2:44][O:45][CH2:46][CH3:47])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][C:34]([NH:37][C:38]([NH:40][CH:41]([CH3:43])[CH3:42])=[O:39])([CH3:35])[CH3:36])[C:31]([CH2:44][O:45][CH2:46][CH3:47])=[N:30][C:25]=3[CH:26]=[N+:27]([O-:9])[C:28]=2[CH:29]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Reaction time: 3 h
Yield: 108.8 %

Procedure:
mCPBA (60% pure, 1.18 g) was added to a solution of N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-N′-isopropylurea (1.96 g, 4.0 mmol) in chloroform (50 mL). The reaction was stirred for 3 hours and then an additional 0.53 g of mCPBA was added. The reaction was stirred for 2 more hours and then quenched with aqueous 1% sodium carbonate. The layers were separated and the aqueous fraction was extracted with dichloromethane. The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 2.2 g of crude N-[2-(7-benzyloxy-2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-N′-isopropylurea as an orange foam.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)(O)[CH3:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][CH:16]=2)=[CH2:9])=[CH:6][N:7]=1
Reactant: CSc1ccc(C(C)(O)c2ccc(F)nc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(c1ccc(SC)cc1)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.7 %

Procedure:
1-(6-Fluoropyridin-3-yl)-1-(4-(methylthio)phenyl)ethanol (1.261 g, 4.789 mmol) was dissolved in DCM (30 mL) and trifluoroacetic acid (1.0 mL, 13 mmol) was added, turning the solution dark green. The reaction was stirred at room temperature for 45 min and then was treated with saturated sodium bicarbonate (15 mL). The reaction was stirred for about 5 min, and then the layers were separated, and the aqueous phase was extracted with DCM. The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum to give 2-fluoro-5-(1-(4-(methylthio)phenyl)vinyl)pyridine (1.183 g). 1H NMR (CDCl3, 400 MHz) δ 8.23 (d, J=2.35 Hz, 1H), 7.71 (td, J=8.12 Hz, 2.54 Hz, 1H), 7.26-7.21 (m, 4H), 6.91 (dd, J=8.51 Hz, 2.64 Hz, 1H), 5.55 (s, 1H), 5.43 (s, 1H), 2.51 (s, 3H). m/z (ESI, +ve ion) 246 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[C:13]([CH:15]([C:29]2[N:34]=[C:33]([NH:35]C(=O)OC(C)(C)C)[CH:32]=[CH:31][CH:30]=2)[CH:16](C2C=CC=CN=2)[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][CH:10]=1)=O)(C)(C)C.[C:43](O)([C:45](F)(F)F)=O>C(Cl)Cl>[NH2:35][C:33]1[N:34]=[C:29]([CH:15]([C:13]2[N:14]=[C:9]([NH2:8])[CH:10]=[CH:11][CH:12]=2)[CH:16]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:12]2[CH:13]=[N:14][CH:9]=[CH:43][CH:45]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(c2cccc(NC(=O)OC(C)(C)C)n2)C(c2cccnc2)c2ccccn2)n1
Solvent: ClCCl
Product: Nc1cccc(C(c2cccc(N)n2)C(c2cccnc2)c2cccnc2)n1
Reaction time: 1 h

Procedure:
To the solution of tert-butyl 6-(1-{6-[(tert-butoxycarbonyl)amino]pyridin-2-yl}-2-pyridin-2-yl-2-pyridin-3-ylethyl)pyridin-2-ylcarbamate (0.12 g, 0.211 mmol) in CH2Cl2 (2 mL) was added CF3COOH (2 mL) and stirred for 1 h. The mixture was concentrated and the residue was dissolved in MeOH (3 mL). Potassium carbonate (200 mg) was added and stirred for 0.5 h. The mixture was filtered and the filtrate concentrated. The residue was purified by silica gel chromatography (10% MeOH in CH2Cl2) to give the title compound. 1H-NMR (500 MHz, DMSO-d6) δ 8.60 (s, 2H), 8.32 (d, 2H, J=4.6), 7.92 (d, 2H, J=7.8), 7.41 (s, 2H), 7.28(dd, 2H, J=7.7, 4.7), 7.15 (broad, 4H), 6.60 (d, 2H, J=7.4), 6.46 (s,2H), 5.25 (d, 1H, J=10.3), 4.98 (broad, 1H). LRMS m/z (M+H) Calcd: 369.4, found: 369.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:11][S:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:17][C:16]2[CH:18]=[CH:19][C:13]([S:12][CH3:11])=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(N)cc1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(C=Nc2ccc(SC)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-methoxybenzaldehyde and 4-methylthioaniline as starting materials, the title compound was obtained as a slightly yellow powder (yield 100%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Na+:11].[Cl-].[S:13](=O)(=[O:16])([OH:15])[OH:14]>>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:13]([O-:16])(=[O:15])=[O:14])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Na+:11]
Reactant: O=S(=O)(O)O
Reactant: c1ccc2c(c1)CCCN2
Agent: [Cl-]
Agent: [Na+]
Product: O=S(=O)([O-])c1ccc2c(c1)NCCC2
Temperature: 100 °C

Procedure:
1,2,3,4-tetrahydroquinoline was added dropwise to 40 mL fuming sulfuric acid at 0° C. over 15 minutes. This mixture was then heated to 100° C. for 1 hour with stirring. After cooling to 0° C. saturated NaCl (aqueous) was added drop wise, precipitating the crude product as a white solid. The solid was washed, first with cold isopropanol, followed by diethyl ether, then dried under vacuum to give the desired product as a white solid. 1H-NMR (300 MHz, d6 DMSO): δ 7.43 (m, 2H), 7.21 (d, 1H), 3.38 (m, 2H), 2.81 (t, 2H) 1.96 (m, 2H) ppm; MS m/z calculated for C9H10NO3S (M−): 212.04. Found 212.0 (M−, ESI−).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27](O)=[O:28])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33][NH:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[CH3:33][N:34]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([CH2:23][C@@H:19]2[CH2:20][CH2:21][CH2:22][C@H:18]2[C:9]2[O:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH:25]=1
Reactant: CNCCc1ccccn1
Reactant: O=C(O)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCc1ccccn1)C(=O)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a mixture of 3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzoic acid (120 mg, 0.284 mmol) and 2-(2-methylaminoethyl)pyridine (0.047 ml, 0.341 mmol) in DMF (5 ml) was added 1-hydroxybenzotrioxazole (58 mg, 0.426 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.568 mmol). After stirring the mixture at room temperature for 2 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with water, saturated sodium hydrogencarbonate solution, water, and brine. The resultant mixture was dried over magnesium sulfate, and evaporated in vacuo. The resultant residue was purified by silica gel column chromatography (methylene chloride: MeOH, 15:1 elution), then treated with 4N hydrogen chloride in EtOAc (1ml) to give N-methyl-N-[2-(pyridin-2-yl)ethyl]-3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzamide (140.9 mg, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].C(Cl)(Cl)(Cl)Cl.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][Br:25])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C)c(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)c(Br)c1

Procedure:
Methyl 3-bromo-4-methylbenzoate (6.56 g, 28.64 mmol), carbon tetrachloride (100 mL), NBS (6.07 g, 34.10 mmol) and AIBN (150 mg, 0.91 mmol) were heated at reflux for 18 h. The reaction mixture was cooled and diluted with DCM (200 mL) and water (100 ml) and washed with 5% NaHCO3 saturated solution (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure (rotary evaporator) affording an oily residue.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C@@H:19]2[CH2:23][C@H:22]([CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]3)[CH2:21][NH:20]2)[NH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[CH:10][CH:9]=1.[CH3:34][C:35]([O:38][C:39]([NH:41][C:42](=[N:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[NH:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](O)=[O:49])=[CH:46][CH:45]=1)=[O:40])([CH3:37])[CH3:36]>>[CH3:60][C:57]([O:56][C:54]([NH:53][C:42](=[N:41][C:39]([O:38][C:35]([CH3:37])([CH3:36])[CH3:34])=[O:40])[NH:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([N:20]2[CH2:21][C@H:22]([CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]3)[CH2:23][C@@H:19]2[C:5]2[NH:6][C:7]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[CH:10][CH:9]=3)=[C:3]([Cl:2])[N:4]=2)=[O:49])=[CH:46][CH:45]=1)=[O:55])([CH3:58])[CH3:59]
Reactant: COC(=O)Nc1ccc(-c2[nH]c([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3)nc2Cl)cc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)O)cc1
Agent: Cl
Product: COC(=O)Nc1ccc(-c2[nH]c([C@H]3C[C@@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)c3ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3)nc2Cl)cc1

Procedure:
The compound prepared in Example 67 was treated with the compound prepared in Example 10 following the procedure described in Example 8 to give the title compound as a light brown solid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13].Cl.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:30])[CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:30])[CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[NH:6][C:5]3=[O:13])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1
Reactant: O=c1[nH]c2ccccc2n1CCCl
Reactant: O=C(CC1CCNCC1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C(CC1CCN(CCn2c(=O)[nH]c3ccccc32)CC1)c1ccc(F)cc1

Procedure:
A mixture of 2.16 parts of 1-(2-chloroethyl)-1,3-dihydro-2H-benzimidazol-2-one, 2.57 parts of 1-(4-fluorophenyl)-2-(4-piperidinyl)ethanone hydrochloride, 5.3 parts of sodium carbonate, 0.2 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 15 hours using a water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanol. The product is filtered off and dried, yielding 2.5 parts of 1-[2-[4-[2-(4-fluorophenyl)-2-oxoethyl]-1-piperidinyl]ethyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 180.6° C.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.CN(C1C=CC=CN=1)C>C1COCC1>[C:16]([NH:15][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)([NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:1]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CCC(=O)N1O
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.33 h

Procedure:
N-hydroxysuccinimide (0.534 g, 4.64 mmol) was added to a solution of Gly-1-Me-HOPO (1.220 g, 3.87 mmol) in dry THF (60 ml) under a nitrogen atmosphere. After stirring for 20 min, dicyclohexylcarbodiimide (DCC, 0.956, 4.64mmol) and dimethylaminopyridine (DMAP, 0.044 g, 0.46 mmol) were added. After 9 h, a white precipitate of dicyclohexylurea (DCU) had formed and the formation of the NHS-activated ester was judged to be complete by TLC. TREN (0.141 g, 0.967 mmol, 0.25 equiv.) was added. The solvent was evaporated and the residue taken up in a 1.0M aqueous solution of HCl (50 ml). The suspension was filtered and the filtrate washed with CH2Cl2 (2×50 ml). The combined organic fractions were then back-extracted once with 1.0 M HCl (50 ml). 10M NaOH was added drop-wise to the combined aqueous fractions until the pH reached 11. The aqueous fractions were then extracted with CH2Cl2 (10×50 ml) and EtOAc (3×50 ml). The organic extracts were combined, dried (Na2SO4) and evaporated to dryness. The product was perified by a gradient flash silica column (2-8% CH3OH in CH2Cl2). Evaporation of the solvent afforded a white foam (Yield: 0.753 g, 56%). 1H NMR (CDCl3, 400 MHz): δ=8.58 (t, J=5.4 Hz, 3H, HOPO-glycine NH), 7.27-7.51 (m, 18H, Bn and glycine-TREN NH), 7.00 (d, J=7.2 Hz, 3H, HOPO), 6.59 (d, J=7.2 Hz, 3H, HOPO), 5.42 (s, 6H, Bn CH2), 3.85 (d, J=5.4 Hz, 6H, glycine CH2), 3.51 (s, 9H, N—CH3), 3.20 (m, 6H, TREN NHCH2), 2.51 (m, 6H, TREN NCH2) ppm. Anal. Calcd (Found) for C54H60N10O12.2H2O: C, 60.21 (59.96); H, 5.99 (5.96); N, 13.00 (12.93). FAB-MS (+): m/z: 1041.5 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(-c2ccc(Cl)cc2)cnc1Br
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ccc(Cl)cc2)cnc1Br

Procedure:
A solution of 5.60 g (17.9 mmol) 2-bromo-5-(4-chloro-phenyl)-3-nitro-pyridine, 20.3 g (90.0 mmol) tin(II)-chloride and 18.9 g (225 mmol) NaHCO3 in 300 mL EtOAc is refluxed for 30 h. After filtration the solvent is eliminated i.vac. The residue is triturated with DCM and after filtration the filter residue is dried in the air.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:10][C:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][N:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:30]=[C:29]([C:31]2[S:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[O:28][N:27]=1>CN(C=O)C>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:10]([CH2:25][C:26]2[CH:30]=[C:29]([C:31]3[S:32][C:33]([Cl:36])=[CH:34][CH:35]=3)[O:28][N:27]=2)[C:9]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[CH:8][N:7]=1)=[O:5]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: CCOC(=O)c1ncc(C(=O)OC(C)(C)C)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc(C(=O)OC(C)(C)C)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 260 mg of 3H-Imidazole-2,4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester [prepared by adopting a procedure described by J.-C. Aloup, F. Audiau, M. Barreau, D. Damour, A. Genevois-Borella, P. Jimonet, S. Mignani, Y. Ribeill PCT Int. Appl. (1996) WO96/02544 A1] in DMF (10 ml) was added potassium carbonate (178 mg) and 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole (301 mg). The mixture was stirred for 2 h at RT. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica (n-heptane/ethyl acetate 2:1 to ethyl acetate) to provide 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-imidazole-2,5-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester (73 mg, 15%; MS (ESI+): m/e=437, chloro pattern) and 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazole-2,4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester (342 mg, 72%; MS (ESI+): m/e=437, chloro pattern) as white solids.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:25](=[O:49])[NH:26][CH2:27][CH2:28][NH:29][C:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].[CH2:52](Br)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH2:52]([O:1][CH2:2][CH2:3][CH:4]([C:25](=[O:49])[NH:26][CH2:27][CH2:28][NH:29][C:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[NH:5][C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: O=C(NCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)C(CCO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: O=C(NCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)C(CCOCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
2-(2-Hydroxyethyl)-3-oxo-1,7-bis(triphenylmethyl) -1,4,7-triazaheptane (10 mmol) is reacted as described by S. Czernecki et al. Tetr. Lett. (1976) 3535 with 80% sodium hydride (11 mmol) and benzylbromide (10 mmol) catalysed by tetrabutyl ammonium iodide (1 mmol) for 24 hours at ambient temperature (in 100 ml dry THF). 2-(2-Benzyloxyethyl)-3-oxo-1,7-bis(triphenylmethyl)-1,4,7-triazaheptane is purified by chromatography on silica.
Reaction SMILES: [Na].[C:2]1([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[SH:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](Br)[CH:23]=[CH2:24]>CO>[CH2:24]([S:9][C:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:23]=[CH2:22]
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCBr
Agent: [Na]
Solvent: CO
Product: C=CCSC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Initially, sodium (2 g) was added to 200 mL MeOH in a reflux apparatus, stirred until the sodium was dissolved, and then 25 g of triphenylmethanethiol (TrSH) was added. The reaction mixture was refluxed for 1 hour, 10 mL allyl bromide was then added, and the mixture was refluxed for another 2 hours. The solution was allowed to cool, 19 g of particulate material, trityl allyl sulfide (TrSAll), was obtained by filtration using filter paper, and it was used directly for the next step without any purification. tert-BuOK (11 g) was added to a solution of 19 g of TrSAll in 100 mL anhydrous tetrahydrofuran (THF) and 200 mL tert-BuOH, and the reaction mixture was stirred at 20-22° C. overnight. The solvent in the reaction mixture was removed by rotary evaporation, water and CH2Cl2 was added to the residue, and the product was extracted into the CH2Cl2 phase. Trityl 1-propenyl sulfide (TrSPe) was obtained as a white color powder by purification of the CH2Cl2 extract on a silica gel column eluted with 10% CH2Cl2 in hexane.