Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2].Br[CH2:18][CH2:19][CH2:20][Cl:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:16])[C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][CH2:19][CH2:20][Cl:21])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(O)c(OC)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)c1ccc(OCCCCl)c(OC)c1

Procedure:
A mixture of 1 mole of 4-hydroxy-3-methoxy-α-oxobenzeneacetic acid ethyl ester, 2 mole of 1-bromo-3-chloropropane and 3 mole of anhydrous potassium carbonate in 3 liters of acetone is heated at reflux for 20 hr. The mixture is cooled, filtered and the filtrate concentrated to give a solid residue. The solid is triturated with petroleum ether (30°-60° C.), collected by filtration and dried to give the title compound.
Reaction SMILES: [CH3:1][C:2]([O-:5])(C)C.[K+].[CH2:7]1[C@@H:11]([OH:12])[CH2:10][NH:9][CH2:8]1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[C:35]3[C:30](=[CH:31][C:32](F)=[CH:33][CH:34]=3)[N:29]=[CH:28][N:27]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:12][CH:11]4[CH2:7][CH2:8][N:9]([C:2](=[O:5])[CH3:1])[CH2:10]4)=[CH:33][CH:34]=3)[N:29]=[CH:28][N:27]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O[C@@H]1CCNC1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Oc2ccc3c(C4CCN(C(=O)OC(C)(C)C)CC4)ncnc3c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of KOt-Bu (55.1 mg, 0.47 mmol) in THF (1 mL) was added (R)-hydroxypyrrolidine (37.7 mg, 0.43 mmol), followed by 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (110.3 mg, 0.33 mmol), which was prepared as described in Example 65b, in THF (1 mL). The mixture was stirred for 1 h at room temperature, quenched with (CH3CO)2O. The mixture was then partitioned between EtOAc and water. The organic extracts were washed with brine and evaporated and the residue was used for the next step reaction without further purification. LC/MS for C24H33N4O4 (MH+) 440.2, found 440.5.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:26])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[S:19][C:20]([CH2:23][CH3:24])=[CH:21][CH:22]=3)[O:15][N:14]=2)=[CH:8][C:7]=1[CH3:25].CCN(C(C)C)C(C)C.[C:36](O)(=[O:39])[CH2:37][OH:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CC(=O)OCC>[CH2:23]([C:20]1[S:19][C:18]([C:16]2[O:15][N:14]=[C:13]([C:9]3[CH:10]=[C:11]([CH3:12])[C:6]([O:5][CH2:4][CH:3]([OH:26])[CH2:2][NH:1][C:37](=[O:38])[CH2:36][OH:39])=[C:7]([CH3:25])[CH:8]=3)[N:17]=2)=[CH:22][CH:21]=1)[CH3:24]
Reactant: O=C(O)CO
Reactant: CCc1ccc(-c2nc(-c3cc(C)c(OCC(O)CN)c(C)c3)no2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1ccc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
To a cold solution (0° C.) of 1-amino-3-{4-[5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (32 mg, 86 μmol) in DCM (1 mL), DIPEA (45 mg, 345 μmol), glycolic acid (13 mg, 172 μmol) and finally TBTU (33 mg, 101 μmol) is added. The mixture is stirred at rt for 1 h before it is diluted with EA and washed with water. The aq. phase is extracted back with EA. The combined org. extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by crystallisation from acetonitrile to give N-(3-{4-[5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide (7 mg) as a white solid; LC-MS: tR=0.95 min, [M+1]+=432.16.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH:29][C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32].C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32])=[O:16])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccn1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 77.3 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (165 mg, 0.56 mmol, 1.0 eq), L-isoleucine pyridin-2-ylmethylamide (246 mg, 1.11 mmol) and dichloromethane (2 mL), was treated with triethylamine (475 uL, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (721 uL, 2.0 eq), to provide 214 mg (77%) of L-isoleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] pyridin-2-ylmethylamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:13][CH:14]([CH3:18])[C:15](Cl)=[O:16]>C(Cl)Cl>[Br:13][CH:14]([CH3:18])[C:15]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[F:8])=[O:16]
Reactant: Fc1cccc(F)c1
Reactant: CC(Br)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccc(F)cc1F
Temperature: 0 °C

Procedure:
To a mixture of m-difluorobenzene (75 ml) and anhydrous aluminium chloride (115 g) was added dropwise, while stirring, 2-bromopropionyl chloride (100 g) during 50 minutes. The mixture was stirred for 2 hours on an oil bath at 50°-55° C. The reaction mixture was cooled, to which was added methylene chloride (500 ml). The resultant solution was added, in limited amounts, to ice-water (1.5 l) while stirring. The methylene chloride layer was separated, and the aqueous layer was subjected to extraction twice with methylene chloride (100 ml). The methylene chloride layers were combined and washed with water (500 ml), which was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave 2-bromo-2',4'-difluoropropiophenone (142.5 g) as a pale yellow oily product. 1H-NMR (CDCl3) δ: 1.90(3H), 5.25(1H), 6.85~7.06(2H), 7.93~8.05(1H)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=3)[O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.FC(F)(F)C(O)=O.[ClH:37]>ClCCl.CCOCC>[ClH:37].[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=3)[O:18][CH2:19][C:20]([OH:22])=[O:21])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: Cc1csc(Nc2cc(Oc3cccc(OCC(=O)OC(C)(C)C)c3)ccn2)n1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(Nc2cc(Oc3cccc(OCC(=O)O)c3)ccn2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)phenoxy)acetate (0.530 g, 1.28 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was stirred at room temperature for one hour, the concentrated. The TFA salt was dissolved in ether (15 mL). 1M HCl in ether (6 mL) was added, and the solids were collected by filtration, washed with hexanes and dried to afford the desired product as a white solid. 1H NMR (d6-DMSO) δ 11.85 (bs, 1H), 8.25 (d, 1H), 7.41 (t, 1H), 6.88 (d, 1H), 6.80-6.83 (m, 2H), 6.67-6.70 (m, 2H), 4.72 (s, 2H), 2.26 (s, 3H).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:23]N(C)C=O>>[CH3:23][N:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([S:12][C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=2)[CH:14]=1)[C:20](=[O:22])[CH3:21]
Reactant: CC(=O)Nc1cccc(Sc2ccc([N+](=O)[O-])cc2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CC(=O)N(C)c1cccc(Sc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
0.265 g (0.00657 mol) of NaH (60%) was suspended in 10 ml of dimethylformamide and treated while cooling with ice with a solution of 1.72 g (0.06 mol) of N-[3-(4-nitrophenylsulphanyl)-phenyl]-acetamide in 20 ml of dimethylformamide. After a few minutes the mixture was left to warm to room temperature and stirred for 1 hr. Then, 1.1 ml (0.0179 mol) of Mel were added slowly. The mixture was stirred at room temperature for 18 hrs., the solvent was thereafter removed and the residue was partitioned in water and ethyl acetate. The organic phase was washed with sat. sodium chloride solution, dried over MgSO4 and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:1. There were obtained 1.51 g (83%) of N-methyl-N-[3-(4-nitrophenylsulphanyl)-phenyl]-acetamide as yellow crystals; m.p.: 66-68° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13]Cl)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([NH2:30])[CH:24]=2)=[CH:19][CH:18]=1.[I-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13][NH:30][C:25]2[CH:24]=[C:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)[CH:28]=[CH:27][C:26]=2[CH3:29])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)O
Reactant: Cc1ccc(-c2ccc(F)cc2)cc1N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(F)cc2)cc1NCC(=O)Nc1ccc(Cl)cc1C(=O)O
Yield: 20 %

Procedure:
1.0 g (4.0 mmol) of 5-chloro-2-[(chloroacetyl)amino]benzoic acid, 1.78 g (8.9 mmol) of 4′-fluoro-4-methylbiphenyl-3-amine, and 60 mg (0.4 mmol) of sodium iodide were stirred in 3 mL of DMF at 90° C. for 5.5 hours. Thereafter, the reaction mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography. The separated fractions containing a target compound were combined and condensed. Ethyl acetate was added to the residue, and solids were collected by filtration. The resulting solids were recrystallized using ethyl acetate/n-hexane, thereby giving 334 mg of the target 5-chloro-2-{[N-(4′-fluoro-4-methylbiphenyl-3-yl)glycyl]amino}benzoic acid (yield: 20%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[I:12].CC(C)([O-])C.[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]([C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)[N:36]=[N:35][N:34]=2)=[CH:23][CH:22]=1>C1COCC1>[CH2:10]([C:4]1[C:3]([I:12])=[C:2]([NH:1][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]([C:38]4[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=4)[N:36]=[N:35][N:34]=3)=[CH:25][CH:26]=2)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=1)[CH3:11]
Reactant: CCc1cc(N)c(I)c(CC)n1
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2-c2ccc(CBr)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1cc(NCc2ccc(-c3ccccc3-c3nnnn3-c3ccc([N+](=O)[O-])cc3)cc2)c(I)c(CC)n1
Reaction time: 0.25 h
Yield: 19.7 %

Procedure:
4-amino-2,6-diethyl-3-iodopyridine (2 g) (obtained as described in Example 7 B) was added to a mixture of potassium t-butoxide (0.97 g) and 1,4,7,10,13,16-hexacyclooctadecane (200 mg) in THF (40 ml) and the mixture was stirred for 15 minutes. Compound E (4 g) was added and the mixture was stirred for 4 hours. Volatile material was removed by evaporation and the residue was dissolved in dichloromethane. The solution was washed with 0.1M citric acid solution and dried (MgSO4). Solvent was removed by evaporation and the residue was purified by flash chromatography eluting with dichloromethane/methanol (12:1 v/v) to give 2,6-diethyl-3-iodo-4-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methylamino]pyridine (F) (0.9 g) as a solid; NMR (CDCl3): 1.26(d of t, 6H), 2.70(q, 2H), 3.00(q, 2H), 4.35(d, 2H), 5.21(broad t, 1H), 6.10(s, 1H), 6.58(d, 2H), 6.79(d, 2H), 7.04(d, 2H), 7.37(m, 1H), 7.65(m, 2H), 7.86(d, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:32][CH:33]1[CH:37]([OH:38])[CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]1.O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:32][CH:33]2[CH:37]([OH:38])[CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(O)C(NC(=O)c2ccc(Cl)s2)C1
Reaction time: 0.5 h

Procedure:
201 mg (1.2 mmol) 5-chlorothiophene-2-carboxylic acid and 436 mg (1.4 mmol) TBTU are suspended in 5 ml DCM and combined with 260 μl (1.9 mmol) TEA. The mixture is stirred for 30 minutes and then a solution of 250 mg (1.2 mmol) tert. Butyl (3SR,4SR)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate in 5 ml DCM is added and the mixture is stirred for 16 hours at RT. Then the reaction mixture is poured into water and extracted with DCM. The organic phase is washed with sat. sodium chloride solution and, after being mixed with activated charcoal, dried on sodium sulphate. The mixture is filtered and the filtrate is evaporated to dryness. The residue thus obtained is purified by column chromatography (silica gel, eluant DCM/MeOH 10:1).
Reaction SMILES: [CH2:1]([O:8][N:9]([C:16](=[O:51])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:25](=[O:42])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:52](Cl)(=[O:54])[CH3:53].C(ON(CCCCC#N)C(=O)CCCCCl)C1C=CC=CC=1>CCOC(C)=O.CCCCCC>[CH2:1]([O:8][N:9]([C:16](=[O:51])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:25](=[O:42])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:52](=[O:54])[CH3:53])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCCCN(OCc1ccccc1)C(=O)CCCCCCCNOCc1ccccc1
Reactant: CC(=O)Cl
Agent: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)N(CCCCCCCC(=O)N(CCCCCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1

Procedure:
Compound [VI] (0.93 g, 1.33 mmol) was treated with acetyl chloride (0.160 g, 2.04 mmol) by the procedure used for (3). Silica gel column chromatography (3:1 EtOAc/hexane) produced 0.95 g (96%) of [VII] as an oil: NMR δ 1.17-1.87 (m, 24H), 2.07 (s, 3H), 2.27-2.47 (m, 6H), 3.47-3.73 (m, 6H), 4.77 (s, 6H), 7.33 (s, 15H). Anal. (C44H60N4O6) C, H, N.
Reaction SMILES: [P:1](Cl)(Cl)Cl.[CH2:5]([C:21]1[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:24]=[C:23]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:22]=1[OH:35])[C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]=1[OH:20].[OH:36][N:37]1[C:42]([CH3:44])([CH3:43])[CH2:41][CH:40]([OH:45])[CH2:39][C:38]1([CH3:47])[CH3:46]>C(N(CC)CC)C>[C:27]([C:25]1[CH:24]=[C:23]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:22]2[O:35][P:1]([O:45][CH:40]3[CH2:41][C:42]([CH3:43])([CH3:44])[N:37]([OH:36])[C:38]([CH3:47])([CH3:46])[CH2:39]3)[O:20][C:7]3[C:8]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][C:10]([C:12]([CH3:15])([CH3:13])[CH3:14])=[CH:11][C:6]=3[CH2:5][C:21]=2[CH:26]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: ClP(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OP(OC1CC(C)(C)N(O)C(C)(C)C1)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2

Procedure:
The above-named compound is prepared by the general procedure of Example 1 by reacting 8.8 ml of phosphorous trichloride, 42.54 grams of 2,2'-methylene bis-(4,6-di-tert-butylphenol), 36.8 ml of triethylamine and 11.03 grams of 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13]Br.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]>C(#N)C>[Br-:1].[Br-:1].[CH2:2]([N+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][N+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: BrCCCC/C=C\C=C/CCCCBr
Reactant: Cc1ccccn1
Solvent: CC#N
Product: Cc1cccc[n+]1CCCC/C=C\C=C/CCCC[n+]1ccccc1C
Product: [Br-]

Procedure:
cis-cis-1,12-Dibromo-dodeca-5,7-diene was added to a solution of 2-picoline (3 mmol) in acetonitrile and the solution refluxed for 24 hours. The acetonitrile was removed in vacuum and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no picoline left in the aqueous layer. The resulting aqueous solution of the product was lyophilized to yield the pure product. (76%). 1HNMR (300 MHz, D2O, ppm) 8.52 (dd, J=6.3, 2H), 8.17 (dt, J=7.8, J=1.5, 2H), 7.72 (d, J=7.8, 2H), 7.64 (t, J=6.3, 2H), 6.18-6.23 (m, 2H), 5.33-5.41 (m, 2H), 4.37 (t, J=7.1, 4H), 2.66 (s, 6H), 2.09 (q, J=7.5, 4H), 1.72-1.82 (m, 4H), 1.36 (p, J=7.5, 4H). 13CNMR, 155.26, 145.01, 144.73, 132.25, 130.23, 125.64, 124.15, 58.06, 29.10, 26.38, 25.61, 19.73.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].[C:34]([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC(=O)CC>[CH:7]([N:8]1[CH2:9][CH2:10][N:11]([CH2:34][CH2:21][CH2:22][N:23]2[C:27](=[O:28])[C:26]3[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]2=[O:33])[CH2:12][CH2:13]1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 110 %

Procedure:
The mixture of 1-(diphenylmethyl)piperazine (505 mg, 2 mmol, 1.0 eq.), N-(2-bromoethyl)phthalimide (508 mg, 2 mmol, 1.0 eq.), K2CO3 (415 g, 3 mmol, 1.5 eq.), and NaI (420 g, 2.8 mmol, 1.4 eq.) in 2-butanone (10 ml) was refluxed for 2-3 hours. The mixture was then cooled to room temperature. The white solid was filtered off and was washed with small amount of CHCl3. The filtrates were combined and concentrated. The resulted residue was dissolved in CHCl3 (100 ml). The solution was washed with water (3×10 ml), then dried over anhydrous Na2SO4. After removed all solvent, the crude product 2-[3-(4-benzhydryl-piperazin-1-yl)-propyl]-isoindole-1,3-dione was yielded (935 mg, 110% yield).
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:25][NH:26][CH3:27]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH3:25][N:26]([CH3:27])[CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(CCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCN(C)C)cc1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of methyl 4-(3-tosyloxypropyl)benzoate (500 mg) in dimethylformamide (3 mL) is added 2M dimethylamine solution in tetrahydrofuran (2.2 mL) and the mixture is stirred at 50° C. for 15 hours. The reaction mixture is diluted with ethyl acetate, washed with a saturated sodium hydrogencarbonate solution and concentrated in vacuo. The residue is purified by column chromatography on silica gel (Solvent; chloroform:methanol=100:0→90:10) to give methyl 4-[3-(dimethylamino)-propyl]benzoate (357 mg, yield; quantitative) as an oil. MS (APCI) m/z; 222 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([NH2:17])=[CH:15][C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])=[N:13]2)=[CH:8][CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31].O>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([NH:17][C:30]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:31])=[CH:15][C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])=[N:13]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a suspension of ethyl[4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenyl]acetate (10 g, 33.2 mmol) and K2CO3 (9.17 g, 66.4 mmol) in THF (300 mL) was added phenyl chloroformate (8.61 mL, 66.4 mmol), and the resulting reaction mixture was stirred at room temperature overnight. The mixture was poured into a mixture of water and EtOAc and the organic phase was separated and dried over Na2SO4, concentrated at reduced pressure to afford a brown syrup, which was purified by MPLC (0% to 20% EtOAc in hexane). The desired product was obtained as a white solid (10.6 g) in 76% yield. 1H-NMR (CD2Cl2-d2) δ 7.51-7.10 (m, 10H), 6.47 (s, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.71 (s, 2H), 1.37 (s, 9H), 1.28 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](O)[CH2:24][OH:25].CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>CCOC(C)=O.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1([CH3:20])[O:25][CH2:24][CH2:23][O:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: CC1(CCCCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)OCCO1

Procedure:
A mixture of ketone 7-2 (695 mmol), ethylene glycol (59 ml, 1040 mmol), p-TSA (500 mg, 2.713 mmol) and benzene (2000 mL) was heated to reflux with azeotropic removal of water for 12 hours. The reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3, brine, dried (MgSO4), and concentrated to give 7-3 as a yellow oil.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:16][O:15][CH:14]3[CH:17]([OH:20])[CH2:18][O:19][CH:13]23)(=O)=O)=CC=1.[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[K].O>CS(C)=O>[OH:20][CH:17]1[CH:14]2[O:15][CH2:16][CH:12]([N:23]3[C:24](=[O:31])[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:22]3=[O:21])[CH:13]2[O:19][CH2:18]1
Reactant: O=C1c2ccccc2C(=O)N1[K]
Reactant: Cc1ccc(S(=O)(=O)OC2COC3C(O)COC23)cc1
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1C1COC2C(O)COC21
Temperature: 130 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of 6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-methylbenzenesulfonate (10.24 g, 34.1 mmol) in DMSO (60 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (8.21 g, 44.3 mmol). The mixture was stirred under N2 atmosphere at 130° C. overnight then cooled down to room temperature, and poured into water. The resulting mixture was extracted with CH2C12 (300 mL×3), and the combined organic layers were washed with water (100 mL×3), dried over Na2SO4, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/1) to afford the title compound as a white solid (2.35 g, 25.0%).