Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]([C@@:6]([C:21](=[O:23])[CH3:22])([C@:8]([C:18](=[O:20])[CH3:19])([C@:10]([C:15](=[O:17])[CH3:16])([C@@H:12]([CH3:14])[OH:13])[OH:11])[OH:9])[OH:7])=[O:5])(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.B(F)(F)F.CCOCC>ClCCl>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C@:15]2([CH3:16])[O:17][C@:4]([C:1](=[O:3])[CH3:2])([OH:5])[C@:6]([C:21](=[O:23])[CH3:22])([OH:7])[C@@:8]([C:18](=[O:20])[CH3:19])([OH:9])[C@@:10]2([C:12](=[O:13])[CH3:14])[OH:11])=[CH:28][CH:27]=1
Reactant: CC(=O)C(=O)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@](O)(C(C)=O)[C@@H](C)O
Reactant: COc1ccc(O)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc([C@]2(C)O[C@@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@]2(O)C(C)=O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
D-Fucose (3) (4.95 g, 30.14 mmol) was dissolved in 30 mL of acetic anhydride and 30 mL of pyridine and stirred for 12 h. The solvent was removed in vacuo. Column chromatography (2:1 hexane/EtOAc) yielded 10.15 g (quant.) of 1,2,3,4-tetraacetyl-D-fucose (as a mixture of α-and β-anomer). 1,2,3,4-tetraacetyl-D-fucose (20.0 g, 60.2 mmol) and p-methoxyphenol (MPOH) (10.46 g, 84.3 mmol) were dissolved in 220 mL of dichloromethane and cooled to 0° C. BF3.OEt2 (21.4 g, 19.0 mL, 150.5 mmol) was added and the mixture stirred overnight. The reaction mixture was quenched by addition of saturated NaHCO3 solution, washed 2 times with water, dried over Na2SO4, concentrated and the residue was purified by column chromatography (3:1 hexane/EtOAc) yielding 16.8 g (71%) of 4-methoxyphenyl 1,2,3,4tetraacetyl-α-D-fucose (Only the β-anomer reacts, α-anomer could be recovered). 4-methoxyphenyl 1,2,3,4-tetraacetyl-α-D-fucose (3.90 g, 9.85 mmol) was dissolved in 150 mL of methanol and 6 mL of 0.5 M NaOMe solution were added. The mixture was stirred for 6 h. The solvent was removed in vacuo. Column chromatography (3:1 dichloromethane/methanol) afforded 2.63 g (99%) as a colorless solid: [α]D: +201.6 (c=0.32, CH3OH). 1H NMR (CD3OD, 300 MHz) δ 1.18 (d, J=6.6 Hz, 3H), 3.74 (s, 3H), 3.89 (m, 2H), 4.09 (quart., J=6.0 Hz, 1H), 5.31 (d, J=3.6 Hz, 1H), 6.82 (d, J=9.3 Hz, 2H), 7.04 (d, J=9.3 Hz, 2H). 13C NMR (CD3OD, 75 MHz) 16.3, 55.7, 67.9, 69.5, 71.2, 73.2, 100.0, 115.1, 119.0, 152.2, 156.0. MALDI-HRMS: m/z [M+Na]+ calcd 293.0996, obsd 293.0994.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=1[NH:14][C:15](=[O:31])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:36]2[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]2)=[O:13])=[CH:7][C:6]=1[NH:14][C:15](=[O:31])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccccc1OC
Product: CCCCCC(CC(=O)Nc1cc(C(=O)N2CCN(C)CC2)ccc1C(C)(C)C)c1ccccc1OC

Procedure:
Following a similar procedure to that described in Example 8, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2-methoxyphenyl)octanamide (prepared as described in Preparation 74F) and 4-methylpiperazine, the title compound was obtained as a colorless foam-like substance.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:44])[F:45])[CH:35]=1)(=[O:42])=[O:41]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3-(trifluoromethyl)benzene sulfonyl chloride (8 uL, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 16 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-3-(trifluoromethyl)benzenesulfonamide (percentage yield: 54%), was obtained.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([NH:1][CH:2]1[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[NH:4][C:3]1=[O:20])=[O:33])=[CH:26]2
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc2[nH]c(C(=O)NC3N=C(c4ccccc4F)c4ccccc4NC3=O)cc2c1

Procedure:
3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (50 mg, 0.186 mmol) was suspended in 1 ml of methylene chloride. 5-Methoxyindole-2-carboxylic acid (36.9 mg, 0.207 mmol) was added to the suspension followed by the addition of 38.5 mg (0.2 mmol) of EDC. The mixture was brought to pH 8 with 60 μl of triethylamine. The solid which formed after 3 min. was filtered after 5 hours and washed with chloroform. The filtrate was applied to a 2000μ preparative TLC plate and eluted with 90:10:1 chloroform:methanol:water (CMW). The product was extracted from silica with methanol and evaporated.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:30]=[C:31](B(O)O)[S:32][CH:33]=1.CC(C)([O-])C.[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:31]4[S:32][CH:33]=[C:29]([CH3:28])[CH:30]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Reactant: Cc1csc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cc(C)cs2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E106) (100 mg, 0.22 mmol) and (4-methyl-2-thienyl)boronic acid (71 mg, 0.50 mmol) in DME (3 ml) was added potassium tert-butoxide (220 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then evaporated in vacuo and purified using an SCX cartridge eluting with methanol followed by ammonia (2M in methanol). The appropriate fractions were combined and solvent evaporated in vacuo and the residue purified further by mass directed autoprep HPLC to afford the title compound (E107). MS (ES+) m/e 472 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1.[I:17]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>C(#N)C>[CH3:1][O:2][C:3](=[O:16])[O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([O:14][CH3:15])=[O:13])=[C:9]([I:17])[CH:10]=1
Reactant: COC(=O)Nc1ccc(OC(=O)OC)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)Nc1ccc(OC(=O)OC)cc1I
Temperature: 0 °C
Reaction time: 72 h
Yield: 92.1 %

Procedure:
A mixture of carbonic acid 4-methoxycarbonylamino-phenyl ester methyl ester (20.0 g, 88.8 mmol) and N-iodosuccinimide (23.8 g, 105.78 mmol) in acetonitrile (330 mL) was cooled to 0° C. (ice-bath). Trifluoromethanesulfonic acid (1.6 mL, 18.2 mmol) was added dropwise. The cooling bath was removed and the reaction stirred 72 h at room temperature. TLC showed the reaction was complete. The mixture was poured into 1M pH7 phosphate buffer, and washed with ethyl acetate. The phases were separated, the aqueous phase was extracted with ethyl acetate and the combined organic phases washed with 10% sodium thiosulfate solution, brine, dried over sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel (500 g, 3:2 hexane/ethyl acetate eluant) to afford the product as an off-white solid (28.7 g, 92%), which was used without further purification. m.p. 106° C.
Reaction SMILES: [NH2:1][C:2](=O)[CH:3]([NH:23][C:24](=[O:33])[C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])[CH:9]=[CH:8]2.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[Cl:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([Cl:31])[C:25]=1[C:24]([NH:23][CH:3]([C:2]#[N:1])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])[CH:9]=[CH:8]2)=[O:33]
Reactant: NC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: N#CC(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Yield: 65 %

Procedure:
To a solution of N-(2-amino-1-{[2-(2,6-dichlorophenyl)-6-quinolinyl]methyl}-2-oxoethyl)-2,6-dichlorobenzamide 122 (1.09 g) in pyridine (9 ml) is added p-toluenesulfonyl chloride (583 mg) at RT. The solution is stirred at 80° C. After one night, 120 mg of p-toluenesulfonyl chloride are added again to the mixture at RT to drive the reaction to completion. The solution is heated at 80° C. for one additional day. The organic phases are evaporated, AcOEt and a small amount of CH2Cl2 are added. The organic phases are washed 3 times with water, one time with a solution of NaHCO3, dried over MgSO4 and evaporated to dryness. The residue so obtained was purified over silica gel using CH2Cl2/CH3OH (99.25/0.75) as eluent to give 2,6-dichloro-N-{1-cyano-2-[2-(2,6-dichlorophenyl)-6-quinolinyl]ethyl}benzamide 58.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[C:23]([F:32])=[C:24]([C:28]([F:31])=[CH:29][CH:30]=1)[C:25](O)=O>>[Cl:21][C:22]1[C:23]([F:32])=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[C:28]([F:31])=[CH:29][CH:30]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1c(F)ccc(Cl)c1F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3c(F)ccc(Cl)c3F)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-chloro-2,6-difluorobenzoic acid: MS (APCl) m/z 440 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([N+:19]([O-])=O)=[C:14]([CH3:22])[CH:13]=1.O.O.[Sn](Cl)Cl.Cl>CO>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([NH2:19])=[C:14]([CH3:22])[CH:13]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccc2c(c1)CCCC2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Cc1cc(Oc2ccc3c(c2)CCCC3)c(C)cc1N
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A solution of 15.00 g (46.9 mmol) of 4-(5,6,7,8-tetrahydro-2-naphthoxy)-2,5-dimethylnitrobenzene in 60 ml of methanol is admixed first of all with 31.8 g (140.7 mmol) of tin(II) chloride dihydrate at room temperature and then slowly, with ice cooling, with 60 ml of concentrated hydrochloric acid. The reaction mixture is refluxed for 2 h, cooled to room temperature, concentrated and admixed with water and the residue is isolated by filtration and dried under reduced pressure (15.3 g, 86% purity, 99.5% yield, log P (pH 2.3)=3.08).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[C:23]([N:27]1[CH2:30][CH:29](Cl)[CH2:28]1)([CH3:26])([CH3:25])[CH3:24].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:29]2[CH2:30][N:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:28]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)N1CC(Cl)C1
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(OC2CN(C(C)(C)C)C2)cc1

Procedure:
A mixture of 3.98 g. (13.5 mmol.) of 2-n-butyl-3-(4-hydroxybenzoyl)benzofuran, 2.0 g. (13.5 mmol.) of N-t-butyl-3-chloroazetidine and 0.54 g. of sodium hydroxide in 75 ml. of ethanol was refluxed for five hours. The reaction mixture was cooled, filtered and 125 ml. of 10% aqueous sodium hydroxide solution was added. The mixture was extracted three times with chloroform, the combined extracts were evaporated to dryness and the residue was chromatographed on alumina with chloroform as eluant to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[CH:16])[CH:5]=[CH:4][C:3]1=2.I[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1>>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C#CCc1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
In a similar manner to Example 16(c), by reaction of 8 g (35.3 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propyne with 8 g (32.1 mmol) of 4-iodobenzoic acid, 10.4 g (94%) of the expected acid are obtained, with a melting point of 167-8° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:37])[CH:12]=[CH:13][CH:14]([N:28](C(OC(C)(C)C)=O)[CH3:29])[CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:9]>C(Cl)Cl>[CH2:8]([O:10][C:11](=[O:37])[CH:12]=[CH:13][CH:14]([NH:28][CH3:29])[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:9]
Reactant: CCOC(=O)C=CC(C(c1ccccc1)c1ccccc1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C=CC(NC)C(c1ccccc1)c1ccccc1

Procedure:
22 ml (0.28 mol) of trifluoroacetic acid are added dropwise to a solution of 14.2 g (34.7 mmol) of 4-(tert-butoxycarbonyl-methyl-amino)-5,5-diphenyl-pent-2-enoic acid ethyl ester in 100 ml of methylene chloride. After 5 hours the reaction mixture is concentrated by evaporation and then twice toluene is added and the mixture concentrated by evaporation. The residue is dissolved in methylene chloride, washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and again concentrated by evaporation. The title compound is obtained in the form of a yellow oil. TLC: methylene chloride/methanol (95:5) Rf =0.26; Rt (HPLC)=12.5 min; 1H-NMR (300 MHz, CDCl3, RT) d 7.38-7.15 (m, 10H), 6.66 (dd, 1H), 5.84 (d, 1H), 4.12 (q, 2H), 3.97 (d, 1H), 3.81 (m, 1H), 2.31 (s, 3H), 1.33 (br, 1H), 1.24 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([O:18]C2C=CC=CC=2)=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][C:40](=[O:55])[C:41]1[CH:46]=[CH:45][C:44]([CH2:47][NH:48][CH2:49][CH2:50][CH2:51][N:52]([CH3:54])[CH3:53])=[CH:43][CH:42]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:18])[N:48]([CH2:47][C:44]2[CH:45]=[CH:46][C:41]([C:40]([NH:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[NH:32][C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31])=[O:55])=[CH:42][CH:43]=2)[CH2:49][CH2:50][CH2:51][N:52]([CH3:53])[CH3:54])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(OCc2ccccc2)c1)Oc1ccccc1
Reactant: CN(C)CCCNCc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCCN(Cc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1)C(=O)Nc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 15 %

Procedure:
1-Benzyloxy-3-(phenoxycarbonylamino)benzene (Reference Compound No. 5-1, 3.7 g, 12 mmol) was added to a solution of the mixture containing N-(2-t-butoxycarbonylaminophenyl)-4-(3-dimethylaminopropylaminomethyl)benzamide (Reference Compound No. 4-5, 10 g, 24 mmol) in DMSO (30 mL), and then the reaction mixture was stirred at room temperature for 15 hours. Water (300 mL) was added thereto, the whole was extracted with ethyl acetate (250 mL) twice, and then the organic layer was washed with brine (250 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 1.1 g of the title reference compound as a white amorphous product. (Yield 15%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:21])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([OH:20])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(Cl)(Cl)Cl.CC1C=CN=C(N)C=1C.CCN(C(C)C)C(C)C.[P:45]([O-:62])([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][P:45](=[O:62])([O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:13]=2)=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(/C=C/C(=O)Nc2cccc(Cl)c2)cc1O
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: Cc1ccnc(N)c1C
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(/C=C/C(=O)Nc2cccc(Cl)c2)cc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
(E)-N-(3-Chloro-phenyl)-3-(3-hydroxy-4-methoxy-phenyl)-acrylamide (compound 55, 1.608 g, 5.31 mmol) was dissolved in dry CH3CN (80 ml) and CCl4 (5.13 ml, 53.1 mmol) and the resulting solution was cooled at 0° C. Dimethyl amino pyridine (65 mg, 0.53 mmol), DIPEA (2.88 ml, 22.3 mmol) and then dibenzyl phosphite (3.52 ml, 15.93 mmol) were added and the mixture was stirred at RT for 1 h. The reaction was quenched with 0.5M KH2PO4 and extracted with AcOEt. The organic layer was dried over sodium sulphate and evaporated to dryness. The crude was purified by column chromatography (eluent DCM/MeOH from 100:1 to 99:1) to give phosphoric acid dibenzyl ester 5-[(E)-2-(3-chloro-phenylcarbamoyl)-vinyl]-2-methoxy-phenyl ester (1.87 g).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][C:7]1[N:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[NH2:27])=[CH:22][C:21]=2[CH3:29])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)C.O.[OH-].[Na+]>C(O)C>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([N:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:10][CH:11]=[C:7]2[CH2:6][CH2:5][C:4]([OH:30])=[O:3])=[C:21]([CH3:29])[CH:22]=1)(=[O:28])[NH2:27]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccc(CCC(=O)O)n2-c2ccc(C(N)=O)cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]propanoic acid ethyl ester (86 mg, 0.216 mmol) was dissolved in ethanol (4 mL). Water (0.5 mL) was added to the ethanolic solution followed by the addition of 1N NaOH (0.51 mL, 0.51 mmol). The reaction mixture was stirred at room temperature for 1 h and then at 45° C. for an additional hour. After removal of the solvent in vacuo, the residue was diluted with water (6 mL) and extracted with ethyl acetate (2×6 mL). The pH of the aqueous layer was adjusted to 2 with 1N HCl and then extracted with ethyl acetate (6 mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent removed in vacuo to obtain 3-[1-(4-Carbamoyl-2-methyl-phenyl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]-propanoic acid as the product (68 mg, 85%).
Reaction SMILES: Cl.[C:2]1(CN[C@@](C)([C@@H](O)C)CO)[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.C1(C=O)C2C3=C4C(=CC=2)C=CC=C4C=CC3=CC=1.NC(C)(COC)CO.[CH3:53][S:54]([O:57][CH2:58][C:59]([CH3:81])([NH:63][CH2:64]C1C2C3=C4C(=CC=2)C=CC=C4C=CC3=CC=1)[CH2:60][O:61][CH3:62])(=[O:56])=[O:55]>>[CH3:53][S:54]([O:57][CH2:58][C:59]([CH3:81])([NH:63][CH2:64][C:3]1[CH:4]=[C:5]2[C:16]3=[C:17]4[C:8](=[CH:9][CH:10]=[CH:11][C:12]4=[CH:13][CH:14]=[C:15]3[CH:2]=1)[CH:7]=[CH:6]2)[CH2:60][O:61][CH3:62])(=[O:56])=[O:55]
Reactant: COCC(C)(COS(C)(=O)=O)NCc1ccc2ccc3cccc4ccc1c2c34
Reactant: C[C@H](O)[C@@](C)(CO)NCc1ccc2ccc3cccc4ccc1c2c34
Agent: COCC(C)(N)CO
Agent: Cl
Agent: O=Cc1ccc2ccc3cccc4ccc1c2c34
Product: COCC(C)(COS(C)(=O)=O)NCc1cc2ccc3cccc4ccc(c1)c2c34

Procedure:
Using the reductive amination procedure outlined in 20G, pyrene-1-carbaldehyde (Aldrich) and 2-amino-3-methoxy-2-methyl-1-propanol (22C) gave after workup using the procedure outlined in 1B 3-methoxy-2-methyl-2-((1-pyrenylmethyl)amino)-1-propanol methanesulfonate.1/3H2O mp 158°-160°, (EtOH/Et2O), (C, H, N, S).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:17][C@H:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19]([OH:21])=[O:20])[C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na:29][Na].[OH-].[Na+].C(O)C>CO.O>[Na+:29].[Na+:29].[CH2:1]([C@@H:8]([CH2:17][C@H:18]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:19]([OH:21])=[O:20])[C:9]([NH:11][CH2:12][CH2:13][C:14]([O-:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([C@@H:8]([CH2:17][C@@H:18]([C:19]([OH:21])=[O:20])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]([O-:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Na][Na]
Reactant: O=C(O)CCNC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CO
Product: O=C([O-])CCNC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)O

Procedure:
N-[(R*,R* -2,4-dibenzyl-4-carboxybutyryl]-3-aminopropionic acid, melting at 122°-124°. N-[(R*,R*)-2,4-dibenzyl-4-carboxybutyryl]-3-aminopropionic acid is converted to the disodium salt by the following procedure: To the solution of 0.38 g of the diacid in 25 ml of methanol:water (2:1) is added 2.0 ml of 1.00N sodium hydroxide. The solution is concentrated to give a solid. Ethanol is added and the suspension is concentrated and the solid is dried at 50° under high vacuum to yield the N-[(R*,R*)-2,4-dibenzyl-4-carboxybutyryl]-3-aminopropionic acid disodium salt.