Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]([S:9][CH3:10])=[C:6]([Cl:8])[N:7]=1
Reactant: CSc1c(Cl)nc(Cl)nc1Cl
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: CSc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2,4,6-trichloro-5-methylsulfanyl-pyrimidine (4.0 g, 17.4 mmol.), morpholine (2.3 g, 26.1 mmol, 1.5 eq.) and THF (20 ml) was stirred at room temperature for 2.0 hr. The reaction mixture was dried and the solvent was evaporated. Thereafter, a 0.1 N HCl washing free morpholine was added to the solution. The solution was extracted with EA and the EA in the solution was removed by evaporation. A crude product was obtained. Purification of the crude by flash chromatography on silica gel (Hexane/EtOAc 6:1) gave a gray solid of 2.34 g (48.2%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[C:22]([N:24]1[CH2:28][CH2:27][S:26][CH2:25]1)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:35]([N:13]([C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:22]([N:24]2[CH2:28][CH2:27][S:26][CH2:25]2)=[O:23])[CH2:10]1)[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][N:15]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Nc2ccc(C#N)cn2)C[C@H]1C(=O)N1CCSC1
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](N(Cc2ccccc2)c2ccc(C#N)cn2)C[C@H]1C(=O)N1CCSC1
Reaction time: 0.17 h

Procedure:
3-[(2S,4S)-1-tert-Butoxycarbonyl-4-(5-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine [product of Example 58(1)] (305 mg) was dissolved in DMF (10 mL), and potassium tert-butoxide (93 mg) was added under ice cooling. After stirring the mixture for 10 min, benzyl bromide (94 μl) was added, and the mixture was stirred at room temperature for 3 days. 10% citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and brine, and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give 3-{(2S,4S)-4-[N-benzyl-N-(5-cyano-2-pyridyl)amino]-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (202 mg) as a pale-yellow solid.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:26])=[CH:10][CH2:11][CH2:12][C:13]([CH3:25])=[CH:14][CH2:15][CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:3]([OH:5])=O.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:26])=[CH:10][CH2:11][CH2:12][C:13]([CH3:25])=[CH:14][CH2:15][CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:3]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: C1CCNC1
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N1CCCC1

Procedure:
Starting materials: 2,6,10,14-tetramethyl-18-oxo-2,6,10,14-nonadecatetraenoic acid and pyrrolidine.
Reaction SMILES: [C:1]([N:4]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:28])[CH2:6]1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:39])=O>C(Cl)Cl>[C:1]([N:4]([C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([Cl:39])=[O:27])=[CH:21][CH:22]=2)=[O:16])[C@@H:7]([CH3:28])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCC(=O)O)cc2)c2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCC(=O)Cl)cc2)c2ccccc21
Temperature: 25 °C

Procedure:
To a suspension of 3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)propanoic acid (50 mg, 0.10 mmol, 1 equ.) in methylene chloride (0.5 mL) was added a 2M solution of oxalyl chloride in methylene chloride (82 uL, 0.16 mmol, 1.6 equ.). Reaction mixture was stirred at room temperature for 30 m., and then concentrated to give 3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)propanoyl chloride. To a solution of the preformed acid chloride in methylene chloride (0.5 mL) was added methyl-alfG-amino-isobutyrate hydrochloride (31 mg, 0.20 mmol, 2 equ.) and diisopropylethylamine (52 uL, 0.30 mmol, 3 equ.). Reaction mixture was stirred at room temperature for 20 h. and concentrated. The residue was dissolved in ethyl acetate and washed with water, brine, and then dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (ethyl acetate/hexane: 4/1 to 10/0 gradient) to afford methyl 2-{[3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)propanoyl]amino}-2-methylpropanoate (105 mg, 46%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]C(C)(C)C([O-])([O-])[O-]>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[I:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: CC(C)(C)C([O-])([O-])[O-]
Reactant: Cc1ccc(I)c(C(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)ccc1I
Temperature: 25 °C

Procedure:
To a solution of 2-iodo-5-methyl benzoic acid (10.0 g, 0.038 mol) in toluene (200 mL) was added trimethylorthoacetate (25 mL) at room temperature. The reaction mixture was refluxed for 12 hours. The reaction mixture was cooled to room temperature and diluted with saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer washed with brine. The organic layer was dried (MgSO4) and solvent removed to give 10.35 g of methyl 2-iodo-5-methylbenzoate (EX-25A) as a yellow oil with an m/z+1=277.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:9](C)[CH2:10][CH2:11][CH2:12]OC2C=CC=CC=2)[CH:5]=[C:6](O)[CH:7]=1.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([CH2:29][NH:30][CH2:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:26]=[CH:25][C:24]=1[OH:44].[OH:45][CH:46]1[C:55](=[O:56])[C:54]2[C:49](=[CH:50][C:51](C(C)CCCOC3C=CC=CC=3)=[CH:52][CH:53]=2)[O:48][C:47]1([CH3:70])[CH3:69]>>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([CH2:29][NH:30][CH2:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:26]=[CH:25][C:24]=1[OH:44].[OH:45][CH:46]1[C:55](=[O:56])[C:54]2[C:49](=[CH:50][C:51]([CH:12]([CH3:21])[CH2:11][CH2:10][CH2:9][C:4]3[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=3)=[CH:52][CH:53]=2)[O:48][C:47]1([CH3:70])[CH3:69]
Reactant: CC(CCCOc1ccccc1)c1cc(O)cc(O)c1
Reactant: CC(CCCOc1ccccc1)c1ccc2c(c1)OC(C)(C)C(O)C2=O
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Product: CC(CCCc1ccccc1)c1ccc2c(c1)OC(C)(C)C(O)C2=O

Procedure:
4-(3,5-dihydroxyphenyl)-1-phenoxypentane is converted to dl-5-hydroxy-2,2-dimethyl-7-(1-methyl-4-phenoxybutyl)-4-chromanone, a light yellow oil:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[CH:29]=[N:28]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:26][N:27]1[CH:31]=[C:30]([NH:32][C:2]2[N:7]=[C:6]([NH:8][CH:9]3[C:13]4([CH2:14][CH2:15][CH2:16][CH2:17]4)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:10]3)[CH:5]=[CH:4][N:3]=2)[CH:29]=[N:28]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2ccnc(Cl)n2)C2(CCCC2)C1
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cn1cc(Nc2nccc(NC3CN(C(=O)OC(C)(C)C)CC34CCCC4)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To a solution of tert-butyl 4-((2-chloropyrimidin-4-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (528 mg, 1.50 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (240.52 mg, 1.8 mmol) in n-BuOH (8 mL) was added DIPEA (581.60 mg, 4.5 mmol). After addition, the reaction mixture was stirred at 150° C. overnight. The resulting mixture was concentrated in vacuo and purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 20/1) to give the product as a yellow oil (550 mg, 88.9%).
Reaction SMILES: [NH3:1].Cl[S:3]([C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].ClCCl>C(#N)C>[NH2:1][S:3]([C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: N
Reactant: COC(=O)Cc1cccc(S(=O)(=O)Cl)c1
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)Cc1cccc(S(N)(=O)=O)c1
Temperature: 22 °C
Reaction time: 2 h

Procedure:
0.880 Ammonia (0.027 ml) was added to a stirred solution of methyl [3-(chlorosulfonyl)phenyl]acetate (0.35 g) in a 1:1 mixture of dichloromethane and acetonitrile (1.75 ml), and the mixture was stirred at 22° C. for 2 h. The mixture was allowed to stand for a further 18 h, and the solvent was evaporated in vacuo. The residue was re-dissolved in dichloromethane and applied to a silica gel cartridge (10 g Varian Bond Elut, pre-conditioned with dichloromethane). The cartridge was eluted with dichloromethane, chloroform, ether, ethyl acetate, acetone, acetonitrile and methanol (1 column volume each), the fractions containing the product evaporated in vacuo, and the residue passed down a 5 g silica gel cartridge which was prepared and eluted in an identical manner. The product containing fractions were evaporated in vacuo to give a residue which was further purified using mass-directed preparative HPLC, to give the title compound as a colourless gum (0.018 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: O=C(O)c1cccc(-c2ccc(Cl)cc2)n1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(-c3ccc(Cl)cc3)n2)c1

Procedure:
Carboxylic acid (149) (50 mg, 0.21 mmol) was coupled to aniline (60) (41 mg, 0.21 mmol) using Method C. The residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][OH:2].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([F:12])[CH:5]=1>O.C(O)C>[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:1][OH:2])=[C:6]([F:12])[CH:5]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: NO
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(Br)cc1F
Reaction time: 66 h

Procedure:
A solution of hydroxylamine in water (50%, 5 ml) was added to a solution of 4-bromo-2-fluorobenzaldehyde (1.0 g) in ethanol (5 ml) and the mixture was stirred at room temp. for 66 h. The ethanol was removed under vacuum and the aqueous residue as extracted with ethyl acetate (×2). The organic extracts were washed with water and brine, dried (MgSO4) and concentrated under vacuum. The residue was purified on a Varian Bond-Elut SPE cartridge (silica, 20 g) eluting with cyclohexane:ethyl acetate (100:0 to 50:50) to give the title compound as a white solid (0.94 g).
Reaction SMILES: C=C1OC(=O)C1.ClCl.[Cl:9][CH2:10][C:11](=[O:16])[CH2:12][C:13](Cl)=[O:14].[CH2:17]([OH:19])[CH3:18]>C(Cl)Cl>[CH2:17]([O:19][C:13](=[O:14])[CH2:12][C:11]([CH2:10][Cl:9])=[O:16])[CH3:18]
Reactant: O=C(Cl)CC(=O)CCl
Reactant: CCO
Agent: C=C1CC(=O)O1
Agent: ClCl
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CCl
Temperature: -20 °C
Reaction time: 6 h

Procedure:
A reactor having interior enameling, a total capacity of 630 liters, an effective capacity of 500 liters and a cooling surface of 2.73 m3, was charged with 500 liters of a 15 weight-percent solution of diketene in methylene chloride, and cooled to -20° C. During a period of about 6 hours, a total of 82 kg of chlorine gas was fed into the reactor. The addition of the chlorine gas was in such a way that the temperature at no time rised above -10° C. The reaction mixture was stirred by means of an impeller during the entire time. To the γ-chloroacetoacetic acid chloride a equimolar quantity of ethyl alcohol was added to form the corresponding γ-chloroacetoacetic ethyl ester. The total reaction time was about two hours. The unreacted excess of chlorine and the methylene chloride were removed by distilling them off. A gas chromatographic analysis showed a yield of:
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[Cl:18][C:19]1[N:24]=[C:23]([NH2:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[CH3:27].CCN(CC)CC>ClCCl>[Cl:18][C:19]1[N:24]=[C:23]([NH:25][C:14]([C:11]2([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]2)=[O:15])[CH:22]=[C:21]([CH3:26])[C:20]=1[CH3:27]
Reactant: Cc1cc(N)nc(Cl)c1C
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (676 mg, 2.6 mmol) and 6-chloro-4,5-dimethylpyridin-2-amine (314 mg, 2.0 mmol), dichloromethane (7.0 mL) and Et3N (835 μL, 6 mmol) were added. The reaction was stirred at room temperature for 1 hour. The reaction was diluted with dichloromethane and washed with 1N HCl (3×) and saturated aqueous NaHCO3 (3×). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (560 mg, 73%). ESI-MS m/z calc. 380.07. found 381.3 (M+1)+. Retention time 2.18 minutes.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[CH:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[C:22][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Brc1ncccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2ncccn2)CC1
Reaction time: 8 h
Yield: 8 %

Procedure:
To a suspension of 2-bromopyrimidine (175 mg, 1.1 mmols), dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05 mmols) and CuI (10 mg, 0.05 mmols) was added a solution of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (209 mg, 1 mmol). The mixture was stirred overnight, filtered through Celite, concentrated. The residue was partitioned between ethyl acetate and water, organic layer was isolated, dried (MgSO4), and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate in hexanes (1:1) to give un-reacted 2-bromopyrimidine (130 mg), then the title compound (23 mg). LCMS m/e (288, M+H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][C@@H:49]([CH2:63][C:64]1[CH:69]=[C:68]([F:70])[CH:67]=[C:66]([F:71])[CH:65]=1)[C@H:50]([OH:62])[CH2:51][NH:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH3:61])[CH:55]=1>C(Cl)Cl>[F:70][C:68]1[CH:69]=[C:64]([CH:65]=[C:66]([F:71])[CH:67]=1)[CH2:63][C@H:49]([NH:48][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[N:7][CH:8]=1)[C@H:50]([OH:62])[CH2:51][NH:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH3:61])[CH:55]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc(CS(C)(=O)=O)nc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 36.9 %

Procedure:
To a stirred solution of 6-[(methylsulfonyl)methyl]nicotinic acid (181 mg), diisopropylethylamine (116 mg), and HBTU (341 mg) in methylene chloride (5 mL) was added a mixture of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (326 mg) and N,N-diisopropylethylamine (233 mg) in methylene chloride (5 mL). The mixture was stirred at room temperature for 15 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 5:95 to 10:90 methanol/methylene chloride) provided 165 mg of the title compound: ESI MS m/z 532 [M+H]+.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH2:7].C(Cl)(Cl)Cl.[CH2:19]([O:26][C:27]([NH:29][C@H:30]([C:36](O)=[O:37])[CH2:31][CH2:32][C:33](=[O:35])[NH2:34])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CS(ON1C2C=CC=CC=2N=N1)(=O)=O>C(N(CC)CC)C>[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH:7][C:36](=[O:37])[C@H:30]([CH2:31][CH2:32][C:33](=[O:35])[NH2:34])[NH:29][C:27]([O:26][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:28]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: CS(=O)(=O)On1nnc2ccccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 58 %

Procedure:
L-Histidine methyl ester dihydrochloride (1.21 g) is suspended into chloroform (20 ml), and therto are added triethylamine (1.40 ml) and further N-benzyloxycarbonyl-L-glutamine (1.40 g) and triethylamine (0.70 ml). After stirring for a while, to the mixture is added 1-methanesulfonyloxy-1,2,3-benzotriazole (1.07 g) and the mixture is stirred for 1 hour. After allowing to stand overnight, the solvent is distilled off. To the residue are added water and 1 N aqueous sodium hydrogen carbonate and the mixture is cooled. The precipitated gelling product is separated by filtration and washed with water. The product is heated together with a small amount of water and cooled. The precipitated by filtration to give N-(N-benzyloxycarbonyl-L-glutaminyl)-L-histidine methyl ester (1.25 g), melting point: 186°-188° C.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].Cl[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].C(N(CC)CC)C>ClCCl>[CH:10]([O:9][C:7](=[O:8])[NH:5][CH2:4][CH2:3][Br:2])([CH3:12])[CH3:11]
Reactant: CC(C)OC(=O)Cl
Reactant: NCCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)NCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of bromoethylamine hydrobromide (5.0 g, 24.4 mmol), isopropyl chloroformate (1.0 M in tetrahydrofuran, 16.3 ml, 16.3 mmol), and anhydrous dichloromethane (100 ml) was treated with triethylamine (4.5 ml, 33 mmol) and stirred at ambient temperature for 18 hr. The mixture was diluted with dichloromethane (200 ml), washed with 1 M hydrochloric acid, 1 M sodium hydroxide, and brine, dried over sodium sulfate and evaporated to give (2-bromo-ethyl)-carbamic acid isopropyl ester clear oil. 1H-NMR δ (CDCl3) 5.01 (1H, br s), 4.92 (m, 1H), 3.58 (m, 2H), 3,48 (m, 2H), 1.25 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]1=[O:18].[OH-].[K+].[CH2:21]([CH:23]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24](Cl)=[O:25])[CH3:22]>C1C=CC=CC=1.C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.CCOCC>[CH2:21]([CH:23]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24]([O:18][C:10]1[CH2:11][C:12]([CH3:16])([CH3:17])[CH2:13][C:14](=[O:15])[C:9]=1[C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])=[O:25])[CH3:22]
Reactant: Cc1ccc(C)c(C2C(=O)CC(C)(C)CC2=O)c1
Reactant: CCCCC(CC)C(=O)Cl
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCCCC(CC)C(=O)OC1=C(c2cc(C)ccc2C)C(=O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A suspension of 1.50 g (6.14 mmol) of 2-(2',5'-dimethylphenyl)-5,5-dimethyl-1,3-cyclohexanedione in 15 ml of dry benzene was prepared and 0.49 g (7.37 mmol) of 85% powered potassium hydroxide was added, followed by 1 drop of dicyclohexyl-18-crown-6-ether. After stirring for 30 minutes, 1.20 (7.37 mmol) of 2-ethylhexanoyl chloride was added, and the reaction mixture refluxed for 12 hrs. The reaction mixture was cooled to room temperature, taken up in 150 ml ether and 50 ml of water, washed three times with 0.25N NaOH, two times with water, two times with 6N HCl, and one more with water. The ether solution was dried and stripped to leave 2.10 g (92% yield) of 3-(2-ethylhexanoyloxy)-5,5-dimethyl-2-(2',5'-dimethylphenyl)-2-cyclohexenone as a clear, colorless oil.
Reaction SMILES: [CH2:1]([P:5](Cl)([CH2:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH:2]([CH3:4])[CH3:3].C(P(=O)CC(C)C)C(C)C.[CH2:22]([Mg]Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>O1CCCC1>[CH2:1]([P:5](=[O:6])([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCCCC[Mg]Br
Reactant: CC(C)CP(=O)(Cl)CC(C)C
Agent: CC(C)C[PH](=O)CC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCP(=O)(CC(C)C)CC(C)C
Temperature: 25 °C

Procedure:
For example, in the preparation of non-radioactive diisobutyl-n-heptylphosphine oxide (Methods for preparing diisobutylphosphinyl chloride by chlorinating diisobutylphosphine oxide, described by R. H. Williams, L. A. Hamilton J. Am. Chem. Soc. (1952), 74, 5418), a solution of diisobutylphosphinyl chloride (3.9 gm) in tetrahydrofuran (50 ml.) was added dropwise to a refluxing solution of n-heptylmagnesium bromide (prepared from magnesium turnings (1.2 gm), n-heptyl bromide (9.0 gm) and tetrahydrofuran (100 ml.)). The mixture was heated under reflux for 18 hours. After cooling to room temperature, the reaction mixture was poured onto ice and 2N HCl (300 ml.), and extracted with methylene dichloride. The combined extracts were washed with lithium hypochlorite solution, 2N NaOH solution and finally with water, then dried (MgSO4). The solvent was removed by distillation and the residual yellow oil (8 gm) was eluted with chloroform down a silica gel column. The product (R1=0.1 to 0.2 on silica t.l.c. (CHCl3)) was finally distilled to yield diisobutyl-n-heptyl-phosphine oxide (coded as WS148) as a colorless liquid, bp. 120° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+:8].[Na+].[O:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[C:12]([C:21](Cl)=[O:22])=[CH:11]1>O.C(Cl)Cl>[O:20]=[C:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[O:10][CH:11]=[C:12]1[C:21]([NH:2][O-:3])=[O:22].[Na+:8]
Reactant: NO
Reactant: O=C(Cl)c1coc2ccccc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(N[O-])c1coc2ccccc2c1=O

Procedure:
A solution of 8.34 g (0.12 mol) of hydroxylamine hydrochloride in 125 ml of water was mixed with 100 ml of methylenechloride. Solid sodium carbonate (50 g) was added with cooling. With stirring, a solution of 16.5 g (0.079 mol) of chromone-3-carbonylchloride in 250 ml of methylene chloride was added over a period of 5 minutes, keeping the temp. at 15° with ice bath cooling. After 15 minutes reaction time the thick mixture was filtered and washed with 200 ml of ice-water. The damp filter cake was recrystallized from 100 ml of water, wt 1.5 g (8.4%); mp > 300°.