Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CO[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1>CCCCCC.C1COCC1>[CH2:6]([N:13]1[CH2:18][CH2:17][N:16]([C:30]2[CH:31]=[CH:32][C:27]([C:24]3[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=3)=[CH:28][CH:29]=2)[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(CN2CCN(c3ccc(-c4ccccc4)cc3)CC2)cc1
Reaction time: 1 h

Procedure:
1.6 ml (0.05 mol) of butyllithium solution in n-hexane is added dropwise to a solution of 8.81 g (0.05 mol) of 1-benzylpiperazine in 50 ml of anhydrous THF under argon at 0° C. and stirred for one hour. Then 9.21 g (0.05 mol) of 4-methoxybiphenyl are added and the reaction mixture is refluxed for 12 hours. The solvent is then evaporated off, the residue is combined with 150 ml of 2 N hydrochloric acid followed by diethyl ether and the precipitate formed is filtered off. The precipitate is washed with diethyl ether, suspended in 20% sodium carbonate solution and extracted several times with dichloromethane. After drying over magnesium sulphate the solvent is removed and the residue is washed with ethyl acetate and diethyl ether.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][CH2:17][CH3:18])[C:11](=[O:19])[CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[CH2:15]([N:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]1=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCn1ccc(OCc2ccccc2)cc1=O
Agent: [Pd]
Solvent: CCO
Product: CCCCn1ccc(O)cc1=O
Yield: 99.3 %

Procedure:
A mixture of intermediate D1 (2.01 g, 7.83 mmol) and a catalytic amount of 10% palladium on activated carbon in ethanol (300 ml) was stirred under a H2 atmosphere for 2 h. The mixture was filtered through diatomaceous earth and the solvent was evaporated in vacuo to yield intermediate D2 (1.3 g, 100%). The crude was used as such in the next reaction step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]([C:25]3[CH:26]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=4[Cl:44])[C:27]([C:33]([O:35][CH3:36])=[O:34])=[C:28]([CH3:32])[NH:29][C:30]=3[CH3:31])=[O:24])[CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H].C>C(O)C.[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]([C:25]3[CH:26]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=4[Cl:44])[C:27]([C:33]([O:35][CH3:36])=[O:34])=[C:28]([CH3:32])[NH:29][C:30]=3[CH3:31])=[O:24])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOc2cc(-c3ccc([N+](=O)[O-])cc3)[nH]n2)C1c1cccc(Cl)c1Cl
Agent: [Ni]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOc2cc(-c3ccc(N)cc3)[nH]n2)C1c1cccc(Cl)c1Cl
Yield: 54 %

Procedure:
12.86 g (20 mmole) of 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5-p-nitrophenyl-3-pyrazolyloxy)hexyl ester (Example 60) was dissolved in 100 ml of ethanol, to which was added 5 ml of Raney nickel, and catalytic hydrogenation was effected at room temperature and atmospheric pressure, thereby 1350 ml (60 mmole) of hydrogen was absorbed. The Raney nickel was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure to obtain a pale yellow oily residue. This residue was purified by chromatography on a silica gel column using a mixed solution of chloroform-methanol (the ratio by volume of 3:1) as an eluent, and the fractions containing the intended compound were concentrated under reduced pressure to obtain a pale yellow oily residue. This residue was dissolved in ethyl acetate, and after adding 5 g of activated charcoal, stirred well, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain 6.63 g (yield 54.0%) of the 1,4-dihydro-2,6-dimethyl-4 -(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5-p-aminophenyl-3-pyrazolyloxy)hexyl ester as a pale yellow powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][C:12]([O:15][C:16]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:17])([CH3:14])[CH3:13].CCN(CC)CC>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:22]2[CH2:21][CH2:20][CH:19]([NH:18][C:16](=[O:17])[O:15][C:12]([CH3:13])([CH3:11])[CH3:14])[CH2:24][CH2:23]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CSc1nc(Cl)cc(Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1nc(Cl)cc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.3 %

Procedure:
To a 100-mL round-bottomed flask was added 4,6-dichloro-2-(methylthio)pyrimidine (2.0 g, 10.25 mmol, Sigma-Aldrich) and 4-(n-boc-amino)-piperidine (2.053 g, 10.25 mmol, Sigma-Aldrich) in DCM (25 mL) followed by Et3N (2.139 mL, 15.38 mmol). The reaction was stirred at RT for 5 h, then diluted with DCM (100 mL). The mixture was washed with water, brine, dried MgSO4, filtered and concentrated to give crude tert-butyl 1-(6-chloro-2-(methylthio)pyrimidin-4-yl)piperidin-4-ylcarbamate (3.80 g, 100%) as a white solid. MS (ESI, pos. ion) m/z: 359.0 (M+1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:43])[C@@H:6]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[O:29][C:28]=3[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO.Cl>O.O1CCCC1>[CH2:36]([C:28]1[O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:27]=1[C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][C@@H:6]([CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:5]([OH:43])=[O:4])=[CH:16][CH:17]=2)=[CH:26][CH:25]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@H](Cc1ccccc1)Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Sodium hydroxide (2.5 N, 10 mL) was added into a mixture of (2S)-2-[4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-yloxy]-3-phenyl-propionic acid methyl ester (2.5 g, 4.65 mmol), methyl alcohol (40 mL) and tetrahydrofuran (40 mL). The reaction mixture was stirred for 1 hour, poured into water, acidified with HCl (2 N), and extracted with ethyl ether. The organic extracts were dried over MgSO4. Evaporation and crystallization from ethyl ether/hexanes gave a white solid (2.32 g, 95% yield): mp 167-169; MS m/e 376 (M+);
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[CH:14][C:13]=1[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:21]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([NH:8][C:9](=[O:10])[N:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:11])=[C:13]([C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:21]=2)[CH:14]=1)[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC(=O)/C=C/c1ccc(-c2cc(NC)ccc2C)cc1
Reactant: CCCCCCCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCNC(=O)N(C)c1ccc(C)c(-c2ccc(/C=C/C(=O)OCC)cc2)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 77.5 %

Procedure:
660 μL (4.0 mmol, 1.5 eq) of heptyl isocyanate are added to a solution of 805 mg (2.72 mmol, 1 eq) of ethyl (E)-3-(2′-methyl-5′-methylaminobiphenyl-4-yl)acrylate in 8 mL of a 7/1 dichloromethane/triethylamine mixture. The reaction medium is stirred at 50° C. for 12 hours and then hydrolyzed with water and extracted with ethyl acetate. The organic phases are combined, washed with sodium chloride solution and dried over sodium sulfate. The solvents are evaporated off and the residual oil is chromatographed on silica (7/3 heptane/ethyl acetate). 920 mg of ethyl (E)-3-[5′-(3-heptyl-1-methylureido)-2′-methylbiphenyl-4-yl]acrylate are obtained in oil form. Yield=77%
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O.[CH2:19]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(#N)C>[CH2:10]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:9][CH2:17][N:27]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCNCCCCCCCC
Reactant: C=O
Solvent: CC#N
Product: CCCCCCCCN(CCCCCCCC)CON(Cc1ccccc1)Cc1ccccc1

Procedure:
The procedure of Example I is repeated using 21.33 g of dibenzylhydroxylamine, 9.73 g of aqueous formaldehyde (37%) solution and 24.15 g of di-n-octylamine in acetonitrile to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH2:4][OH:5].[F:11][C:12]([F:22])([F:21])[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.Cl[C:24]([N:26]1[C@H:31]([CH3:32])[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][C@@H:27]1[CH3:40])=[O:25]>>[CH3:40][C@H:27]1[CH2:28][NH:29][CH2:30][C@@H:31]([CH3:32])[N:26]1[C:24]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([O:10][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([C:12]([F:22])([F:21])[F:11])[CH:14]=2)[CH:8]=[CH:9][C:2]=1[F:1])=[O:25]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Reactant: OCc1cc(O)ccc1F
Reactant: FC(F)(F)c1cccc(CBr)c1
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1cc(OCc2cccc(C(F)(F)F)c2)ccc1F

Procedure:
2-Fluoro-5-(3-trifluoromethylbenzyl)oxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate was prepared from 2-fluoro-5-hydroxybenzyl alcohol, 3-trifluoromethylbenzyl bromide and 1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazine according to the methods described for Examples 54 and 121 to give the product as a yellow oil (10.5%); HPLC (XTERRA, 50/80, 220 nm) 96.9% (6.20 min); NMR δH (400 MHz, DMSO-d6) 1.164(6H, d, J 6.5 Hz), 2.668(4H, m), 3.889(2H, m), 5.082(2H, s), 5.199(2H, s), 7.057(2H, m), 7.175(1H, t, J 6.5 Hz) and 7.688(4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>C(#N)C.C(N(CC)CC)C>[CH3:32][N:33]([O:34][CH3:35])[C:7]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:10]=1)=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cncc(Br)c1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a suspension of 5-bromonicotinic acid (5.0 g) and N-hydroxysuccinimide (4.27 g) in acetonitrile (60 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (7.12 g) at room temperature, and the mixture was stirred for 30 minutes. To the reaction mixture were added N,O-dimethyl-hydroxylamine hydrochloride (2.66 g) and triethylamine (10 ml), and the mixture was stirred for 64 hours and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=2:1) to give N-methyl-N-methoxy-5-bromopyridine-3-carboxamide (3.71 g) as pale yellow oil.
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[CH3:24][NH:25][C:26]([NH2:28])=[O:27].C[O-].[Mg+2].C[O-].CO>C(OCC)(=O)C>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH2:21][CH3:22])(=[O:19])=[O:20])=[CH:16][CH:17]=2)[C:4]([NH:28][C:26]([NH:25][CH3:24])=[O:27])=[O:23])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)CC)cc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)NC(=O)NC)cc1
Temperature: 25 °C
Yield: 32.8 %

Procedure:
3-Cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid ethyl ester (500 mg, 1.48 mmol) and methyl urea (274 mg, 3.70 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 6.5 mL, 4.43 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was then heated under reflux for 2 d. The reaction mixture was allowed to cool to 25° C. and then diluted with ethyl acetate (25 mL). The mixture was filtered through a pad of celite, and the celite pad was washed with ethyl acetate (50 mL). The resulting filtrate was washed with water (40 mL) then the water layer was further extracted with ethyl acetate (40 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a colorless oil. The oil was treated with a solution of 2/1 hexanes/ethyl acetate (10 mL), and a white solid began to precipitate. The suspension was placed in the freezer to enhance crystallization. The solid was filtered to afford 1-[3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionyl]-3-methyl-urea (178 mg, 33%) as a white solid: mp 200-201° C.; FAB-HRMS m/e calcd for C18H26N2O4S (M+H)+367.1691, found 367.1697.
Reaction SMILES: O.[SH-:2].[Na+].F[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]>CN(C=O)C>[SH:2][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)N2CCOCC2)c1
Reactant: [SH-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(S)c(S(=O)(=O)N2CCOCC2)c1
Temperature: 60 °C
Yield: 89.6 %

Procedure:
Sodium hydrosulfide monohydrate (237 mg, 4.3 mmol) was added to a solution of 4-fluoro-3-(morpholine-4-sulfonyl)-benzoic acid (Example 6, 350 mg, 1.2 mmol) in DMF (15 mL) and the reaction mixture was heated at 60° C. for 20 hours under N2. After cooling to room temperature and quenching with 2M HCl, the reaction mixture was partitioned between ethyl acetate and water. Further extraction of the aqueous layer with ethyl acetate, combination of all organic layers, drying and concentration provided a white powder (326 mg, 89% yield): 1HNMR DMSO-d6) δ2.99 (t, J=4 Hz, 4H), 3.58 (t, J=4. Hz, H), 7.48 (d, J=8 Hz,1H), 7.87 (dd, J=8, 2 Hz, 1H), 8.29 (d, J=2 Hz, 1H), 13.20 (s, 1H): MS (ESI) [M−H]− m/z 304.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].C=CC.[C]=O.[H][H].[CH2:13](O)[CH2:14][CH2:15][CH3:16]>>[CH2:1]([O:5][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: [H][H]
Reactant: CCCC=O
Agent: [C]=O
Solvent: C=CC
Product: CCCCOCCCC

Procedure:
It is known to produce n-butanol by the hydrogenation of the n-butyraldehyde obtained, for example, by the hydroformylation of propylene by reaction with carbon monoxide and hydrogen. However, in order to be suitable for various applications, e.g., as a solvent for fats, waxes and resins, and in the manufacture of rayon, detergents and various butyl compounds, the n-butanol must have a high degree of purity including a specified low level of various impurities produced by the hydroformylation and hydrogenation reactions. To deal with this problem, the crude n-butanol produced by the hydrogenation reaction must be purified, generally by fractional distillation. One of the impurities intended to be removed by the distillation is di-n-butylether (DBE) which has an atmospheric boiling point of 142° C., but in the absence of water forms a binary azeotrope with n-butanol having an atmospheric boiling point of about 117.6° C. This is very close to the boiling point of pure n-butanol of about 117.2° C., making it difficult to separate DBE from n-butanol when water is not present. However in the presence of water, a ternary azeotrope of water, n-butanol and DBE is formed having a boiling point of about 90.6° C. which can be exploited in the separation of DBE from the bulk of the n-butanol product. Other impurities produced during the catalytic hydrogenation of n-butyraldehyde to form n-butanol are so-called "heavy ends," which are relatively high boiling and tend to break down during purification by distillation to form "permanganate time consumers" (PTC's), i.e., certain unsaturated compounds and chromophores such as olefins, aldehydes and ketones, during distillation. The PTC's, like other impurities such as DBE, may also produce an adverse effect on end use applications if present in the n-butanol product, and like DBE, their separation from the n-butanol product is facilitated by the presence of water in the distillation column.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([Br:24])=[CH:5][C:4]=2[N:3]=1>C(#N)C.CO.C(Cl)(Cl)Cl.CO.[Pd]>[BrH:24].[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:17])([OH:18])[CH3:19])[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COCCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Agent: [Pd]
Solvent: CC#N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Br
Product: COCCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)O
Yield: 88.3 %

Procedure:
A Parr vessel was charged with 10% Pd/C (0.6 g) and a suspension of 1-[4-amino-7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (4.0 g) in acetonitrile (150 mL) and methanol (50 mL). The vessel was placed under hydrogen pressure (50 psi, 3.4×105 Pa) for 3 hours. The reaction mixture was diluted with 1/1 chloroform/methanol (100 mL), filtered through a layer of CELITE filter aid, and concentrated under reduced pressure. The residue was triturated with acetonitrile to provide 3.55 g of 1-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol hydrobromide as a white powder, mp 234-235° C. Anal. calcd for C16H22BrN5O2: % C, 48.49; % H, 5.60; % N, 17.67. Found: % C, 48.64; % H, 5.69; % N, 17.62.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].Cl[C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: Clc1cnccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5 %

Procedure:
n-Butyllithium (30.0 ml, 1.6M in hexanes, 48.0 mmol) was added dropwise to a cooled (−40° C.) solution of diisopropylamine (7 ml, 50.1 mmol) in tetrahydrofuran (30 ml), so as to maintain the temperature below −30° C. Once addition was complete, the solution was allowed to warm to room temperature for 2 minutes, then re-cooled to −70° C. Tri-n-butyltin hydride (12 ml, 45.8 mmol) was added dropwise over 10 minutes, and once addition was complete, the reaction was stirred at −60° C. for 2 hours. A solution of 2-chloropyrazine (5.0 g, 43.7 mmol) in tetrahydrofuran (5 ml) was added, and the reaction allowed to warm to room temperature. Aqueous ammonium chloride solution was added to quench the reaction, followed by dilution with ethyl acetate. The resulting suspension was filtered through Celite®, and the filtrate separated. The organic phase was washed with brine, dried (MgSO4), and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (100:0 to 90:10) to afford the title compound, (800 mg, 5%) as a yellow oil.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:27][P:28]([CH:38]([NH:42][C:43](=[O:53])[CH2:44][CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH:39]([CH3:41])[CH3:40])([O:30]CC1C=CC=CC=1)=[O:29])[C:17]([O:19]CC1C=CC=CC=1)=[O:18])=O)C1C=CC=CC=1>O1CCOCC1.O.[OH-].[Pd+2].[OH-]>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:27][P:28]([CH:38]([NH:42][C:43](=[O:53])[CH2:44][CH2:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[CH:39]([CH3:41])[CH3:40])([OH:30])=[O:29])[C:17]([OH:19])=[O:18]
Reactant: CC(C)C(NC(=O)CCCc1ccccc1)P(=O)(OCc1ccccc1)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(NC(=O)CCCc1ccccc1)P(=O)(O)O[C@@H](CCCCN)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The benzyl (S)-6-benzyloxycarbonylamino-2-((2-methyl-1-(4-phenylbutanoylamino)propyl)(benzyloxyphosphinoyl)oxy)hexanoate (43.9 mg) obtained in the above step (f) was dissolved in a mixed solvent of dioxane and water (3:1) (439 ml), and the solution was added with palladium hydroxide (8.8 mg) and stirred under a hydrogen atmosphere at room temperature for 18 hours. The reaction mixture was filtered with celite, and the filtrate was concentrated under reduced pressure. The residue was purified by HP-20 (Diaion, 5 g, water to methanol) to obtain the title compound: (S)-6-amino-2-(2-methyl-1-(4-phenylbutanoylamino)propyl(hydroxyphosphinoyl)oxy)hexanoic acid (17.5 mg, 7.0%, a diastereoisomeric mixture of 1:1).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:18]([N:17]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CCOC(=O)CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.8 %

Procedure:
Mix ethyl 4-iodobutyrate (43.5 g, 0.18 mol), dibenzylamine (35.5 g, 0.18 mol), potassium carbonate (24.9 g, 0.18 mol) and ethanol (114 mL dried over 4A molecular sieves). Reflux for 24 hours then stir at room temperature for 48 hours. Add methylene chloride (100 mL) and filter. Evaporate the filtrate to a residue and purify by silica gel chromatography (methylene chloride) to give the title compound (47 g).
Reaction SMILES: C(C1C=[CH:5][C:6](O)=[C:7](C=1)[C:8]([NH2:10])=O)=O.[OH-].[K+].[C:15]([OH:18])(=[O:17])C.[C:19]([OH:22])(=O)[CH3:20].I[C:24]1C=CC=CC=1.Cl>C(OCC)(=O)C.CO>[O:17]=[C:15]1[NH:10][C:8]2[CH:24]=[C:20]([CH:19]=[O:22])[CH:5]=[CH:6][C:7]=2[O:18]1
Reactant: NC(=O)c1cc(C=O)ccc1O
Reactant: CC(=O)O
Reactant: Ic1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=Cc1ccc2oc(=O)[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of methanol (50 mL) and 5-formyl-2-hydroxy-benzamide (Reich et al. J. Med. Chem., 2000;43(9):1670–1683) (2.0 g, 12.11 mmol) was added potassium hydroxide (1.35 g, 24.22 mmol) and then iodobenzene diacetate (3.90 g, 12.11 mmol). The reaction was stirred at 0° C. for 1 hour, then diluted with ethyl acetate (200 mL) and carefully acidified to pH 2 with 1N HCl. The organic layer was then washed with sodium chloride (2×50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. This was used in the next step without purification. MS: M+−1=162.0 Da.