Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C@@H:9]1[CH2:11][C@H:10]1[C:12]1[CH:17]=[C:16]([O:18]C)[CH:15]=[CH:14][C:13]=1[O:20]C)([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C@@H:9]1[CH2:11][C@H:10]1[C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:13]=1[OH:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(OC)c([C@@H]2C[C@H]2CNC(=O)OC(C)(C)C)c1
Agent: BrB(Br)Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@@H]1C[C@H]1c1cc(O)ccc1O
Temperature: 25 °C
Yield: 66.6 %

Procedure:
To a solution of trans-[2-(2,5-dimethoxyphenyl)cyclopropylmethyl]carbamic acid tert-butyl ester (13) (4.20 g, 13.7 mmol) in CH2Cl2 (30 mL) at −78° C. was added BBr3 (1.0 M solution in CH2Cl2) (47.8 mL, 47.8 mmol) dropwise. The solution was warmed to rt, and the reaction mixture was quenched with MeOH (110 mL) and concentrated in vacuo. This process was repeated until no white fumes were observed upon addition of MeOH to give a crude product as pale yellow oils. The crude product was used without any further purification. A solution of the crude product, Boc2O (3.28 g, 15.0 mmol), and triethylamine (7.62 mL, 54.7 mmol) in CH2Cl2 (30 mL) was stirred at rt for 30 min. To the resulting mixture were added sat. aq NaHCO3, and the aqueous layer was extracted with CH2Cl2 (×2). The organic layer was further washed with water (×1), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using gradient elution from 0% EtOAc-hexane to 30% EtOAc-hexane to afford the title compounds as a pale yellow oil (2.55 g, 66.8% yield). 1H NMR (400 MHz, CDCl3) δ 6.73 (d, J=8.4 Hz, 1 H), 6.57 (dd, J=8.8 Hz, J=2.6 Hz, 1 H), 6.42 (d, J=2.6 Hz, 1 H), 5.01 (bs, 1 H), 4.45 (s, 1 H), 3.51-3.44 (m, 1 H), 2.92-2.85 (m, 1 H), 1.89-1.87 (m, 1 H), 1.47 (s, 9 H), 1.06-1.01 (m, 1 H), 0.92-0.90 (m, 1 H), 0.75-0.72 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6](=[S:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:16])=[O:15])=[CH:10][C:9]=1[N+:17]([O-])=O)=[O:4].CO>[Fe].O>[NH2:17][C:9]1[CH:10]=[C:11]([S:14]([CH3:16])=[O:15])[CH:12]=[CH:13][C:8]=1[NH:7][C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[S:20]
Reactant: COC(=O)NC(=S)Nc1ccc(S(C)=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: O
Product: COC(=O)NC(=S)Nc1ccc(S(C)=O)cc1N

Procedure:
1.5 G. of 1-(3-methoxycarbonyl-2-thioureido)-4-methylsulfinyl-2-nitrobenzene is treated in a boiling mixture of 240 ml. methanol and 60 ml. water with 1.5 g. iron powder and 0.75 g. ferrous sulfate for 3 hours. The mixture is filtered and the filtrate concentrated to a small volume, and diluted with water. The white solid is collected and recrystallized from ethanol, yielding pure 2-amino-4-methylsulfinyl-1-(3-methoxycarbonyl-2-thioureido)-benzene.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>O>[C:23]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COC(=O)C(C)(C)c1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C(C)(C)c1ccc(CNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(4-aminomethylphenyl)-2-methylpropionate (29.4 g) and triethylamine (23.8 ml) indichloroethane (300 ml) was added dropwise acetyl chloride (11.1 ml) at 5° C. over 30 min. The mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=3:1, ethyl acetate) to give the title compound (23.47 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1([N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C@@H:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C@H:16]4[NH:15][C:14]3=[O:22])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[O:22]=[C:14]1[N:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:2]3([CH3:1])[CH2:6][CH2:5][N:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:3]3)[CH2:8][CH2:9]2)[C@@H:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C@H:16]2[NH:15]1
Reactant: CCOC(=O)Cl
Reactant: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CCNC1
Product: CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)C1

Procedure:
Following the procedure used in step G of the example 8 and starting with (3aR,7aR)-1-[1-(3-methylpyrrolidin-3-yl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (160 mg, 0.522 mmol) and ethyl chloroformate (85 mg, 0.783 mmol), the title compound was obtained as a gum (120 mg). 1H NMR (Methanol-D4) δ 4.60 (brs, 1H), 4.13-4.08 (q, 2H), 3.74-3.51 (m, 4H), 3.43-3.34 (m, 2H), 3.20 (br d, 1H), 3.04-2.90 (m, 3H), 2.73 (br s, 1H), 2.4-2.31 (m, 3H), 1.98-1.60 (br m, 8H), 1.43 (m, 3H), 1.25 (t, 3H), 1.10 (s, 3H). MS (M+1): 379.34.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[F:47][C:48]([F:56])([F:55])[C:49]1([CH2:53][OH:54])[CH2:52][CH2:51][CH2:50]1>>[Cl:17][C:18]1[C:19]([O:54][CH2:53][C:49]2([C:48]([F:56])([F:55])[F:47])[CH2:52][CH2:51][CH2:50]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC1(C(F)(F)F)CCC1
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC2(C(F)(F)F)CCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with (1-(trifluoromethyl)cyclobutyl)methanol, the title compound was obtained as a colorless solid (0.05 g, 12%): 1H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.76 (d, J=7.4 Hz, 1H), 7.38 (d, J=12.2 Hz, 1H), 4.41 (s, 2H), 2.88 (s, 6H), 2.38-2.26 (m, 2H), 2.19-2.08 (m, 3H), 2.02-1.91 (m, 1H); MS (ES−) m/z 431.1, 433.1 (M−1).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([CH2:34][C:35](O)=[O:36])[CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1
Reactant: NC1CCC(CCN2CCN(c3nccc4ccoc34)CC2)CC1
Reactant: O=C(O)CC1CCOCC1
Agent: Cl
Product: O=C(CC1CCOCC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccoc34)CC2)CC1

Procedure:
The title compound, white solid (43 mg, 47%), MS (ISP) m/z=455.4 [(M+H)+], mp 213° C., was prepared in accordance with the general method of example 6 from 4-[2-(4-furo[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and tetrahydropyran-4-yl-acetic acid.
Reaction SMILES: [C:1]1([CH:11]2[CH2:25][NH:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl-:26].[Mn+2:27].[Cl-:28]>CO>[Cl:26][C:11]1([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:25][NH:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][N:12]1[Cl:28].[Mn+2:27]
Reactant: c1ccc2c(C3CNCCNCCNCCNCCN3)cccc2c1
Reactant: [Cl-]
Agent: [Mn+2]
Solvent: CO
Product: ClN1CCNCCNCCNCCNCC1(Cl)c1cccc2ccccc12
Reaction time: 96 h
Yield: 46 %

Procedure:
2-(1-Naphthyl)-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 32H (0.23 g, 0.67 mmol) was added to a refluxing anhydrous MeOH solution (50 ml) containing anhydrous manganese(II) chloride (84.4 mg, 0.671 mmol) under a dry nitrogen atmosphere. The solution was refluxed overnight and then filtered through celite. The solution was taken to dryness and the residue was redissolved in hot EtOH (10 ml). The resultant yellowish solution was filtered through celite and ethyl ether (30 ml) was added. A flocculent yellowish precipitate formed which was filtered and discarded. The filtrate was diluted to 50 ml with ethyl ether and allowed to sit undisturbed for 4 days. A white microcrystalline precipitate was collected by filtration to give 0.144 g (46% yield) of product after drying in vacuo: FAB mass spectrum (NBA) m/z (relative intensity) 466 (M+, 3), 431/433 [(M+ -Cl), 100/32]; Anal. calcd for C20H31N5MnCl2 : C, 51.40; H, 6.69; N, 14.99. Found: C, 52.10; H, 6.73; N, 14.71.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:11][C:10]([O:14][CH3:15])=[O:13])=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)CO
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of 4-hydroxy benzaldehyde, (1.22 g, 0.01 m), methyl glycolate (0.97 g, 0.01 m), and triphenylphosphine, (3.93 g, 0.015 m), in dry tetrahydrofuran, (50 ml) was stirred with cooling in ice and diethylazodicarboxylate, (2.61 g, 0.015 m), added dropwise. The solution was stirred at room temperature for 0.5 hours, then evaporated in vacuo to dryness. Column chromatography of the residue on silica gel eluting with chloroform yielded 1.30 g (67%) of the title compound as an oil which crystallized on standing, mp 39°-41° C., νmax (mull) 1750, 1680, 1595, 1575, 1505 cm-1.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][CH2:11][OH:12])=[C:5]([CH3:13])[N:4]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[CH3:1][S:2][C:3]1[N:8]([CH3:16])[C:7](=[O:9])[C:6]([CH2:10][CH2:11][OH:12])=[C:5]([CH3:13])[N:4]=1
Reactant: CI
Reactant: CSc1nc(C)c(CCO)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(C)c(CCO)c(=O)n1C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-methylthio-5-(2-hydroxyethyl)-6-methyl-3H-pyrimidin-4-one (34 g, 0.17 mol) in DMF (300 ml) was added slowly one equivalent of sodium hydride (55%, 7.4 g). Next was added slowly one equivalent of methyl iodide (10.5 ml). The mixture was stirred for two hours at 50° C., after which most of the DMF was removed in vaccuum. Water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and then concentrated and purified by flash chromatografy (eluens: ether followed by ether/methanol=9/1). Yield 20.3 g (56%), mp. 117-118° C.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:9]([OH:28])[CH2:10][N:11]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])(C)(C)C.N(CCO)(CCO)CCO.[H][H].[OH-].[Na+]>C(O)(C)C.[C].[Pd]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:11]([CH2:10][C@@H:9]([OH:28])[C@@H:8]([NH2:7])[CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: OCCN(CCO)CCO
Product: CC(C)CN(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc(N)cc1
Temperature: 42.5 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
(1S,2R)-{1-benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl}-carbamic acid tert-butyl ester (3, 100 g), 10% palladium carbon (10 gm) and triethanolamine (2 gm) were suspended in isopropyl alcohol. The reaction was heated to 40-45° C. and maintained under 4-6 kg/cm2 of hydrogen pressure for 3 hours. After completion of reaction, the mass was filtered and hydrochloric acid (70 mL) was added to the filtered mass. The solution was heated to reflux and maintained for 2-3 hours. After completion of reaction the mass was cooled to 25-35° C., the reaction mass pH was adjusted to 6.0-7.0 with 20% sodium hydroxide solution and distilled out isopropyl alcohol under vacuum at below 55° C. Ethanol (200 mL) and water (400 mL) was added to the distillate, the mass pH was adjusted to 9.0-10.0 with 20% sodium hydroxide solution at 25-35° C. and maintained the stirring for 2 hours at 25-35° C. The mass was cooled to 0-5° C., filtered and wash with water. The wet product was taken into ethanol (350 mL), maintained the stirring for 30 minutes at reflux temperature. The mass was cooled to 2-4° C., stirred for 2 hours, filtered and washed with ethanol (50 mL). The wet product was dried under normal drying to get title compound 1 (Yield 60 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].[Cl:14][CH2:15][CH2:16][OH:17].CCOCC>CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:13])[O:17][CH2:16][CH2:15][Cl:14]
Reactant: OCCCl
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)OCCCl
Temperature: 15 °C
Reaction time: 0.03 h

Procedure:
50.0 g of 2-chloro-4-nitrophenyl isocyanate was added, with stirring, to 100 g of 2-chloroethanol. After 2 minutes, the temperature of the mixture rose to 65° C. The mixture then was heated at 80°-90° C. for 10 minutes, and cooled. 200 ml of ether and 200 ml of hexane were added, the mixture was cooled to 15° C. and filtered. Drying of the filter cake gave 2-chloroethyl (2-chloro-4-nitrophenyl)carbamate (1A), as a white solid, mp: 128°-130° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[C:5]2[O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[C:4]=2[N:3]=1.[Cl:22]C1C=C2C(C3OC4C=CC=CC=4C=3N=C2O)=CC=1>>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]3[O:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=4[C:4]=3[N:3]=[C:2]2[Cl:22])=[CH:7][CH:8]=1
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Reactant: COc1ccc2oc3c4ccc(Cl)cc4c(O)nc3c2c1
Product: COc1ccc2oc3c4ccc(Cl)cc4c(Cl)nc3c2c1

Procedure:
The procedure was similar to step S19C, while the starting material was 26B in stead of 19B.
Reaction SMILES: [CH:1]([N:4]([CH:23]([CH3:25])[CH3:24])[CH2:5][CH2:6][CH:7]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[OH:22])C=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[NH2:26][CH:27](C1C=CC(O)=CC=1)[C:28]([OH:30])=[O:29].C(N(C(C)C)CC=CC1C=CC=CC=1)(C)C>>[NH2:26][CH:27]([C:16]1[CH:19]=[CH:20][C:21]([OH:22])=[C:14]([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH:23]([CH3:24])[CH3:25])[CH:1]([CH3:3])[CH3:2])[CH:15]=1)[C:28]([OH:30])=[O:29]
Reactant: CC(C)N(CCC(c1ccccc1)c1cc(C=O)ccc1O)C(C)C
Reactant: NC(C(=O)O)c1ccc(O)cc1
Agent: CC(C)N(CC=Cc1ccccc1)C(C)C
Product: CC(C)N(CCC(c1ccccc1)c1cc(C(N)C(=O)O)ccc1O)C(C)C

Procedure:
In a preferred embodiment of the invention, 3-(3-(diisopropylamino)-1-phenylpropyl)-4-hydroxybenzaldehyde (PHB) is synthesized comprising a reaction of 2-amino-2-(4-hydroxyphenyl)acetic acid (hydroxyphenylglycine) with N,N-diisopropyl-3-phenylprop-2-en-1-amine (DIPCA) in the presence of an acid, preferably at 80-150° C., to give 2-amino-2-(3-(3-(diisopropylamino)-1-phenylpropyl)-4-hydroxyphenyl)acetic acid (HFG), and a further reaction with a suitable oxidant, preferably in water at 30-105° C., to give PHB. Intermediate compound HFG can be isolated. But advantageously and preferably, the synthesis from DIPCA to PHB can be carried out in one pot, without intermediate isolation of HFG.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]2[O:20][CH2:19][CH2:18][O:17]2)=[CH:11][C:10]=1[CH3:21])C1C=CC=CC=1>C(O)C.O>[O:17]1[CH2:18][CH2:19][O:20][CH:16]1[C:12]1[C:13]([CH3:15])=[CH:14][C:9]([NH2:8])=[C:10]([CH3:21])[CH:11]=1
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1C1OCCO1
Solvent: O
Solvent: CCO
Product: Cc1cc(C2OCCO2)c(C)cc1N
Reaction time: 8 h
Yield: 92 %

Procedure:
The crude dibenzyl-(4-[1,3]dioxolan-2-yl-2,5-dimethyl-phenyl)amine was dissolved in a 2:1 mixture of ethanol and water (150 mL total) and the resulting mixture was purged with dry nitrogen for 5 minutes. Palladium on carbon (2.3 g, 10 wt. % containing about 50% water) and solid sodium bicarbonate (1.0 g) were added and the resulting mixture was hydrogenated at about 1 atm of hydrogen at 25° C. to 30° C. for about 8 hours. The mixture was then filtered through Celite and the filtrate was concentrated on a rotary evaporator to provide crude 4-[1,3]dioxolan-2-yl-2,5-dimethylphenylamine (5.6 g, 92% yield) as a thick oil. 1H NMR (300 MHz, DMSO-d6) δ 2.05 (s, 3H), 2.22 (s, 3H), 3.7-3.9 (m, 4H), 3.95 (s, 4H), 5.59 (s, 1H), 6.72 (s, 1H), 7.0-7.25 (m, 11H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:37][N:38]1[CH2:43][CH2:42][CH2:41][CH:40]([CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:39]1>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH:40]4[CH2:41][CH2:42][CH2:43][N:38]([CH3:37])[CH2:39]4)[CH2:50][CH2:49]3)=[O:22])[CH:17]=2)(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CN1CCCC(CN2CCNCC2)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N3CCN(CC4CCCN(C)C4)CC3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (63 mg, 0.18 mmol), CDI (58 mg, 0.36 mmol) and 1-[(1-methylpiperidin-3-yl)methyl]piperazine (59 mg, 0.30 mmol) in DCE (4.5 mL).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10](=[O:30])[NH:11][CH2:12][C@H:13]([OH:29])[CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([F:25])[CH:24]=1)[N:21]([CH2:26][CH3:27])[C:20](=[O:28])[CH2:19]2)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([O:9][C:10](=[O:30])[NH:11][CH2:12][C@@H:13]1[O:29][C:1](=[O:2])[N:15]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([F:25])[CH:24]=2)[N:21]([CH2:26][CH3:27])[C:20](=[O:28])[CH2:19]3)[CH2:14]1)([CH3:6])([CH3:7])[CH3:8]
Reactant: CCN1C(=O)Cc2cc(NC[C@@H](O)CNC(=O)OC(C)(C)C)cc(F)c21
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1C(=O)Cc2cc(N3C[C@H](CNC(=O)OC(C)(C)C)OC3=O)cc(F)c21
Reaction time: 0.5 h

Procedure:
Phosgene (20% solution in toluene, 3.58 ml, 36.7 mmol) is added to (R)-[3-(1-ethyl-7-fluoro-2-oxo-2,3-dihydro-1H-indol-5-ylamino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (1.80 g, 4.89 mmol) and triethylamine (3.38 ml, 24.5 mmol) in dichloromethane (20 ml) at 0° C. and stirred for 30 minutes. The mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated to give the title compound as a light brown solid. HPLC r.t. 4.92 min; MS for C19H24FN3O5 m/z 394.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[C:10]([O:14][C:15](=[O:22])[NH:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21])([CH3:13])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[C:10]([O:14][C:15](=[O:22])[NH:16][CH2:17][CH2:18][NH:19][C:20]([NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])=[O:21])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCCN=C=O
Reactant: CCOC(CN)OCC
Solvent: Cc1ccccc1
Product: CCOC(CNC(=O)NCCNC(=O)OC(C)(C)C)OCC
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Add 2,2-diethoxy ethanamine (3.33 g, 25.04 mmol) to a solution of (2-isocyanato-ethyl)-carbamic acid tert-butyl ester (3.73 g, 20.03 mmol) in toluene (50 mL). After 1 hour, concentrate the mixture to afford a white solid (6.39 g). 1H NMR (DMSO-d6) δ 6.74 (t, J=5 Hz, 1H), 6.03 (t, J=5.6 Hz, 1H), 5.85 (t, J=5.8 Hz, 1H), 4.39 (t, J=5.4 Hz, 1H), 3.61-3.55 (m, 2H), 3.48-3.42 (m, 2H), 3.06 (t, J=5.7 Hz, 2H), 3.01 (q, J=6.2 Hz, 2H), 2.92 (q, J=6.2 Hz, 2H), 1.37 (s, 9H), 1.11 (t, J=6.4 Hz, 6H).
Reaction SMILES: [CH2:1]([O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([C:35]([N:37]2[CH2:41][C:40](=[CH2:42])[CH2:39][CH:38]2[CH2:43][OH:44])=[O:36])=[CH:29][C:28]=1[N+:45]([O-])=O)[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([N:15]2[CH2:19][C:18](=[CH2:20])[CH2:17][CH:16]2[CH2:21][OH:22])=[O:14])=[CH:7][C:6]=1[N+:23]([O-])=O.O.O.Cl[Sn]Cl.C(Cl)(Cl)Cl.CO>CO>[CH2:3]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([N:15]2[CH2:19][C:18](=[CH2:20])[CH2:17][CH:16]2[CH2:21][OH:22])=[O:14])=[CH:7][C:6]=1[NH2:23])[CH2:2][CH2:1][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([C:35]([N:37]2[CH2:41][C:40](=[CH2:42])[CH2:39][CH:38]2[CH2:43][OH:44])=[O:36])=[CH:29][C:28]=1[NH2:45]
Reactant: C=C1CC(CO)N(C(=O)c2cc([N+](=O)[O-])c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)CC4CO)cc3[N+](=O)[O-])cc2OC)C1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=C1CC(CO)N(C(=O)c2cc(N)c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)CC4CO)cc3N)cc2OC)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60.7 %

Procedure:
A mixture of the diol 35 (0.98 g, 1.49 mmol) and SnCl2.2H2O (3.36 g, 14.9 mmol) in MeOH (35 mL) was heated at reflux and the progress of the reaction monitored by TLC (90% CHCl3/MeOH). After 45 minutes, the MeOH was evaporated in vacuo and the resulting residue was cooled (ice), and treated carefully with saturated NaHCO3 (120 mL). The mixture was diluted with EtOAc (120 mL), and after 16 hours stirring at room temperature the inorganic precipitate was removed by filtration through celite. The organic layer was separated, washed with brine (100 mL), dried (MgSO4), filtered and evaporated in vacuo to give a brown solid. Flash chromatography (95% CHCl3/MeOH) afforded the pure bis-amine 36 as an orange solid (0.54 g, 61%): [α]19D=−31.8° (c=0.30, CHCl3); 1H NMR (270 MHz, CDCl3) δ 6.74 (s, 2Harom), 6.32 (s, 2Harom), 5.00 (br s, 2H, NCH2C═CH2), 4.93 (br s, 2H, NCH2C═CH2), 4.54 (br s, 2H, NCHCH2OH), 4.24-4.14 (m, 4H, OCH2CH2CH2O), 3.98-3.50 (m, 14H, NCHCH2OH, NCH2C═CH2 and OCH3), 2.76 (dd, 2H, J=8.61, 15.91 Hz, NCH2C═CH2CH2), 2.46-2.41 (m, 2H, NCH2C═CH2CH2), 2.33-2.28 (m, 2H, OCH2CH2CH2O); 13C NMR (67.8 MHz CDCl3) δ 171.0 (NC═O), 151.0 (Cquat), 143.5 (Cquat), 141.3 (Cquat), 140.6 (Cquat), 112.4 (C—Harom), 111.9 (Cquat), 107.8 (NCH2C═CH2), 102.4 (C—Harom), 65.2 (OCH2CH2CH2O), 65.0 (NCHCH2OH), 59.8 (NCHCH2OH), 57.1 (OCH3), 53.3 (NCH2C═CH2), 34.4 (NCH2C═CH2CH2), 29.0 (OCH2CH2CH2O); MS (FAB) (Relative Intensity) 596 (M+, 13), 484 (M-NCH2CCH2CH2CHCH2OH, 14), 389 (10), 371 (29), 345 (5), 224 (8), 206 (44), 166 (100), 149 (24), 112 (39), 96 (34), 81 (28); IR (NUJOL7) 3600-3000 (br, OH), 3349 (NH2), 2922, 2852, 2363, 1615, 1591 (NH2), 1514, 1464, 1401, 1359, 1263, 1216, 1187, 1169, 1114, 1043, 891, 832, 761 cm−1.