Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@:10]([NH:24][C:25]([NH:27][CH2:28][CH:29](OC)OC)=O)([CH3:23])[C:11]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([F:21])=[C:16]([Cl:22])[CH:15]=2)=[O:12])=[CH:5][CH:4]=1)#[N:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.C(Cl)(Cl)(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCCC.C(OC(C)C)(=O)C>CC#N>[Cl:22][C:16]1[CH:15]=[C:14]([N:13]2[C:11](=[O:12])[C@:10]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)([CH3:23])[N:24]3[CH:29]=[CH:28][N:27]=[C:25]23)[CH:19]=[C:18]([Cl:20])[C:17]=1[F:21]
Reactant: COC(CNC(=O)N[C@](C)(Cc1ccc(C#N)cc1)C(=O)Nc1cc(Cl)c(F)c(Cl)c1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: CC(=O)OC(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2nccn21
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a room temperature suspension of (R)-3-(4-cyano-phenyl)-N-(3,5-dichloro-4-fluoro-phenyl)-2-[3-(2,2-dimethoxy-ethyl)-ureido]-2-methyl-propionamide (62.6 g, 125.9 mmol), PPh3 (51.98 g, 198.17 mmol), and Et3N (29.35 mL, 210.6 mmol) in MeCN (250 mL) was added CCl4 (20.3 mL, 210.6 mmol) in one portion. The reaction was stirred for 2 h and then cooled to 0° C. To this solution was added p-toluenesulfonic acid monohydrate (37.7 g, 198.2 mmol) and the reaction was heated at 70° C. for 2 h. The volatiles were evaporated in vacuo, and the residue was diluted with isopropyl acetate (i-PrOAc) (500 mL) and water (500 mL). The water layer was removed and the organic layer was washed with aqueous Na2CO3 (5 wt %, 500 mL) and then aqueous NaCl (3 wt %, 500 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give an oily solid. A mixture of Heptane/i-PrOAc (150 mL, 80:20 heptane:i-PrOAc) was added causing precipitation of a solid. The resulting slurry was stirred overnight and then filtered. The filtrate was evaporated in vacuo to give a brown oil. The oil was re-processed using the same conditions 3 more times. The remaining brown oil from the filtrate was then purified by flash chromatography on silica gel (20-50% EtOAc/hexanes) to give 48.0 g of the title compounds as a white solid, m/z 415.7 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1.F[C:14]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:12][O:11][C:9](=[O:10])[CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[CH:16][CH:15]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Reactant: COC(=O)CCC1CCNCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCC1CCN(c2ccc(C(=O)OC(C)(C)C)cc2)CC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 32.7 %

Procedure:
Methyl 3-(piperidin-4-yl)propanoate (WO2004/92124 A2) (206 mg, 1.11 mmol) was dissolved in N,N-dimethylformamide (10 mL), tert-butyl 4-fluorobenzoate (141 mg, 1.11 mmol) and potassium carbonate (100 mg, 1.11 mmol) were added, and the mixture was stirred at 120° C. under a nitrogen atmosphere for 16 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture under ice cooling, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate, 10:1, v/v) to give the title compound (126 mg; yield, 31%) as a colorless oily substance.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:12]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccccc1F
Reaction time: 1 h

Procedure:
0.063 mL of triethylamine and 0.040 mL of 2-fluorobenzoyl chloride were added to 3.0 mL of Methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-phenylbenzoate at room temperature sequentially and stirred at the same temperature for 1 hour. 0.51 g of aminomethylated polystyrene was added to the reaction mixture and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(2-fluorobenzamido)-4-phenylbenzoate.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12]C)=[CH:9][CH:10]=2)[C:5]([CH3:14])=[N:4][N:3]=1.B(Br)(Br)Br>ClCCl.O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5]([CH3:14])=[N:4][N:3]=1
Reactant: COc1ccc2c(Cl)nnc(C)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1nnc(Cl)c2ccc(O)cc12
Temperature: 25 °C
Yield: 19.7 %

Procedure:
A solution of 1-chloro-6-methoxy-4-methylphthalazine (7) (1.0 g, 4.8 mmol), 1.0 M boron tribromide (17.00 mmol) in dichloromethane (17 mL), and dichloromethane (50 mL) is stirred under argon at −78° C. for 0.5 h, at room temperature for 22 h, and at reflux for 4 h. After being cooled to room temperature, the mixture is diluted with H2O (100 mL) and sat. NaHCO3 (80 mL) and extracted with ethyl acetate (150 mL and 4×100 mL). The extract is washed (brine) and dried. Solvent is removed at reduced pressure to give 184 mg of an impure brown solid consisting of by-products. The aqueous layer is filtered, and the isolated solid is washed (H2O) and dried to give 640 mg (68%) of 8 as a yellow solid, mp >260° C. (dec). IR 3328, 2945, 1608, 1221 cm−1; 1H NMR (DMSO-d6) δ 2.74(s, 3H, CH3), 7.30 (d, J=1.8 Hz, 1H, 5-PhthH), 7.53 (dd, J=8.5, 1.8 Hz, 1H, 7-PhthH), 8.08 ppm (d, J=8.5 Hz, 1H, 8-PhthH).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[NH2:17]>C(O)C>[F:13][C:14]1[CH:15]=[C:16]([N:17]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: COc1ccc(N)cc1F
Solvent: CCO
Product: COc1ccc(N2CCC(C(=O)O)C2=O)cc1F
Yield: 91.5 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) 3-fluoro-4-methoxyaniline (0.628 g; 4.36 mmol) in ethanol (3 mL). 1-(3-fluoro-4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid 0.336 g (91%) was obtained as a white solid.
Reaction SMILES: N1C(C)=CC=CC=1C.[Si:9]([O:13]S(C(F)(F)F)(=O)=O)([CH3:12])([CH3:11])[CH3:10]>ClCCCl.C(OCC)C>[Si:9]([O:13][Si:9]([CH3:12])([CH3:11])[CH3:10])([CH3:12])([CH3:11])[CH3:10]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCCl
Solvent: CCOCC
Product: C[Si](C)(C)O[Si](C)(C)C
Temperature: 70 °C
Yield: 42.1 %

Procedure:
To a solution of hydroxy aldehyde 54 (21 mg, 41 μmol) in 1,2-dichloroethane (4 mL) was added 2,6-lutidine (72 μL, 620 μmol) and TMSOTf (79 μL, 410 μmol). The mixture was heated at 70° C. for 4.5 h before being cooled, diluted with ethyl ether (50 mL), washed with CuSO4 (20 mL), NaHCO3 (20 mL) and dried (MgSO4). Concentration under reduced pressure and purification by flash chromatography (silica gel, 10% ethyl acetate in toluene) gave pure silyl ether 55 (14 mg; 60%): Colorless oil; Rf =0.29 (silica gel, 70% ethyl ether in petroleum ether); 1H NMR (500 MHz, C6D6) δ9.61 (s, 1 h, CHO), 7.25 (d, J=8.7 hz, 2 h, Ar), 6.79 (d, J=8.7 hz, 2 h, Ar), 5.32 (s, 1 h, CHCN), 5.08 (d, J=14.0 hz, 1 h, allylic CH2), 4.85 (d, J=15.1 hz, 1 h, benzylic CH2), 4.75 (d, J=15.1 hz, 1 h, benzylic CH2), 4.60 (d, J=14.0 hz, 1 h, allylic CH2), 4.24 (dd, J=8.5, 2.2 hz, 1 h, THP anomeric CH), 3.93 (s, 1 h, CHOTHP), 3.74-3.68 (m, 1 h, ketal), 3.58-3.54 (m, 1 h, ketal), 3.30-3.24 (m, 3 h, ketal and THP), 3.29 (s, 3 h, OCH3), 3.03-2.96 (m, 1 h, THP), 1.4-0.9 (m, 6 h, THP), 0.34 (s, 9 h, TMS); IR (film) νmax 2929, 2856, 2211, 1734, 1616, 1513, 1424, 1376, 1247, 1180, 1118, 1035, 946, 910, 847 cm-1 ; HRMS Calcd. for C29H36O9N2Si (M+Na+): 607.2088. Found: 607.2080.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[C:9](/[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:10](/[F:15])\[C:11](O)([CH3:13])[CH3:12])=[C:6]([OH:8])[CH:7]=1.Cl>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:10]([F:15])[C:11]([CH3:13])([CH3:12])[O:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)/C(F)=C(/c1ccc(F)cc1)c1ccc(Cl)cc1O
Agent: Cl
Product: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1F

Procedure:
The compound obtained in (4) described above (314 mg) and concentrated hydrochloric acid (4 mL) were treated in the same manner as Reference Example 5(3) to give the titled compound (132 mg) as a colorless powder.
Reaction SMILES: O.[Br:2][C:3]1[CH2:4][CH:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]([C:16]([C:18](OCC)=[O:19])=[O:17])[CH:8]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:7][CH2:6]2>CC(C)=O.[Cl-].[Cl-].[Cl-].[Ti+3]>[Br:2][C:3]1[CH:4]=[C:5]2[CH2:6][CH2:7][CH:8]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[N:9]3[C:16](=[O:17])[C:18](=[O:19])[NH:13][C:11]([CH:12]=1)=[C:10]23
Reactant: CCOC(=O)C(=O)N1C2=C([N+](=O)[O-])C=C(Br)CC2CCC1CC(=O)OC
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a mixture of 20% aqueous titanium trichloride (670 g, 0.867 mol), water (500 mL), and acetone (500 mL) was added dropwise a solution of 6-bromo-2-methoxycarbonylmethyl-8-nitro-N-ethoxalyltetrahydroquinoline (52.0 g, 0.121 mol) in acetone (600 mL) at 0° C. The mixture was stirred overnight at room temperature, concentrated to ca. 1 L and diluted with water (1 L). The precipitates formed were collected by filtration, washed with water, and dried in vacuo to give 35.2 g of the title compound. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with ethyl acetate to give 6.0 g of the title compound (total 89%).
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([C:7]1[CH:11]=[C:10](Br)[O:9][C:8]=1[CH3:13])=[O:6].[N+:14]([C:17]1[CH:18]=[C:19]([NH2:32])[CH:20]=[CH:21][C:22]=1B1OC(C)(C)C(C)(C)O1)([O-:16])=[O:15].C(=O)(O)[O-].[Na+]>COCCOC.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>[CH3:3][O:4][C:5]([C:7]1[CH:11]=[C:10]([C:22]2[CH:21]=[CH:20][C:19]([NH2:32])=[CH:18][C:17]=2[N+:14]([O-:16])=[O:15])[O:9][C:8]=1[CH3:13])=[O:6]
Reactant: COC(=O)c1cc(Br)oc1C
Reactant: CC1(C)OB(c2ccc(N)cc2[N+](=O)[O-])OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(N)cc2[N+](=O)[O-])oc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
(The following reaction is done in a N2 atmosphere.) Dissolve Pd(PPh3)4 (59 mg, 0.05 mmol) and 5-Bromo-2-methyl-furan-3-carboxylic acid methyl ester (23) (447 mg, 2.04 mmol) in DME (3 mL) and stir for 10 min at rt. Add 3-Nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (57) (465 mg, 1.76 mmol) followed by an aqu. 1M sodium bicarbonate solution (5.10 mL, 5.10 mmol). Degas the reaction mixture carefully, flush with N2 (5 times) and stir for 4.5 h at 90° C. (reflux). Cool reaction mixture to rt, remove organic solvent under reduced pressure and partition the residue between water and EtOAc. Extract the aqu. layer with EtOAc (3 times), wash the combined organic layer with water and brine and dry it with Na2SO4. Purify the obtained crude product by flash chromatography (silica gel, EtOAc/CyH 1+3, later 1+2) to obtain 5-(4-Amino-2-nitro-phenyl)-2-methyl-furan-3-carboxylic acid methyl ester (58) (167 mg, 34%) as a red solid. 1H NMR (400 MHz, CDCl3): 2.57 (s, 3H); 3.81 (s, 3H); 4.05 (br.s, 2H); 6.68 (s, 1 H); 6.81 (dd, 1H, J1=8.3 Hz, J2=2.3 Hz); 6.99 (d, 1H, J=2.3 Hz); 7.39 (d, 1H, J=8.3 Hz).
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:41].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:41].[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 0.17 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 3 mL of ethyl acetate, 6.0 mL of a 4.0 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature. The mixture was stirred at the same temperature for 1 hour, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the resultant residue, and the solid was filtered off to obtain 0.16 g of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:12][O:13][CH3:14]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:12][O:13][CH3:14])=[CH:6][N:7]=1
Reactant: COCCl
Reactant: Oc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1000 mg (1 eq) of 6-chloropyridin-3-ol was dissolved in 50 mL of N,N-dimethylformamide, and 370 mg (1.2 eq) of sodium hydride was added thereto, followed by stirring at room temperature for 1 hour. Then, 688 uL (1.1 eq) of chloro(methoxy)methane was added slowly thereto, and the solution was stirred at room temperature for 2 hours. N,N-dimethylformamide was removed by concentrating under reduced pressure. After extracting with ethyl acetate, the extract was treated with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (developing solvent, hexane:ethyl acetate=9:1) to obtain 1200 mg of 2-chloro-5-(methoxymethoxy)pyridine.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C@H:3]([OH:6])[CH2:4][OH:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12].Cl>N1C=CC=CC=1.ClCCl>[CH3:10][S:11]([O:5][CH2:4][C@@H:3]([OH:6])[C:2]([CH3:9])([CH3:1])[CH2:7][O:8][S:11]([CH3:10])(=[O:13])=[O:12])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CO)[C@H](O)CO
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(COS(C)(=O)=O)[C@H](O)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.6 %

Procedure:
To a 0° C. solution of 25.3 g (189 mmol) of (2S)-3,3-dimethyl-1,2,4-butanetriol in 170 mL of pyridine was added dropwise 29.1 mL (378 mmol) of methanesulfonyl chloride. The reaction mixture was allowed to warm slowly to room temperature, and was stirred for 18 h. It was then diluted with dichloromethane. To the resulting solution was added 200 mL of 1 N hydrochloric acid, followed by enough concentrated hydrochloric acid to acidify the aqueous phase (pH=2). The mixture was extracted with dichloromethane, and the combined extracts were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with acetone:dichloromethane (1:9) to afford 21.75 g (52%) of (2S)-2-hydroxy-3,3-dimethyl-4-[(methylsulfonyl)oxy]butyl methanesulfonate. 1H-NMR (300 MHz, DMSO-d6): δ 5.48 (d, J=6 Hz, 1H), 4.30 (dd, J=3 Hz, J=10 Hz, 1H), 4.05–3.91 (m, 3H), 3.16 (d, J=4 Hz, 6H), 0.90 (d, J=13 Hz, 6H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH:6]([C:13]1[C:19]([OH:20])=[CH:18][C:17]([CH:21]([CH:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH3:22])=[CH:16][C:14]=1[OH:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.Cl.CN(C)CC(NC(C1C(O)=CC(C(C(C)CCCCC)C)=CC=1O)C1C=CC=CC=1)=O>CO>[ClH:1].[N:30]1([CH2:2][C:3]([NH:5][CH:6]([C:13]2[C:19]([OH:20])=[CH:18][C:17]([CH:21]([CH:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH3:22])=[CH:16][C:14]=2[OH:15])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCCCCC(C)C(C)c1cc(O)c(C(NC(=O)CCl)c2ccccc2)c(O)c1
Reactant: C1CCNCC1
Agent: CCCCCC(C)C(C)c1cc(O)c(C(NC(=O)CN(C)C)c2ccccc2)c(O)c1
Agent: Cl
Solvent: CO
Product: CCCCCC(C)C(C)c1cc(O)c(C(NC(=O)CN2CCCCC2)c2ccccc2)c(O)c1
Yield: 37.8 %

Procedure:
A solution of 4.18 g (0.01 mol) of crude 2-(α-chloroacetylaminobenzyl)-5-(3-methyl-2-octyl)-resorcinol (7) and 4.25 g (0.05 mol) of piperidine in 30 ml of methanol was heated under reflux for 3 hrs and worked up as described above for the preparation of 2-(α-dimethylaminoacetylaminobenzyl)-5-(3-methyl-2-octyl)-resorcinol hydrochloride (9). There was obtained 1.9 g of (10), mp 195°-198° (from ethanol-ether).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[S:15](Cl)(=[O:17])=[O:16]>>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[S:15]([NH:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)(=[O:17])=[O:16]
Reactant: Cn1cccc1CCN
Reactant: O=S(=O)(Cl)c1cccs1
Product: Cn1cccc1CCNS(=O)(=O)c1cccs1

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrole and 2-thienylsulphonylchloride analogously to Example A.
Reaction SMILES: C(N)C1C=CC=CC=1.[CH2:9]([N:12](C(OCC1C=CC=CC=1)=O)[CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:21][C@H:22]([C:24]([NH:26][C@H:27]([P:29](=[O:32])([OH:31])[OH:30])[CH3:28])=[O:25])[CH3:23])=[O:20])[CH3:18])=[O:15])[CH:10]=[CH2:11]>O.C(O)C>[CH2:9]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:21][C@H:22]([C:24]([NH:26][C@H:27]([P:29](=[O:30])([OH:32])[OH:31])[CH3:28])=[O:25])[CH3:23])=[O:20])[CH3:18])=[O:15])[CH2:10][CH3:11]
Reactant: C=CCN(CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O)C(=O)OCc1ccccc1
Solvent: NCc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCNCC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 1(B)(ii), from the monobenzylamine salt of (1R)-1-[(N-allyl-N-benzyloxycarbonyl-glycyl-L-alanyl-L-alanyl)amino]-ethylphosphonic acid, but using water/ethanol (1:1) for the ion-exchange step to generate the free acid, there was obtained, after hydrogenolysis of the N-benzyloxycarbonyl group in the usual way but with concomitant reduction of the allyl group to the n-propyl group, the crude product in the form of a gel. Crystallisation from water/ethanol gave (1R)-1-[N-(n-propyl)-glycyl-L-alanyl-L-alanylamino]-ethylphosphonic acid of melting point 263°-264° C. (decomposition); [α]D20 =-110°; [α]36520 =-392° (c=1% in water).
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:12]([CH3:26])[C:11]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[I:30]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[C:1]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[C:22]([I:30])[CH:23]=3)[N:12]([CH3:26])[C:11]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 1-(4-tert-Butyl-benzyl)-4-[3-(4-methoxy-phenyl)-propyl]-3-methyl-imidazolidin-2-one (0.630 g, 1.60 mmole) in ethanol (15 mL), is added iodine (0.810 g, 3.20 mmole) followed by silver sulfate (0.998 g, 3.20 mmole). The reaction mixture is stirred at room temperature overnight. The precipitate is removed through filtration, and the solution is concentrated in vacuo. The residue is purified by column chromatography (silica gel, gradient elution 0-20% acetone in hexane) to provide a white foamy solid (0.584 g, 70%). Mass [EI+] 521 (M+H)+.
Reaction SMILES: N[C:2]([NH2:4])=[O:3].[CH2:5]([N:12]1[CH2:17][CH2:16][C:15]([CH2:22]C(O)=O)([CH2:18][C:19](O)=[O:20])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[CH2:5]([N:12]1[CH2:13][CH2:14][C:15]2([CH2:22][C:2](=[O:3])[NH:4][C:19](=[O:20])[CH2:18]2)[CH2:16][CH2:17]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)CC1(CC(=O)O)CCN(Cc2ccccc2)CC1
Reactant: NC(N)=O
Solvent: CCO
Product: O=C1CC2(CCN(Cc3ccccc3)CC2)CC(=O)N1
Temperature: 160 °C
Reaction time: 3 h
Yield: 104.1 %

Procedure:
Urea (242 mg, 4.03 mmol) was added to 2,2′-(1-benzylpiperidine-4,4-diyl)diacetic acid (390 mg, 1.34 mmol). The mixture was heated to 160° C. After 3 h, additional urea (242 mg, 4.03 mmol) was added and the mixture was heated to 185° C. After 18 h, additional urea (242 mg, 4.03 mmol) was added. After 48 h, the reaction mixture was allowed to cool to ambient temperature and ethanol was added. After 1 h, the mixture was filtered and solid was washed with ethanol. Saturated aqueous sodium bicarbonate was added to the solid and the suspended solution was stirred until gas release was complete. The mixture was filtered and the solid was washed with water, and concentrated to give the title compound (380 mg). MS 273.1 (M+1).