Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][P:9]([O:12][CH2:13][C@@H:14]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3[CH:30]=[N:31][C:32]([NH:44][C:45](=[O:49])[NH:46][CH2:47][CH3:48])=[CH:33][C:34]=3[C:35]3[S:36][CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:39]=3)=[CH:26][N:27]=2)[C:22](=[O:50])[C:21]([C:51]([O:53]CC)=[O:52])=[CH:20]1)[CH2:15][CH:16]([CH3:18])[CH3:17])([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[CH2:1]([O:8][P:9]([O:12][CH2:13][C@@H:14]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3[CH:30]=[N:31][C:32]([NH:44][C:45](=[O:49])[NH:46][CH2:47][CH3:48])=[CH:33][C:34]=3[C:35]3[S:36][CH:37]=[C:38]([C:40]([F:41])([F:43])[F:42])[N:39]=3)=[CH:26][N:27]=2)[C:22](=[O:50])[C:21]([C:51]([OH:53])=[O:52])=[CH:20]1)[CH2:15][CH:16]([CH3:17])[CH3:18])([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCC)cn3[C@H](COP(=O)(O)OCc2ccccc2)CC(C)C)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)O)cn3[C@H](COP(=O)(O)OCc2ccccc2)CC(C)C)cn1
Temperature: 62.5 °C
Yield: 37.8 %

Procedure:
To a stirred suspension of ethyl 1-[(2S)-1-{[(benzyloxy)(hydroxy)phosphoryl]oxy}-4-methylpentan-2-yl]-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Example 23, 330 mg, 0.41 mmol) in ethanol (20 mL) was added 10% potassium hydroxide (69 mg, 1.23 mmol). The reaction mixture was heated to 60-65° C. overnight. The reaction mixture was cooled and then washed with ethyl acetate (20 mL). The pH of the aqueous layer was adjusted to 4 with dilute hydrochloric acid (2N) solution to give a solid precipitate which was filtered and dried to afford 120 mg (30%) of 1-[(2S)-1-{[(benzyloxy)(hydroxy)phosphoryl]oxy}-4-methylpentan-2-yl]-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:8][C:7]=1[CH3:32]>O>[CH3:13][O:12][C:10]1[C:9]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)=[CH:8][C:7]([CH3:32])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:33])=[O:2]
Reactant: COC(=O)COc1cc(OC)c(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1C
Solvent: O
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 4A. mp 170-171° C.; 400 MHz 1H NMR (DMSO-d6) δ 7.81 (d, 2H, J=8 Hz), 7.60 (d, 2H, J=8.4 Hz), 7.32 (d, 2H, J=8.4 Hz), 7.02 (s, 1H), 6.52 (s, 1H), 4.70 (s, 2H), 4.03 (s, 2H), 3.73 (s, 3H), 2.00 (s, 3H). MS m/z 463 (M+1). Anal. Calc'd for C24H21F3NO4S.0.1 H2O C, 62.09; H, 4.60. found: C, 62.00; H, 4.36.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:15][CH2:16][CH:17]([O:22][S:23]([O-:26])(=[O:25])=[O:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH3:14].[Na+:27].[CH3:28]CCCCCCCCC1C=CC(OCCO)=CC=1>C(Cl)Cl>[CH3:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:15][CH2:16][CH:17]([O:22][S:23]([O-:26])(=[O:25])=[O:24])[CH2:18][CH:19]([CH3:20])[CH3:21])[CH2:13][CH3:14].[Na+:27].[S:23]([O-:26])(=[O:24])(=[O:22])[CH3:28]
Reactant: CCCCCCCCCc1ccc(OCCO)cc1
Agent: CCCCC(CC)CCC(CC(C)C)OS(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)[O-]
Reaction time: 0.17 h

Procedure:
The Tergitol-mesylate was synthesized as depicted in Reaction Scheme 3 and FIG. 1. In step S1, 4.86 g (48 mmol) of triethylamine (Aldrich) was added to a solution of Tergitol®NP-9 (16 mmol, Aldrich) in anhydrous methylene chloride (20 ml) in a reactor. The mixture was stirred under a nitrogen atmosphere for 10 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH:18]([OH:35])[C:19](=[O:34])[NH:20][CH2:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:13]([O:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:17][CH:18]([O:35][S:49]([C:46]1[CH:47]=[CH:48][C:43]([CH3:53])=[CH:44][CH:45]=1)(=[O:51])=[O:50])[C:19](=[O:34])[NH:20][CH2:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])([CH3:14])([CH3:16])[CH3:15]
Reactant: COc1cc(OC)c(CNC(=O)C(O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(OC)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(CNC(=O)C(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OS(=O)(=O)c2ccc(C)cc2)c(OC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a stirred solution of 10 (0.546 g, 1.09 mmol) in CH2Cl2 (10 mL) cooled with ice bath (0° C.) was added Et3N (0.76 mL, 5.45 mmol), p-toluenesulfonyl chloride (TsCl, 0.416 g, 2.18 mmol) and catalytic amount 4-dimethylaminopyridine (DMAP, 0.11 mmol, 0.013 g). After maintaining at 0° C. for 15 min., the ice bath was removed, the reaction kept at r.t. overnight and then submitted to standard workup with CH2Cl2. The crude product was purified by FC (EtOAc/Hexanes, 40/60 to 50/50, V/V) to provide a pale white solid 11 (0.68 g, 96%). HPLC of 11: isomer one: 50%, Rt=12.53 min; isomer two: 50%, Rt=18.72 min; [column: Lux 3u Cellulose-1 (150×4.6 mm), UV detector, 210 nm, 5% 2-propanol in hexanes; flow rate: 1.0 mL/min]. 1HNMR (200 MHz, CD2Cl2) δ 7.72 (d, 2H, J=8.2 Hz), 7.28 (d, 2H, J=8.2 Hz), 6.79 (d, 1H, J=20.6 Hz), 6.15 (s, 2H), 5.14 (br s, 1H), 4.83 (t, 1H, J=6.8 Hz), 4.50-3.94 (m, 3H), 3.82 (s, 6H), 3.81 (s, 3H), 2.41 (s, 3H), 2.28-2.11 (m, 2H), 1.43 (s, 9H), 1.42 (s, 9H). 13C NMR (50 MHz, CD2Cl2) δ 171.0, 167.3, 161.8, 159.9, 155.8, 146.3, 133.3, 130.6, 128.5, 128.4, 106.6, 106.4, 91.3, 82.8, 82.5, 80.2, 78.0, 77.7, 56.4, 56.0, 35.7, 35.3, 32.9, 28.7, 28.3, 22.0. HRMS calcd for C31H45N2O11S (M+H)4: 653.2744. found: 653.2734, 653.2739.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH2:33][CH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][C:38](=[O:44])[NH:39]2.[Cl:45][C:46]1[CH:47]=[C:48](O)[CH:49]=[N:50][CH:51]=1>O1CCCC1>[Cl:45][C:46]1[CH:47]=[C:48]([O:32][CH2:33][CH2:34][C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH2:37][C:38](=[O:44])[NH:39]3)[CH:49]=[N:50][CH:51]=1
Reactant: Oc1cncc(Cl)c1
Reactant: O=C1Cc2c(CCO)cccc2N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1Cc2c(CCOc3cncc(Cl)c3)cccc2N1
Reaction time: 0.25 h
Yield: 36.4 %

Procedure:
Diethyl azodicarboxylate (1.74 g, 10 mmol) was added to a solution of triphenylphosphine (2.62 g, 10 mmol) in tetrahydrofuran (20 mL) under nitrogen atmosphere. The mixture was stirred for 15 minutes. To it was then added 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (1.77 g, 10 mmol) followed by 5-chloro-3-pyridinol (1.29 g, 10 mmol). The mixture was stirred at room temperature for 2 days. The precipitate was collected by vacuum filtration, washed with ethyl acetate and dried to give 1.05 g (36%) of 4-[2-(5-chloro-pyridin-3-yloxy)-ethyl]-1,3-dihydro-indol-2-one as a light brown solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:26])[CH:10]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]=2[O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>CN(C=O)C>[CH2:34]([O:26][C:9]1[CH:10]=[C:11]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:12]([O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCI
Reactant: COCCOCOc1c(-c2ccccc2)cc(O)cc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cc(-c2ccccc2)c(OCOCCOC)c(-c2ccccc2)c1
Temperature: 63 °C
Reaction time: 20 h
Yield: 67.7 %

Procedure:
To a stirred solution of 3,5-diphenyl-4-[(2-methoxyethoxy)methoxy]-phenol (0.946 g, 2.7 mmol) in DMF (15 ml) was added K2CO3 (0.746 g, 5.4 mmol) and iododecane (1.632 g, 5.4 mmol). The reaction mixture was warmed to ˜63° C. After ˜20 h, additional K2CO3 (0.373 g, 2.7 mmol) and iododecane (0.816 g, 2.7 mmol) were added. Heating was continued for an additional 20 h followed by stirring at room temperature for ˜20 h. The reaction mixture was concentrated in vac and the residue taken up in EtOAc (50 ml) and water (20 ml). The layers were shaken and separated and the organic layer was washed with water (3×10 ml), brine (2×10 ml), dried over Na2SO4, filtered and the filtrate concentrated in vac and dried. The residue was purified by flash chromatography (hexane and 5% EtOAc/Hex) to give the product as a brown oil (0.897 g, 68%); 1H NMR (400 MHz, DMSO-d6) δ 0.83–0.88 (m, 3H), 1.20–1.37 (m, 12H), 1.37–1.46 (m, 2H), 1.68–1.76 (m, 2H), 2.71–2.75 (m, 2H), 2.86–2.88 (m, 2H), 3.01 (s, 3H), 4.03 (t, J=6.4 Hz, 2H), 4.22 (s, 2H), 6.87 (s, 2H), 7.34–7.39 (m, 2H), 7.42–7.48 (m, 4H), 7.56–7.60 (m, 4H); IR (film) 2940, 1590, 1460, 1190 cm−1; mass spectrum [(+)ESI], m/z 508 (M+NH4)−.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Br:20][C:21]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.[C:44]([O:48][C:49](=[O:60])[NH:50][CH2:51][C:52](=[O:59])[N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([O:48][C:49](=[O:60])[NH:50][CH2:51][C:52]([N:53]1[CH2:54][CH2:55][N:56]([C:23](=[O:25])[C:22]2[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:21]=2[Br:20])[CH2:57][CH2:58]1)=[O:59])([CH3:47])([CH3:45])[CH3:46]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)c1
Temperature: 10 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
HOBt (125 mg, 0.93 mmol) and DIPEA (287 mg, 2.2 mmol) were added to a stirred solution of 2-bromo-5-methoxy-benzoic acid (171 mg, 0.74 mmol) in DMF (2.5 mL). The mixture was then cooled to 10° C. and EDCI.HCl (178 mg, 0.93 mmol) followed by (2-oxo-2-piperazin-1-yl-ethyl)-carbamic acid tert-butyl ester (200 mg, 0.82 mmol) were added. The reaction mixture was then stirred at room temperature overnight. Water was added, and the product was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification using column chromatography (silica gel (60-120 mesh) and 50% ethyl acetate in hexane as the eluent) afforded {2-[4-(2-Bromo-5-methoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester in 97% yield. LC-MS purity: 97.79%
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[C:11]([C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)#[N:12]>C([O-])(O)=O.[Na+].C(OCC)C.O>[C:11]([C:13]1[CH:14]=[C:15]([S:19]([O:5][C:4]2[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)#[N:12]
Reactant: Cc1cc(O)cc(O)c1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 3-cyanobenzenesulfonyl chloride (2.02 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (2.40 g, 83%). 1H-NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.68 (t, J=7.9 Hz, 1H), 6.56 (s, 1H), 6.36 (s, 1H), 6.30 (s, 1H), 5.35 (s, 1H), 2.22 (s, 3H).
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[NH:31][C:30]4=[O:38])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][N:10]=1)=O)(C)(C)C.[ClH:39]>C(OCC)(=O)C>[ClH:39].[ClH:39].[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[NH:31][C:30]4=[O:38])[CH2:25][CH2:24]3)[CH2:21][CH2:22]2)=[O:16])=[CH:13][N:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)N2CCC(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)CC2)cn1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ncc(C(=O)N2CCC(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)CC2)cn1
Temperature: -50 °C

Procedure:
The 1,3-dihydro-1-{1-[1-(2-tert-butoxycarbonylamino-5-pyrimidinylcarbonyl)piperidin-4-yl]piperidin-4-yl}-2H-benzimidazol-2-one was dissolved in ethyl acetate, cooled to -50° C. and treated with a stream of HCl gas for 2 min. The reaction mixture was allowed to warm to room temperature and stir for several hours, and then concentrated to dryness under reduced pressure. The product 1,3-dihydro-1-{1-[1-(2-amino-5-pyrimidinecarbonyl)piperidin-4-yl]piperidin-4-yl}-2H-benzimidazol-2-one dihydrochloride salt, was obtained as white solid: Analysis calculated for C22H25N7O2.2 HCl.1.0 C7H8.3.0 H2O: C: 54.38, H: 6.77, N: 15.31; found C: 54.31, H: 6.48, N: 15.23.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@@H:12]1[CH2:19][C@H:15]2[O:16][CH2:17][CH2:18][C@@:14]2([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=2[OH:34])=[O:21])[CH2:13]1.C=O.O.[C:38]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:27]=[CH:26][C:25]2[O:34][CH2:38][N:22]([C:20]([C@:14]34[CH2:13][C@H:12]([N:3]5[C:4](=[O:11])[C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[C:2]5=[O:1])[CH2:19][C@H:15]3[O:16][CH2:17][CH2:18]4)=[O:21])[CH2:23][C:24]=2[CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H]2OCC[C@@]2(C(=O)NCc2cc(C(F)(F)F)ccc2O)C1
Agent: C=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)C1
Temperature: 25 °C

Procedure:
A solution of the product of Step C (7.97 g, 15.5 mmol, 1 eq), paraformaldehyde (9.28 g, 310 mmol, 20 eq) and p-toluenesulfonic acid hydrate (2.94 g, 15.5 mmol, 1 eq) in toluene (300 mL) was heated to 130° C. for 18 hours in a flask equipped with a Dean-Stark trap. The solution was cooled to rt and concentrated. Purification by chromatography (200 g column) eluting with 25 to 60 to 100% ethyl acetate/heptane afforded the product of Step D. Calculated for C25H21F3N2O5: 487.1 (M+1). found: 487.2.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[Na:12].C1C(=O)[N:17](OC(ON2C(=O)CCC2=O)=O)[C:15](=[O:16])C1.C(OCC)(=O)C>CS(C)=O>[S:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:15]([NH2:17])=[O:16])=[CH:7][CH:8]=1)([OH:11])(=[O:10])=[O:2].[Na:12]
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: NC(=O)Nc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 115 %

Procedure:
A solution of sodium sulfanilic acid (195 mg; 1 mmol) in dry DMSO (3 ml) was added dropwise to a solution of N,N′-disuccinimidyl carbonate (530 mg; 2 mmol) in dry DMSO (4 ml) and the resulting brownish solution stirred at room temperature for 20 hours. A solution of PAMAM 4.0 (EDA) (75 mg; 0.011 mmol) in dry DMSO (1 ml) added and the solution stirred for a further 18 hours. The solution was then concentrated under high vacuum (10−5 mmHg; 35°) to give a yellowish semi-solid. The crude product was dissolved in DMSO (4 ml) and the solution added to 200 ml of well stirred ethyl acetate. The precipitated white solid was collected by filtration and washed with ethyl acetate (2×) and ether (2×), then dried to give a white powder (275 mg). This material was further purified by gel filtration (Sephadex LH20; water) to give PAMAM 4.0 (EDA) terminated with 32 sodium 4-sulfophenylurea groups (106 mg). 1H nmr (D2O): δ 2.31; 2.55; 2.75; 3.19; 7.32 (d, J=9 Hz); 7.63 (d, J=9 Hz). 13C nmr (D2O): δ 36.3; 40.7; 43.3; 43.8; 53.7; 55.7; 123.3; 130.9; 140.9; 146.0; 161.4; 178.2; 178.6.
Reaction SMILES: O[CH:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH:6]2[C:9]([O:11][CH3:12])=[O:10])[CH2:3]1.[C:13]([O:17][C:18]([NH:20][C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:13]([O:17][C:18]([N:20]([CH:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH:6]2[C:9]([O:11][CH3:12])=[O:10])[CH2:3]1)[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)C(=O)NC(=O)OC(C)(C)C
Reactant: COC(=O)C1CC2CC(O)C1C2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)N(C(=O)OC(C)(C)C)C1CC2CC(C(=O)OC)C1C2
Temperature: 85 °C

Procedure:
To a cold (0° C.) solution of methyl 6-hydroxynorbornane-2-carboxylate, 72e, (3.2 g, 18.8 mmol) in THF (150 mL) was added ethyl 2-(tert-butoxycarbonylamino)-2-oxo-acetate (4.9 g, 22.6 mmol) and triphenylphosphine (5.9 g, 22.6 mmol) followed by dropwise addition of diisopropyl azodicarboxylate (4.5 g, 22.6 mmol). The reaction was then heated to 85° C. and maintained at that temperature for 2 days. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel chromatography (0-100% EtOAc/hexanes gradient) to provide 6 g of methyl 6-(N-(tert-butoxycarbonyl)-2-ethoxy-2-oxoacetamido)bicyclo[2.2.1]heptane-2-carboxylate: LCMS 392.34 (M+Na+); 1H NMR (300 MHz, CDCl3) δ 4.26 (q, J=7.2 Hz, 2H), 4.08 (dt, J=14.3, 7.2 Hz, 1H), 3.62 (d, J=2.1 Hz, 3H), 2.72 (s, 1H), 2.42-2.26 (m, 2H), 2.08-1.80 (m, 2H), 1.80-1.51 (m, 3H), 1.45 (s, 9H), 1.38-1.25 (m, 3H).
Reaction SMILES: O[CH:2]1[CH2:6][C:5]2=[C:7]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:4]2[O:3]1.O>P(=O)(O)(O)O>[N+:11]([C:10]1[CH:9]=[CH:8][C:7]([C:14]([O:16][CH3:17])=[O:15])=[C:5]2[C:4]=1[O:3][CH:2]=[CH:6]2)([O-:13])=[O:12]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c2c1CC(O)O2
Agent: O=P(O)(O)O
Solvent: O
Product: COC(=O)c1ccc([N+](=O)[O-])c2occc12
Reaction time: 0.17 h
Yield: 33.9 %

Procedure:
Methyl 2-hydroxy-7-nitro-2,3-dihydrobenzofuran-4-carboxylate 1e (2 g, 8.40 mmol) was suspended in 250 mL of 85% phosphoric acid, stirred for 10 minutes, puted into a 100° C. oil bath and stirred for another 20 minutes. The resulting reaction mixture was added with 50 mL of water, extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated sodium carbonate solution (50 mL×3) and saturated sodium chloride solution (50 mL×3) successively, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 7-nitrobenzofuran-4-carboxylate 1f (0.63 g, yield: 34.0%) as a light yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)[C:20](=[O:32])[NH:19]2)=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[CH3:31][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[CH3:30])[CH2:23][N:21]1[CH2:22][CH:18]([CH2:17][CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:33])=[O:3])=[CH:14][CH:13]=2)[NH:19][C:20]1=[O:32]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(C)c(C)c3)C(=O)N2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(CN2CC(CCOc3ccc(OC(C)(C)C(=O)O)cc3)NC2=O)cc1C
Yield: 72.4 %

Procedure:
A solution of 2-(4-{2-[1-(3,4-dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (0.087 g, 0.191 mmol) in ethanol (8 mL) was treated with aqueous 5 N NaOH (0.4 mL) and heated to reflux 1.5 h. The reaction mixture was cooled, the solvent removed in vacuo. The resultant residue was acidified with aqueous 1 N HCl (5 mL) and extracted with Et2O. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford 0.059 g (72%) 2-(4-{2-[1-(3,4-dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid. HRMS (ES+) m/z exact mass calcd for C24H31N2O5 [M+1] 427.2233, found 427.2232. 1H NMR.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=O)=[O:4].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[CH2:36][NH2:37])=[O:29])([CH3:26])([CH3:25])[CH3:24]>CO>[CH3:1][O:2][C:3]([C:5]1[N:37]([CH2:36][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][N:30]2[C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[C:7](=[O:6])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: COC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1CC1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 7.7 %

Procedure:
To a solution of 6-bromo-4-phenyl-3-isocoumarincarboxylic acid methyl ester (539 mg) in methanol (10 ml) was added 2-aminomethylpiperidine-1-carboxylic acid tert-butyl ester (1.07 g), and the mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, and 4N hydrogen chloride-ethyl acetate solution (5 ml) was added to the obtained residue. The mixture was stirred at room temperature for 10 hrs. The solvent was evaporated under reduced pressure, and 1N aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (10 ml) and di-tert-butyl carbonate (437 mg) were added. The mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure, and the obtained residue was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=9/1→4/1) to give the title compound (64 mg, 12%).
Reaction SMILES: [OH:1][CH:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][CH2:4][CH2:5][N:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:7]([NH2:9])=[O:8].[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(OCC)C>[C:24]([O:1][CH:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][CH2:4][CH2:5][N:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:7]([NH2:9])=[O:8])(=[O:26])[CH3:25]
Reactant: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(N)=O
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CCCCCC(CCCN(CCCCCCC(=O)O)C(N)=O)OC(C)=O
Temperature: 60 °C

Procedure:
A mixture of 7-[1-(4hydroxynonyl)ureido]heptanoic acid (9.9 g., 0.03 mole) (Example 1, Step C) and acetic anhydride (6.1 g., 0.06 mole) is heated at 60° C. for 18 hours. The mixture is cooled and taken up in 80 ml. of ethyl ether. The solution is extracted with an ice-cold solution of 8 g. of sodium hydroxide in 150 ml. of water. The basis solution is separated and acidified with concentrated hydrochloric acid. The oil that separates is extracted into ether, washed with water and dried over sodium sulfate. The ether is evaporated and the residual oil is purified by chromatography on silica gel using 2% methanol in chloroform as the eluting solvent. Thus there is obtained 7-[1-(4-acetoxynonyl)ureido] heptanoic acid as a yellow oil.