Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6]C(CO)[O:8][C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[C:52]([CH3:56])([CH3:55])[C:53]#[N:54]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH:55]([CH:52]([CH3:56])[C:53]#[N:54])[O:8][C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19]
Reactant: CC(C)(O)C#N
Reactant: OCC1Cc2ccc(Cl)c(-c3ccccc3Cl)c2O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C#N)C1Cc2ccc(Cl)c(-c3ccccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (0.5 g, 1.69 mmol) in toluene (10 mL) was added triphenylphosphine (0.66 g, 2.54 mmol), diethyl azodicarboxylate (0.44 g, 2.54 mmol), and 2-hydroxy-2-methylpropanenitrile (0.21 g, 2.53 mmol) and the reaction mixture was allowed to stir at room temperature for 48 h. The solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9-3:7) provided 0.22 g (43%) of (±)-{2-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]propanenitrile. To a solution of the nitrile in tetrahydrofuran (10 mL) was added borane-tetrahydrofuran (8 mL) and the reaction mixture was heated to reflux for 3 h. The reaction mixture was quenched with 1.0 N aqueous hydrogen chloride (100 mL) and then neutralized with 1.0 N aqueous sodium hydroxide (100 mL). The aqueous layer was extracted with ethyl acetate (2×200 mL) and the combined organic extracts were washed with saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent removed in vacuo. Purification by flash column chromatography (silica, 10% ammonium hydroxide in methanol:dichloromethane 1:9) provided 0.1 g (19%) of (±)-{2-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]ethyl}amine as a white solid, hydrochloride salt. mp 211-213° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[NH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(OCC)(=O)C>CN(C=O)C>[C:24]([O:23][C:21](=[O:22])[NH:20][C@H:16]([C:17](=[O:19])[NH:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: NCCN1CCCCC1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
A solution of 27.9 g (75 mmol) 3-(4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid, (Bachem Inc.,Torrance, Calif. 90505) 16.5 mL (150 mmol) 4-methylmorpholine, and 28.5 g (75 mmol) O-Benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate in 110 mL dry DMF was stirred in an ice-bath for 30 minutes. Next, 10.7 mL (75 mmol) of 1-(2-aminoethyl)piperidine (Aldrich, Milwaukee, Wis.) was added, and the resulting solution was warmed to 25° C. and stirred 60 minutes. The mixture was poured into 200 mL ethyl acetate, and washed sequentially with 200 mL each of 2.5% aqueous HCl solution, brine, saturated aqueous sodium bicarbonate solution, and finally twice with brine. The mixture was then dried over anhydrous sodium sulfate and concentrated at reduced pressure to give 33.7 g (94%) of (S)-[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester as a pale amber solid; mp 54-61° C.
Reaction SMILES: [CH3:1][CH2:2][NH:3][C:4]([C@H:6]1[O:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([NH:21][CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:26][CH:25]=4)[N:18]=[C:19]([NH2:20])[C:14]=3[N:13]=[CH:12]2)[C@@H:8]([OH:35])[C@H:7]1[OH:36])=[O:5].[Si](C=[N+]=[N-])(C)(C)[CH3:38].CO.O>CO.C(Cl)Cl>[CH3:38][O:33][C:32](=[O:34])[CH2:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][NH:21][C:17]2[N:16]=[C:15]3[C:14]([N:13]=[CH:12][N:11]3[CH:9]3[CH:8]([OH:35])[CH:7]([OH:36])[CH:6]([C:4](=[O:5])[NH:3][CH2:2][CH3:1])[O:10]3)=[C:19]([NH2:20])[N:18]=2)=[CH:25][CH:26]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCNC(=O)[C@H]1OC(n2cnc3c(N)nc(NCCc4ccc(CCC(=O)O)cc4)nc32)[C@@H](O)[C@H]1O
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCNC(=O)C1OC(n2cnc3c(N)nc(NCCc4ccc(CCC(=O)OC)cc4)nc32)C(O)C1O
Reaction time: 0.5 h
Yield: 66 %

Procedure:
The methyl ester, JR2171, was synthesized by dissolving approximately 10.0 mg of 3-(4-{2-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-ylamino]-ethyl}-phenyl)-propionic acid (CGS21680) in 5 mL 10% MeOH/CH2Cl2 and adding TMS Diazomethane (2.0 M solution in hexanes) dropwise until a yellow color persisted. After stirring for 30 minutes the solvent was removed under reduced pressure. The crude compound was then purified by HPLC using a C18 column and a MeOH/H2O gradient, yielding 6.7 mg of compound (66% yield). Characterization by HRMS, APCI MS, 1H NMR, and 13C NMR were consistent with the putative structure.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=O>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:1])=[CH:9][C:8]=1[O:7][CH3:6]
Reactant: COc1ccc(C=O)cc1OC
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of n-butyllithium (4 mL, 2,5 M solution in hexane, 10 mmol) (Aldrich) in ether (30 mL) was added methyltriphenylphosphonium bromide (3.57 g, 10 mmol) (Aldrich) over a period of 5 min. The reaction mixture was stirred for 4 h at room temperature. To the resulting orange solution was added 3,4-dimethoxybenzaldehyde (1.82 g, 11 mmol) (Aldrich) dropwise. The solution became colorless, and a white precipitate separated. The mixture was then heated to reflux and immediately allowed to cool to room temperature. The precipitate was removed by filtration. The precipitate was washed with ether and the combined ethereal filtrates were washed with water until neutral and then dried over anhydrous MgSO4. The solvent was removed and the residue, 1,2-dimethoxy-4-ethenyl -benzene, was used in the next reaction without further purification.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17]C)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[Cl-].[NH+]1C=CC=CC=1.C(OCC)(=O)C>CN(C=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([OH:17])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1ccnc(OC)c1)C1CC1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1ccnc(O)c1)C1CC1
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(2-methoxypyridin-4-yl)propanoate (4.17 g) in DMF (10 mL) was added pyridinium chloride (19.3 g), and the mixture was stirred at 130° C. for 15 min. Ethyl acetate was added to the reaction mixture at 0° C., and the resulting white precipitate was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (3.61 g) as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:45])[C:23]([CH3:44])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][CH:41]([CH3:43])[CH3:42])=[C:35]([CH:39]=2)[C:36](O)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:45])[C:23]([CH3:44])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][CH:41]([CH3:42])[CH3:43])=[C:35]([CH:39]=2)[C:36]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)C)c(C(=O)O)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)C)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.7 %

Procedure:
Morpholine (0.030 g, 0.348 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.100 g, 0.521 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-isopropoxybenzoic acid (0.065 g, 0.174 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:6) to obtain the titled compound (0.026 g, 0.0586 mmol, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH:14]=1)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>CC(O)=O.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:15])=[C:6]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CN1CCOCC1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(Cl)cc1CN1CCOCC1
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of 4-(5-chloro-2-nitrobenzyl)morpholine (5.1 g, 19.9 mmol) in HOAc (75 mL) is carefully added zinc dust (3.9 g, 59.6 mmol). After 2 h, the reaction is filtered through a bed of Celite and the filtrate is concentrated to remove most of the HOAc. The residue is then taken up in 2M aqueous K2CO3 and extracted with ethyl acetate. The organic layer is dried (Na2SO4) and concentrated to afford a brown oil. The crude material is partially purified by flash chromatography using a gradient of 0-5% methanol in CH2Cl2 to afford the title compound (4.0 g, 62%, 70% purity).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[CH:14]=[CH:15][NH:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=1[F:38]>CN(C=O)C.CC#N>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=3[F:38])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCc1ccccc1
Yield: 40.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 7-Benzyloxy-6-methoxy-1H-quinolin-4-one (12.2 g, 43.3 mmol, 1.0 eq.), acetonitrile (150 ml), DMF (150 ml) and cesium carbonate (28.2 g, 86.5 mmol, 2.0 eq). The mixture was stirred at room temperature for 30 minutes at which time 1,2-difluoro-4-nitro-benzene (7.57 g, 47.6 mmol, 1.1 eq) was added over a 10 minute period. After 2 hours the reaction was complete at which time 75% of the MeCN and DMF was removed and the resulting solution was poured over into ice water. The solid was filtered and dried and further columned with a biotage system. The eluent was 1:3 ethyl acetate/hexane. Removal of the solvent afforded 7-Benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline as a pale green solid (7.4 g, 41% yield). 1H NMR (400 MHz, CDCl3): 8.53 (d, 1H), 8.42 (dd, 1H), 8.16 (m, 1H), 7.5 (m, 8H), 6.76 (d, 1H), 5.31 (s, 2H), 3.92 (s, 3H); MS (EI) for C23H27FN2O5: 421 (MH+).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7](S([O-])(=O)=O)=[CH:8][C:9]([C:11](=[O:12])[C:4]2=[CH:3][CH:2]=1)=[O:10].[Na+].[CH3:18][NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O>[CH3:18][N:19]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:11](=[O:12])[C:9](=[O:10])[CH:8]=1
Reactant: O=C1C=C(S(=O)(=O)[O-])c2ccccc2C1=O
Reactant: CNC1CCCCC1
Agent: [Na+]
Solvent: O
Product: CN(C1=CC(=O)C(=O)c2ccccc21)C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 10.4 g of 1,2-naphthoquinone-4-sulfonic acid-sodium salt in 350 ml of water is stirred at room temperature for 30 minutes. To this solution is added 4.52 g of N-methylcyclohexylamine in one portion. The solution is stirred five hours at room temperature and the precipitate then filtered. The product is washed with 200 ml of water and dried at 100° C. in vacuo overnight to afford 4-(N-methylcyclohexylamino)-1,2-naphthoquinone melting at 168°-170° C. The preparation of the same compound from 4-ethoxy-1,2-naphthoquinone is reported in J. Med. Chem. 13, 97 (1970).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](C)[CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:12][O:13]C1C=C(C=C([N+]([O-])=O)C=1)C(O)=O.N>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:12])[CH:10]=1)[C:5]([NH2:7])=[O:6]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: Cc1cc(N)cc(C(N)=O)c1
Agent: N
Product: COc1cc(N)cc(C(N)=O)c1

Procedure:
Using a procedure analogous to that described for preparation of 89C, 93C was converted to an acid chloride, reacted with aqueous ammonia, and hydrogenated to give 93D. 1H NMR (400 MHz, CD3OD) δ ppm 3.76 (s, 3H) 6.45 (t, J=2.20 Hz, 1H) 6.71-6.74 (m, 1H) 6.77 (t, J=1.54 Hz, 1H); LC/MS 167 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1.Cl.[N:32]1([C:37](N)=[NH:38])C=CC=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O.CO.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:37]([NH2:38])=[NH:32])=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:29][CH:30]=1
Reactant: Cc1nn2ccc(CN)cc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn2ccc(CNC(=N)N)cc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Temperature: 25 °C
Reaction time: 23 h
Yield: 30.3 %

Procedure:
To a mixture of 1-{3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridin-5-yl}methanamine (0.0250 g, 0.0553 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (8.20 mg, 0.0559 mmol) in dry N,N-dimethylformamide (0.50 mL) was added N,N-diisopropylethylamine (7.15 mg, 0.0553 mmol). The solution was stirred at rt for 23 hours. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (5×15 mL). The EtOAc solution was washed with brine, dried over Na2SO4, filtered, and concentrated in a rotary evaporator to give a crude residue. The residue was dissolved in ˜0.2 mL of MeOH, then diluted with ˜5 mL of EtOAc. The resulting solid was collected by filtration to give a pale yellow powder product (0.008 g, 30%). LCMS: (FA) ES+ 478, 480; ES− 476, 478. 1H NMR (400 MHz, CDCl3 and d4-methanol) δ: 8.25-8.27 (d, J=7.28 Hz, 1H), 8.17 (s, 1H), 7.92 (s, 1H), 7.21-7.23 (d, J=8.53 Hz, 2H), 7.08-7.10 (d, J=8.28 Hz, 2H), 6.72-6.74 (dd, J=7.28, 1.76 Hz, 1H), 4.48 (s, 2H), 4.30 (s, 2H), 2.57 (s, 3H).
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][C:18]([O:20][C@H:21]3[CH2:25][CH2:24][O:23][CH2:22]3)=[O:19])[CH:11]=2)C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH2:40])[CH:32]=[CH:33][C:34]=1[C:35]1[O:39][CH:38]=[N:37][CH:36]=1>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:40][C:8](=[O:26])[NH:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][NH:17][C:18](=[O:19])[O:20][C@H:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[CH:32]=[CH:33][C:34]=1[C:35]1[O:39][CH:38]=[N:37][CH:36]=1
Reactant: COc1cc(N)ccc1-c1cnco1
Reactant: O=C(Nc1cccc(CNC(=O)O[C@H]2CCOC2)c1)Oc1ccccc1
Product: COc1cc(NC(=O)Nc2cccc(CNC(=O)O[C@H]3CCOC3)c2)ccc1-c1cnco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
Added 15 g of {3-[((S)-tetrahydro-furan-3-yloxycarbonylamino)-methyl]-phenyl}-carbamic acid phenyl ester 2e and 8.58 g of 3-methoxy-4-(oxazol-5-yl)benzenamine 2g into a 500 ml 3-necked flask and then purged the system with nitrogen before adding 225 ml of ethyl acetate. Next added 5.43 g of diisopropylethylamine over 1 minute, then heated at reflux for 24 hours. Once the reaction was complete, the mixture was cooled to room temperature and stirred for an additional 1 hour. Precipitated solid was filtered, washed with 45 ml of EtOAc 2 times, then dried at 58° C. for 18 hours (until a LOD is achieved of less than 1%) to give 17.46 g of crude (S)-tetrahydrofuran-3-yl 3-(3-(3-methoxy-4-(oxazol-5-yl)phenyl)ureido)benzylcarbamate 2h (90.4% yield, 98.46% a/a) as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]([CH2:4][CH2:5][P:6]([Cl:10])([CH2:8][CH3:9])=[O:7])=[O:3].[CH2:11](P(Cl)Cl)C.C(O)(=O)C=C.C(O)(=O)C(C)=C>C1C=CC=CC=1>[Cl:1][C:2]([CH:4]([CH3:11])[CH2:5][P:6]([Cl:10])([CH2:8][CH3:9])=[O:7])=[O:3]
Reactant: CCP(=O)(Cl)CCC(=O)Cl
Reactant: CCP(Cl)Cl
Agent: C=C(C)C(=O)O
Agent: C=CC(=O)O
Solvent: c1ccccc1
Product: CCP(=O)(Cl)CC(C)C(=O)Cl
Reaction time: 2.5 h
Yield: 37.2 %

Procedure:
USSR Patent Specification No. 173,763 also describes the preparation of beta-chloroformyl-ethyl ethyl phosphinic acid chloride by reacting ethyldichlorophosphine and acrylic acid in benzene at temperatures of up to 60° C., over a period of 2.5 hours, and distilling the reaction product, which is obtained in a yield of 62.4 % of the theoretical. In the absence of the benzene solvent, the temperature increases spontaneously to 150° C., and the yield falls to 31.6 % of the theoretical. The reaction of ethyldichlorophosphine with methacrylic acid, in the absence of a solvent, produces beta-chloroformyl-beta-methyl-ethyl ethyl phosphinic acid chloride in a yield of 37.2 % of the theoretical.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][S:5]([CH2:8][CH:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12]CC1C=CC=CC=1)=[O:11])(=[O:7])=[O:6]>C(O)C.[Pd]>[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][S:5]([CH2:8][CH:9]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:10]([OH:12])=[O:11])(=[O:7])=[O:6]
Reactant: CN(C)CCS(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCS(=O)(=O)CC(Cc1ccccc1)C(=O)O
Yield: 91.9 %

Procedure:
The title compound of Step 11 (150 mg, 0.4 mmol) was debenzylated in ethanol with 5 psi H2 at room temperature for 1.5 hours using 4% Pd/C catalyst. After filtering, the solvent was stripped off to give the title compound as white powder (110 mg, 70% yield). 1H NMR: 300 MHz spectrum consistent with proposed structure. Anal: calcd. for C14H21NO4S: C, 56.16; H, 7.07; N, 4.68. Found: C, 55.88; H, 6.99; N, 4.35.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[S:21]1[CH2:25][CH2:24][NH:23][C:22]1=[S:26].C1CCC(N=C=NC2CCCCC2)CC1.C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>CN(C1C=CN=CC=1)C.C1CCC(N=C=NC2CCCCC2)CC1>[C:1]([N:23]1[CH2:24][CH2:25][S:21][C:22]1=[S:26])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C/CCCCCCCC(=O)O
Reactant: S=C1NCCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCC/C=C/CCCCCCCC(=O)N1CCSC1=S
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A mixture of elaidic acid (2.0 g, 7.1 mmol), DMAP (86 mg, 0.7 mmol), 1,3-thiazolidine-2-thione (1.0 g, 8.4 mmol) and DCC (1.7 g, 8.2 mmol) in dichloromnethane (20 ml) was stirred under N2 at 0° C. for 1 hour and then at ambient temperature for another 5 hours. Additional DCC (41 mg, 0.2 mmol) was added, andthe reaction was stirred at the same temperature for 2 hours. Work up followed by flash chromatography (SiO2; carbon tetrachloride-chloroform 1:0, 1:1, 0:1) gave 2.56 g (94%) of the title compound as a yellow waxy solid.
Reaction SMILES: [ClH:1].Cl.[Cl:3]C1C=C[C:7]([C:10]2O[C:13]([CH:15]=[C:16]3[CH2:21][CH2:20][CH2:19][N:18]=[C:17]3[C:22]3[CH:23]=NC=CC=3)=[CH:12][CH:11]=2)=[C:6]([N+:28]([O-])=O)C=1.Cl.[C:32]1([CH:42]=O)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>C(O)(C)C>[ClH:3].[ClH:1].[C:32]1([CH:42]=[C:11]2[CH2:10][CH2:7][CH2:6][N:28]=[C:12]2[C:13]2[CH:15]=[C:16]3[C:17](=[CH:22][CH:23]=2)[N:18]=[CH:19][CH:20]=[CH:21]3)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: O=[N+]([O-])c1cc(Cl)ccc1-c1ccc(C=C2CCCN=C2c2cccnc2)o1
Agent: Cl
Solvent: CC(C)O
Product: C(=C1CCCN=C1c1ccc2ncccc2c1)c1cccc2ccccc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
Intermediate 15 (196 mg, 0.93 mmol) (prepared as described in Example 55) was dissolved into isopropanol (6 mL) in a reaction vessel and treated with 6 N HCl(aq) (310 μL, 1.9 mmol). 1-Naphthaldehyde (219 mg, 1.4 mmol) was added, the reaction vessel was sealed, and the reaction heated to 85° C. with stirring overnight. The reaction was cooled to room temperature, concentrated under reduced pressure, treated with saturated NaHCO3(aq), and extracted three times with EtOAc. The EtOAc extracts were washed with brine, combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The recovered material was eluted through a 20 gram column of silica gel with a 10.5:7:7:0.3:0.03 (750 mL) and 7:7:7:0.5:0.05 (300 mL) Hexane:MtBE:CH2Cl2:MeOH:NH4OH step gradient. The material recovered from this column was then further purified by preparative HPLC using the same conditions and method described for Example 47. The recovered material was dissolved into MeOH and treated with 2 eq. of 6 N HCl(aq). This solution was then concentrated under reduced pressure and the recovered material dissolved into hot isopropanol. After this solution had cooled to room temperature, ether was added until the solution became cloudy. This mixture was cooled to −20° C. Crystals did form and were recovered by vacuum filtration, washed with fresh ether, and dried under vacuum giving 31 mg (6.9%) of a brown solid. LC-MS: RT=5.45 min, [M+H]+=349.0.
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH:18]([O:21][CH3:22])OC)[N:11]=[C:10]([NH:23][CH2:24][CH2:25][CH2:26][CH:27](OC)[O:28][CH3:29])[N:9]=1>C(Cl)Cl>[CH3:29][O:28][CH:27]1[CH2:26][CH2:25][CH2:24][N:23]1[C:10]1[N:11]=[C:12]([N:14]2[CH2:15][CH2:16][CH2:17][CH:18]2[O:21][CH3:22])[N:13]=[C:8]([N:7]2[CH2:6][CH2:5][CH2:4][CH:3]2[O:2][CH3:1])[N:9]=1
Reactant: COC(CCCNc1nc(NCCCC(OC)OC)nc(NCCCC(OC)OC)n1)OC
Solvent: ClCCl
Product: COC1CCCN1c1nc(N2CCCC2OC)nc(N2CCCC2OC)n1
Reaction time: 0.08 h
Yield: 55.3 %

Procedure:
A mixture of strongly acidic AMBERLYST® 15 ion-exchange resin (6.6 g), a product of Rohm and Haas Company, Philadelphia, Pa., and methylene chloride (20 ml) in a 100 ml flask equipped with a magnetic stirrer, condenser and nitrogen inlet was stirred for 5 minutes and thereafter, the solvent was removed by decanting. A solution of the 2,4,6-tris-(4,4-dimethoxybutylamino)-1,3,5-triazine of Example 1 (6.1 g, 0.0129 mole) in methylene chloride (120 ml) was then added in one portion to the flask and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The ion exchange resin was then filtered and the volatiles removed under reduced pressure to give 2,4,6-tris-(2-methoxypyrrolidinyl)-1,3,5-triazine (2.7 g, 56% isolated yield) as a glassy solid. The structure of the product was confirmed by nuclear magnetic resonance (NMR) and mass spectroscopic (MS) analysis: 1H NMR (δ): 5.6 (m, 1H, --NCHOCH3); 3.8-3.2 (m, 5H, --OCH3 and --NCH2); 2.2-1.6 (m, 4H, --CH2 --); 13C NMR (ppm): 165, 88, 56, 46, 32, 22; MS (m/e, MH): 379.