Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][N:15]([CH2:39][CH2:38][CH2:37][CH:36]=[CH2:35])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCCCBr
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43 %

Procedure:
To a mixture of methyl 2(S)-(tert-butoxycarbonylamino)-3-(2-nitrophenylsulfonamido)propanoate iii (150 mg, 0.37 mmol) in 3 mL of DMF was added potassium carbonate (102 mg, 0.74 mmol.). This mixture was stirred at rt for 20 min followed by the addition of 5-bromo-1-pentene (65 □L, 0.55 mmol.). The reaction mixture was stirred at rt for 2 days. It was then filtered, concentrated and purified by silica gel chromatography (eluting with 25% ethyl acetate in hexane) to give 75 mg (43%) of methyl 2(S)-(tert-butoxycarbonylamino)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoate iv as a yellow solid. 1H NMR (CD3OD, 300 MHz) δ 1.42 (s, 9H), 1.54-1.64 (m, 2H), 1.97 (q, J=7.20 Hz, 2H), 3.37 (m, 2H), 3.57-3.80 (m, 2H), 3.72 (s, 3H), 4.42 (dd, J=8.60, 5.31 Hz, 1H), 4.91-5.01 (m, 2H), 5.69-5.79 (m, 1H), 7.75-7.85 (m, 3H), 8.04 (m, 1H); MS m/z 372 (M++1-Boc).
Reaction SMILES: [CH:1]([Sn](CCCC)(CCCC)CCCC)=[CH2:2].[O:16]([CH2:23][C:24]([NH:26][CH:27]1[C:55](=[O:56])[N:29]2[C:30]([C:39]([O:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])=[C:31](OS(F)(=O)=O)[CH2:32][S:33][C@H:28]12)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN1CCCC1=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:16]([CH2:23][C:24]([NH:26][CH:27]1[C:55](=[O:56])[N:29]2[C:30]([C:39]([O:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])=[C:31]([CH:1]=[CH2:2])[CH2:32][S:33][C@H:28]12)=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(=O)(=O)F)CS[C@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 0.05 h
Yield: 88.8 %

Procedure:
A solution of palladium (II) acetate (3.6 mg, 0.016 mmol, 0.1 eq.) in 1-methyl-2-pyrrolidinone (2 mL) was treated with vinyl tri-n-butylstannane (58.4 mL, 0.2 mmol, 1.2 eq.) under an inert atmosphere and allowed to stir for 3 minutes. The resulting dark suspension was then treated with diphenylmethyl 7-phenoxyacetamido-3-[(fluorosulfonyl)oxy] -3-cephem-4-carboxylate (100.0 mg, 0.16 mmol, 1.0 eq.) in one portion and the reaction mixture was allowed to stir for 10 minutes. The reaction mixture was diluted with ethyl acetate and washed with 3×20 mL of water. The organic fraction was dried over magnesium sulfate then concentrated. The crude brown residue was purified by flash filtration through a pad of silica gel (W. R. Grace, 951W) first with dichloromethane (50 mL) to remove the residual stannane and then with 10% ethyl acetate in dichloromethane (75 mL), which upon concentration furnished 74.8 mg (85%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](=[O:22])[CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[B-].[Na+]>CO.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([OH:22])[CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCN(CC)CCC(=O)c1ccc(C2CCCCC2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [B-]
Agent: [Na+]
Solvent: CO
Product: CCN(CC)CCC(O)c1ccc(C2CCCCC2)c(Cl)c1
Reaction time: 12 h
Yield: 69.4 %

Procedure:
116 g of the product of step (a) were suspended in a mixture of 1 liter of methanol and 60 ml of 40% sodium carbonate. 40 g of sodium borohydrate were then added slowly to this suspension, maintaining the temperature below 8° C. After all of the sodium borohydrate had been added, the mixture was left for 12 hours at ambient temperature, after which 1.5 liters of 5% soda solution were added and the mixture was extracted with 700 ml of isopropyl ether. The organic phase was washed with water, dried over sodium sulphate and then evaporated to dryness. 81 g (yield 77% of theory) of 3-chloro-4-cyclohexyl-1-(3-diethylamino-1-hydroxy-propyl)-benzene were obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH:14]=O)[C:7](=[O:16])[CH:6]=[N:5]2.[NH2:17][CH2:18][C@@H:19]1[CH2:23][N:22]([C:24]2[CH:25]=[CH:26][C:27]3[O:28][CH2:29][C:30](=[O:34])[NH:31][C:32]=3[N:33]=2)[C:21](=[O:35])[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][NH:17][CH2:18][C@@H:19]1[CH2:23][N:22]([C:24]3[CH:25]=[CH:26][C:27]4[O:28][CH2:29][C:30](=[O:34])[NH:31][C:32]=4[N:33]=3)[C:21](=[O:35])[CH2:20]1)[C:7](=[O:16])[CH:6]=[N:5]2
Reactant: NC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reactant: O=CCCn1c(=O)cnc2cc(F)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1COc2ccc(N3C[C@@H](CNCCCn4c(=O)cnc5cc(F)ccc54)CC3=O)nc2N1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 3-(6-fluoro-2-oxoquinoxalin-1(2H)-yl)propanal (0.1 g, 0.45 mmol), 6-[(4R)-4-(aminomethyl)-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Examples 54, 0.11 g, 0.45 mmol) DMF (3 ml) and molecular sieve (4 A, 0.1 g) was stirred at room temperature for 20 minutes. The reaction mixture was cooled on ice and sodium triacetoxyborohydride (0.12 g, 0.54 mmol) was gradually added thereto. Then, the mixture was stirred at room temperature for 4 hours, a sodium hydrogen carbonate aqueous solution was added thereto and the mixture was extracted with ethyl acetate. The obtained crude product was purified by thin layer chromatography (dichloromethane/methanol) to yield the title compound. 8 mg (2%).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([Cl:21])[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[C:7]=2[O:6]1)=[N+]=[N-]>[Pt]>[Cl:21][C:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[C:7]2[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=2[CH:10]=1
Reactant: Cc1cccc(-c2cc(Cl)cc3c2OC(CN=[N+]=[N-])C3)c1
Agent: [Pt]
Product: Cc1cccc(-c2cc(Cl)cc3c2OC(CN)C3)c1
Yield: 58.8 %

Procedure:
Treatment of (±)-2-(azidomethyl)-5-chloro-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran (0.26 g, 0.87 mmol) with sulfided platinum on carbon (85 mg, 5 wt. %) generally according to the procedure described for Example 1 afforded 0.14 g (59%) of (±)-1-[5-chloro-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 268-271° C.; Anal. calcd. for C16H16ClNOHCl: C, 61.95; H, 5.52; N, 4.52. Found: C, 61.01; H, 5.44; N, 4.35.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[N:15]2[CH2:16][CH2:17][CH:18]([C:19]([O:21]CC)=[O:20])[C:14]2=[C:13]([C:24]([O:26]CC)=[O:25])[C:12]=1[CH3:29])=[O:10].[OH-].[K+]>CO.O>[CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[N:15]2[CH2:16][CH2:17][CH:18]([C:19]([OH:21])=[O:20])[C:14]2=[C:13]([C:24]([OH:26])=[O:25])[C:12]=1[CH3:29])=[O:10]
Reactant: CCOC(=O)c1c(C)c(C(=O)c2ccc(SC)n2C)n2c1C(C(=O)OCC)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1ccc(C(=O)c2c(C)c(C(=O)O)c3n2CCC3C(=O)O)n1C
Yield: 97 %

Procedure:
Diethyl 5-(1-methyl-5-methylthio-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate (25 g) in 200 ml methanol, 50 ml H2O and 25 g KOH were heated to reflux for 8 hours. The resulting mixture was treated with 200 ml of std. NaCl and distilled to remove the methanol. The mixture was acidified with 6N HCl while stirring and then cooled. The crystalline mass obtained was separated by filtration, air dried and recrystallized from ethylacetate-ethanol to yield 21 g of 5-(1-methyl-5 -methylthio-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo-[1,2-a]-pyrrole-1,7-dicarboxylic acid, m.p. 212°-3° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH2:37][CH3:38]>C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:30][CH2:31][CH:32]4[CH2:36][CH2:35][CH2:34][N:33]4[CH2:37][CH3:38])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCN1CCCC1CN
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCN1CCCC1CNS(=O)(=O)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Temperature: 0 °C
Yield: 39.3 %

Procedure:
4-(7-Chloro-4-quinolinylamino)benzenesulphonyl chloride hydrochloride (23.4 g, 0.06 mol) was added portionwise to a well stirred mixture of aqueous sodium carbonate (60 g in 600 ml water) and 2-aminomethyl-1 ethyl pyrrolidine (7.8 g, 0.06 mol) in chloroform (600 ml) at about 10° C. The ice bath used for cooling was removed and, after 11/2 hours, the mixture was filtered. The chloroform layer was separated and dried (MgSO4). Concentration under reduced pressure caused precipitation of a solid, which was collected by filtration and dried. Recrystallisation from ethanol gave the title compound (10.5 g), melting point 200°-201.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[O:18][CH2:19][CH2:20][O:21][CH2:22][C:23]([F:26])([F:25])[F:24].C[Si](C)(C)[O:29][C@@H:30]1[C@@H:35]([O:36][Si](C)(C)C)[C@H:34]([O:41][Si](C)(C)C)[C@@H:33]([CH2:46][O:47][Si](C)(C)C)[O:32][C:31]1=O.[Li]CCCC>C1COCC1>[Cl:17][C:5]1[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:2]([C@H:31]2[C@H:30]([OH:29])[C@@H:35]([OH:36])[C@H:34]([OH:41])[C@@H:33]([CH2:46][OH:47])[O:32]2)=[C:3]([O:18][CH2:19][CH2:20][O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:4]=1
Reactant: CCc1ccc(Cc2cc(Br)c(OCCOCC(F)(F)F)cc2Cl)cc1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(OCCOCC(F)(F)F)cc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-bromo-4-chloro-5-(4-ethylbenzyl)-2-(2-(2,2,2-trifluoroethoxy)ethoxy)benzene (BR) (96 mg, 0.21 mmol) and (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)-tetrahydropyran-2-one (0.20 g, 0.43 mmol) in anhydrous THF (3 mL), was added n-BuLi (1.6 M, 0.40 mL) in a dropwise fashion at −78° C. over 15 min. The resulting solution was stirred at −78° C. for 30 min. After quenching with methanesulfonic acid (61 μL in 1.0 mL MeOH), the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was filtered through silica and purified by preparative TLC eluting with 7% MeOH in CH2Cl2 to collect the crude product. To a solution of the crude product in a mixture of 1:1 CH3CN:CH2Cl2 (4 mL) was added Et3SiH (200 μL), followed by cooling to −40° C. To the cooled mixture was added BF3.Et2O (40 μL), and it was allowed to warm to 0° C. over 2 h. Triethylamine (100 μL) was then added, the mixture was evaporated, and the residue was purified by preparative HPLC to give compound BS. 1H-NMR (CD3OD, 300 MHz) δ 7.32 (s, 1H), 7.04 (m, 5H), 4.59 (d, J=9.3 Hz, 1H), 416-3.96 (m, 8H), 3.66-3.30 (m, 7H), 2.57 (q, J=7.5, 2H), 1.19 (t, J=7.2 Hz, 3H); MS ESI m/z 532.8 (M−1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14]([OH:16])=O)=[CH:10][CH:9]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl.CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:16])=[CH:17][CH:18]=1
Reactant: O=C(O)COc1ccc(Br)cc1
Reactant: C1CCNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(COc1ccc(Br)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.5 mL, 5.9 mmol) was added to a suspension of (4-bromophenoxy)acetic acid (0.462 g, 2.0 mmol) in methylene chloride (10 mL) and 2 drops of N,N-dimethylformamide. The mixture was stirred at RT for 2 h. The solvent was evaporated under reduced pressure. The residue was diluted with methylene chloride (10 mL), cooled with ice-water bath, and 1M of sodium hydroxide aqueous solution (3.0 mL) was added. To the mixture was added pyrrolidine (167 μL, 2.0 mmol). The mixture was stirred and allowed to warm to RT. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was directly used in next step without further purification (550 mg, 96.7%). LCMS: (M+H)=286.0/284.0
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[C:11](=[O:13])[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=2[S:6][C:5]=1[C:17]([O:19]CC)=[O:18])[CH:2]=[CH2:3].[OH-].[K+]>C(O)C>[CH2:1]([C:4]1[C:12]2[C:11](=[O:13])[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=2[S:6][C:5]=1[C:17]([OH:19])=[O:18])[CH:2]=[CH2:3]
Reactant: C=CCc1c(C(=O)OCC)sc2c1c(=O)n(C)c(=O)n2C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCc1c(C(=O)O)sc2c1c(=O)n(C)c(=O)n2C

Procedure:
To a stirred solution of Step 6 intermediate (4.6 g, 14.93 mmol) in ethanol (50 ml) was added 1.25 M aqueous KOH (15.5 ml) and mixture was refluxed for 2 h. The solvent was concentrated under reduced pressure and acidified with 1 N HCl. The solid separated out was filtered and dried to give 3.50 g of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 3.42 (s, 3H), 3.56 (s, 3H), 4.24 (d, J=6.0 Hz, 2H), 5.01-5.18 (m, 2H), 5.95-6.05 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH3:11])=[O:9])[CH:3]=1.[Li+].[CH3:13]C([N-]C(C)C)C.CI>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH3:11])=[O:9])[C:3]=1[CH3:13]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CNC(=O)c1nccc(Cl)c1C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 9.2 %

Procedure:
To a solution of 4-chloro-N-methylpyridine-2-carboxamide (0.700 g, 4.12 mmol) in THF was added LDA (4.12 mL, 2M in THF, 8.24 mmol) dropwise at −78° C. under an atmosphere of argon. The mixture was allowed to stir for 90 min at −78° C. and then methyl iodide (1.51 mL, 24.71 mmol) was added. After stirring for 90 min, the solution was allowed to warm to 0° C. The reaction was quenched at 0° C. with sat. sodium hydrogen sulfite and extracted with EtOAc. The combined organic solutions were washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give the desired product (0.070 g, 23%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32]>>[CH2:27]([O:26][C:20]1[CH:19]=[C:18]([C@H:12]([N:8]2[C:9](=[O:11])[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][C:31](=[O:32])[N:30]([CH3:34])[CH3:29])[CH2:7]2)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25])[CH3:28]
Reactant: CN(C)C(=O)Cl
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(NC(=O)N(C)C)c3C2=O)ccc1OC
Yield: 49.1 %

Procedure:
A mixture of (1S)-7-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-2,3-dihydro-isoindol-1-one (0.5 g, 1.2 mmol) and dimethylcarbamyl chloride (0.6 mL, 6.5 mmol) was heated to reflux for 2 hours. The solvent was removed in vacuo. The residue was extracted with methylene chloride (50 mL) and sodium hydrogen carbonate (sat, 50 mL). The organic layer was washed with brine (50 mL) and dried over MgSO4. The solvent was removed in vacuo, and the residue was purified with prep HPLC to give (1S)-3-(2-[1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3,dihydro-1H-isoindol-4-yl}-1,1-dimethyl-urea as a white solid (280 mg, 48% yield): mp 170-172° C.; 1H NMR (CDCl3) δ 1.44 (t, J=7 Hz, 3H, CH3), 2.91 (s, 3H, CH3), 3.11 (s, 6H, 2 CH3), 3.70 (dd, J=5, 15Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.08 (q, J=7 Hz, 2H, CH2), 4.16-4.25 (m, 2H, CHH, NCHH), 4.41 (d, J=17Hz, 1H, NCHH), 5.69 (dd, J=5, 10 Hz, 1H, NCH), 6.83-6.95 (m, 4H, Ar), 7.43 (t, J=8 Hz, 1H, Ar), 8.33 (d, J=8Hz, 1H, Ar), 9.85 (s, 1H, NH); 13C NMR(CDCl3) δ 14.71, 3.32, 41.50, 48.06, 51.89, 55.99, 56.16, 64.65, 131.62, 112.30, 115.09, 116.63, 116.77, 119.34, 129.51, 133.68, 139.67, 141.19, 148.93, 149.80, 155.31, 170.64. Analy. Calculated for C23H29N3O6S+1 H2O: C 55.97; H 6.33; N 8.51; H2O 3.65. Found: C 55.57; H 6.02; N 8.44; H2O, 2.97.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CN(Cc2ccccc2)Cc2cccc(OC)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(O)CN(Cc2ccccc2)Cc2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of 2-[benzyl-(3-methoxy-benzyl)-amino]-1-(4-methoxy-phenyl)-ethanone (13.8 g, 36.75 mmol, see Preparation 62) in MeOH (150 ml) cooled to 0° C. was added NaBH4 in five equal portions over 30 minutes. The reaction was stirred overnight while slowly warming to RT. Water (100 ml) was added to the reaction mixture, the volume was reduced by half in vacuo, and the mixture extracted with CH2Cl2 (3×100 ml). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography of the residue (SiO2, gradient elution 20%-50% EtOAc/hexanes) gave the title product (12.87 g, 34.1 mmol, 93% yield).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]([O:22]C)=[O:21])=[CH:14]1)([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[Si:1]([O:8][CH2:9][C:10]([N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]([OH:22])=[O:21])=[CH:14]1)([CH3:12])[CH3:11])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(=O)n(C(C)(C)CO[Si](C)(C)C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)O)ccc1=O
Temperature: 23 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 1-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (3600 mg, 10.6 mmol) in THF (10 mL) and MeOH (5 mL) was added NaOH (3181 μl, 31.8 mmol). The solution was stirred at 23° C. for 48 h and was partitioned between CH2Cl2 and 10% citric acid (aq. pH˜4). The aqueous was extracted with CH2Cl2 (3×50 mL). The combined organics were dried with brine and MgSO4, and concentrated to a yellow solid under reduced pressure. MS (ESI pos. ion) m/z (MH+): 326. Calc'd exact mass for C16H27NO4Si: 325.
Reaction SMILES: CS(O[C@@H:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)=O.[C:13]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:25])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[F-].[Cs+].O>CN(C=O)C>[CH:14]([C:13]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@@H:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:12]
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CCOC(=O)[C@H](C)OS(C)(=O)=O
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](C)C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 50 °C
Yield: 60 %

Procedure:
To a solution of (S)-ethyl 2-(methylsulfonyloxy)propanoate (28.4 g, 0.1 mol) in N,N′-dimethylformamide (400 mL) was added dibenzyl malonate (23.5 g, 0.12 mol) and cesium fluoride (15.2 g, 0.1 mol). The mixture was heated at 50° C. for 2 days. After cooled to room temperature, the mixture was poured into water and then extracted with ethyl acetate. The organic phases were combined, washed with brine, water and dried over anhydrous sodium sulfate, and then concentrated to afford the crude product (S)-1,1-dibenzyl 2-ethyl propane-1,1,2-tricarboxylate, which was purified by silica gel chromatography (23 g, yield 60%).
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[I:13].[CH2:14](O)[CH2:15][CH2:16][CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:14]([O:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[I:13])[CH2:15][CH2:16][CH3:17]
Reactant: O=Cc1cc(I)c(O)c([N+](=O)[O-])c1
Reactant: CCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCOc1c(I)cc(C=O)cc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 73.3 %

Procedure:
To a slurry of 4-hydroxy-3-iodo-5-nitrobenzaldehyde (3.16 g, 10.7 mmol) in THF (100 ml) was added n-butanol (1.94 ml, 21.5 mmol), triphenyl phosphine (3.10 g, 11.8 mmol) and diethylazodicarboxylate (1.85 ml, 11.8 mmol). The mixture was stirred 18 h then filtered and all volatiles removed the residue was chromatographed on silica to afford the title compound (2.74 g, 73%).). 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.54 (d, j=2.0 Hz, 1H), 8.28 (d, j=2.0 Hz, 1H), 4.18 (t, j=6.5, 2H), 1.86-1.94 (m, 2H), 1.52-1.61 (m, 2H), 1.01 (t, j=7.1 Hz, 3H). M+1=350.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:29](O)(=[O:32])[C:30]#[CH:31]>CN(C)C1C=CN=CC=1.CCOCC>[C:29]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:32])[C:30]#[CH:31]
Reactant: C#CC(=O)O
Reactant: OCCCCCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: C#CC(=O)OCCCCCCc1ccccc1
Temperature: 25 °C
Yield: 61 %

Procedure:
Under a nitrogen atmosphere at -20° C., a mixture of 1.3 g of dicyclohexylcarbodiimide, 0.051 g of 4-dimethylaminopyridine in 15 ml of dried ether is added dropwise, with stirring, to a mixture of 1 g of 6-phenylhexanol and 0.43 g of propiolic acid in 15 ml of dried ether. After the addition was over, the reaction solution was warmed to the room temperature and stirred at the room temperature for ten hours. After the reaction was completed, the reaction solution was filtered. The filtrate was washed twice with cold 1N hydrochloric acid and twice with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue was subjected to silicagel column chromatography to yield 0.788 g of 6-phenylhexyl propiolate (compound 2).