Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:43])=[C:38]([CH:42]=1)[C:39](Cl)=[O:40])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:43])=[C:38]([C:39]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:40])[CH:42]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 5-(benzyloxy)-2-methylbenzoyl chloride (compound F2) as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]([OH:19])=O)[C:9]=2[F:20])[CH:5]=[CH:6][CH:7]=1.Cl[CH:22](Cl)C.S(Cl)(Cl)=O.C[Si](C=[N+]=[N-])(C)C.[BrH:36].C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Br:36][CH2:22][C:17](=[O:19])[CH2:16][C:10]1[C:9]([F:20])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1
Reactant: Br
Reactant: COc1ccc(CC(=O)O)c(F)c1-c1cccc(Cl)c1
Reactant: CC(Cl)Cl
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CC(=O)CBr)c(F)c1-c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Into a 20 mL vial with stir bar was added (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid (I-74, R1=Me, Y═F) (306 mg, 1.04 mmol), dichloroethane (4 mL), thionyl chloride (151 uL, 2.08 mmol) and the solution was stirred at 80° C. for 1 hour. The solution was cooled to 0° C., 4 mL of dichloromethane were added, and a solution of (trimethylsilyl)diazomethane (1.56 mL, 3.11 mmol, 2.0 M in ether) was added and the reaction stirred at room temperature for 16 hours. The reaction was cooled to 0° C. and 0.5 mL HBr (48% in H2O) was added. After 30 minutes at 0° C., Na2CO3 was added until bubbling ceased and the reaction was dried by the addition of Na2SO4. The suspension was filtered and concentrated to yield product (390 mg, 99%) as a brown oil, which was used as is.
Reaction SMILES: C[Si](C)(C)NC(N[Si](C)(C)C)=O.[C:13]1([C@@H:19]([CH2:21][OH:22])[NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:23]1(=[O:29])[O:28][C:26](=O)[CH:25]=[CH:24]1.O.C1C[O:34][CH2:33][CH2:32]1>>[C:33]([O:22][CH2:21][C@@H:19]([N:20]1[C:23](=[O:29])[CH:24]=[CH:25][C:26]1=[O:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:34])[CH3:32]
Reactant: O=C1C=CC(=O)O1
Reactant: N[C@H](CO)c1ccccc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)NC(=O)N[Si](C)(C)C
Solvent: O
Product: CC(=O)OC[C@H](c1ccccc1)N1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
1,3-Bis(trimethylsilyl)urea (0.745 g, 3.65 mM) was added to (S)-(+)-2-phenylglycinol (0.5 g, 3.65 mM) dissolved in THF (10 ml, distilled from Na/benzophenone). The mixture was refluxed for 1 hr. A precipitate formed. Maleic anhydride (0.376 g, 3.83 mM) was added and the mixture was refluxed for 0.5 hr. H2O (66 μl, 3.65 mM) was added to the cooled mixture and stirred for 30 min. to form the intermediate ##STR46## which was not recovered from the reaction mixture. Tetrabutyl-ammonium fluoride (TBAF.3H2O, 0.115 g, 0.365 mM), acetic anhydride (Ac2O) (3.44 ml, 36.5 mM), and TEA (3.0 ml, 21.9 mM) were added and the mixture refluxed for 2.5 hrs. After cooling to room temperature, H2O (15 ml) was added and stirred for 1 hr. The reaction mixture was taken up in EtOAc (75 ml), washed with water (2×50 ml), 5% NaHCO3 (50 ml), brine (25 ml), dried (MgSO4), and evaporated to a black oil: 0.88 g. The oil was Kugalrohr distilled under vacuum (~0.3 mm), oven temperature 110°-30°, giving the title compound as a colorless oil: 0.79 g (83% yield). TLC (silica gel, EtOAc/hexane 7:3 visualized with UV and KMnO4) showed the product as one spot at Rf 0.60.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[C:33]([F:32])([F:44])[F:45])(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccccc4C(F)(F)F)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2-(trifluoromethyl)-benzenesulfonyl chloride. Purity (ELSD, based on MW=629.6)=90%.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.[Cl:20][C:21]1[NH:25][N:24]=[C:23]([CH3:26])[CH:22]=1>>[Cl:20][C:21]1[N:25]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH3:11])=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:3]=2)[N:24]=[C:23]([CH3:26])[CH:22]=1
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Reactant: Cc1cc(Cl)[nH]n1
Product: Cc1cc(Cl)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 6 from (2-chloro-9-methyl-9H-purin-6-yl)(4-chloro-phenyl)-amine and 5-chloro-3-methyl-1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:22][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Cl)cc2)CC1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCOC(c1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl 4-((4-chlorophenyl)(hydroxyl)methyl)piperidine-1-carboxylate (1.25 g, 3.84 mmol) in DMF (50 mL) was added sodium hydride 60% w/w dispersion on mineral oil (384 mg, 9.59 mmol). The reaction mixture was stirred for 10 minutes at room temperature then 2-chloro-N,N-dimethylethanamine hydrochloride (608 mg, 4.22 mmol) ws added. The reaction mixture was stirred at 70° C. for 12 h. LC-MS of the reaction mixture showed no more starting material. The reaction mixture was cooled to room temperature and was diluted with EtOAc (50 mL) and washed with 10% LiCl in water (2×50 mL) followed by water (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to yield tert-butyl 4-((4-chlorophenyl)(2-(dimethylamino)ethoxy)methyl)piperidine-1-carboxylate that was purified by reversed phase HPLC followed by separation on enantiomers by SFC. (253 mg and 246 mg, 33%) m/z: 397 (MH+)
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([O:24]COCCOC)=[C:14]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(Cl)Cl.[Zn+2].[Br-].[Br-]>[C:31]1([C:14]2[CH:13]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:17]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:15]=2[OH:24])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCCCCCCCCCOc1cc(-c2ccccc2)c(OCOCCOC)c(-c2ccccc2)c1
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CCCCCCCCCCOc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.1 %

Procedure:
A mixture of 3,5-diphenyl-4-[(2-methoxyethoxy)methoxy]-phenyl decyl ether (0.880 g, 1.793 mmol) and ZnBr2 (2.019 g, 8.967 mmol) in methylene chloride (10 ml) under nitrogen was stirred at room temperature. After 48 h, the reaction mixture was concentrated in vac and the residue was taken up in EtOAc (60 ml) and saturated NaHCO3 solution (20 ml). The layers were shaken and separated and the organic layer was washed with saturated NaHCO3 solution (2×10 ml), water (3×10 ml), brine (1×10 ml), dried over Na2SO4, filtered and the filtrate concentrated in vac and dried. The residue was purified by flash chromatography (hexane and 1% EtOAc/Hex) to give the product as a light brown oil (0.571 g, 79%); 1H NMR (400 MHz, DMSO-d6) δ 0.83-0.88 (m, 3H), 1.20-1.36 (m, 12H), 1.36-1.45 (m, 2H), 1.65-1.73 (m, 2H), 3.96 (t, J=6.6 Hz, 2H), 6.77 (s, 2H), 7.31-7.36 (m, 2H), 7.40-7.45 (m, 4H), 7.54-7.58 (m, 4H), 7.80 (s, 1H); IR (film) 3550, 2940, 1600, 1460, 1180 cm−1; mass spectrum [EI], m/z 402 M+.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[C:3]=1[OH:17].C(N(C(C)C)CC)(C)C.[CH3:27][O:28][CH2:29]Cl>C1COCC1.O>[Br:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[C:3]=1[O:17][CH2:27][O:28][CH3:29]
Reactant: CCCc1cc2cc(OC)ccc2c(O)c1Br
Reactant: COCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1cc2cc(OC)ccc2c(OCOC)c1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.7 %

Procedure:
To a solution of 2-Bromo-6-methoxy-3-propyl-naphthalen-1-ol (94) (1.41 g, 4.78 mmol) in dry THF (23 mL) at 0° C. was added diisopropylethylamine (3.3 mL, 19.1 mmol) followed by chloromethyl methyl ether (1.1 mL, 14.3 mmol) slowly. Reaction mixture was stirred at ambient temperature for 24 h. Reaction mixture was diluted with water and the aqueous layer was extracted with DCM, washed organic layer with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified using 1:9 EtOAc:hexanes to provide 1.26 g (78%) of the title compound (95) as a solid. 1H NMR (400 MHz, d-CDCl3): δ 1.01 (t, J=7.4 Hz, 3H), 1.70-1.75 (m, 2H), 2.85 (t, J=7.7 Hz, 2H), 3.72 (s, 3H), 3.91 (s, 3H), 5.23 (s, 2H), 7.04 (s, 1H), 7.12 (dd, J1=2.6 Hz, J2=9.1 Hz, 1H), 7.39 (s, 1H), 8.03 (d, J=9.1 Hz, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.Cl[CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:12][CH2:14][CH2:15][OH:16])=[CH:10][CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: OCCCl
Reactant: Oc1ccc(-n2cncn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCOc1ccc(-n2cncn2)cc1
Reaction time: 24 h

Procedure:
A stirred mixture of 4(1H-1,2,4-triazol-1-yl)phenol (16.1 g, 0.10 mole), 2-chloroethanol (25.5 g, 0.30 mole), potassium carbonate (42 g, 0.30 mole) and methyl ethyl ketone (100 ml) was heated at reflux temperature for 10 hr. An additional 16.1 g (0.20 mole) of 2-chloroethanol was added to the reaction mixture and heating at reflux temperature continued for another 24 hr. The hot mixture was filtered and the filtrate chilled. The crystalline precipitate was collected by filtration and the filter cake rinsed with water to remove most of the dark color. The solid was triturated with hot ethyl acetate, the mixture cooled, and the light tan crystals collected to yield 14.0 g (68%); mp 151°-152° C.
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)[CH2:16][C:17]([C:19]([OH:21])=[O:20])=[O:18].Cl>O.C1(C)C=CC=CC=1>[CH2:9]([C:10]([OH:14])([C:11]([OH:13])=[O:12])[CH2:16][C:17](=[O:18])[C:19]([OH:21])=[O:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: O=C(O)CC(=O)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)C(=O)CC(O)(Cc1ccccc1)C(=O)O
Yield: 37 %

Procedure:
After 16.23 g of potassium hydroxide (having a purity of 85% by weight) was dissolved in 48 ml of water, 5.0 g (30.5 mmol) of phenylpyruvic acid and 12.1 g (91.4 mmol) of oxalacetic acid were added to the resulting solution, for reaction at ambient temperature for 72 hours (about pH 13 at the start of the reaction). Using conc. hydrochloric acid, the reaction solution was adjusted to pH 2.2, and extracted in ethyl acetate. The organic layer was rinsed in aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated to obtain the residue. The residue was recrystallized in ethyl acetate and toluene, to obtain 2.8 g (11.3 mmol) of 4-benzyl-4-hydroxy-2-ketoglutaric acid in crystal form.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[O:11][CH:10]([CH2:13][NH2:14])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH2:28]([O:27][C:25](=[O:26])[NH:14][CH2:13][CH:10]1[CH2:9][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:12]=2[O:11]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)c1cccc2c1OC(CN)C2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cccc2c1OC(CNC(=O)OCc1ccccc1)C2
Yield: 38.2 %

Procedure:
Treatment of (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylamine (2.2 g, 9.66 mmol) with diisopropylethylamine (3.12 g, 24.15 mmol) and benzyl chloroformate (1.81 g, 10.63 mmol) generally according to the procedure described for Intermediate 12 gave 1.2 g (59%) of (±)-benzyl(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a colorless oil. Anal. calcd. for C20H23NO3 C, 73.82; H, 7.12; N, 4.3. Found C, 73.32; H, 7.33; N, 4.15. Chiral HPLC separation of (±)-benzyl(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol) provided two fractions. Fraction 1 (Rt=9.319 min, Chiralcel OJ, ethanol); Fraction 2 (Rt=11.868 min, Chiralcel OJ, ethanol).
Reaction SMILES: N1C(=O)CC[C@@H]1C(O)=O.[NH2:10][C@@H:11]1[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[NH:13][C:12]1=[O:22].CN(C)C=O.C(N(CC)CC)C.[C:35](Cl)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCC)C>[C:35]([NH:10][C@@H:11]1[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[NH:13][C:12]1=[O:22])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Agent: O=C1CC[C@H](C(=O)O)N1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2CC[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A round-bottom flask was fitted with a condenser, stirbar and septa. 3(R)-Amino-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one D-pyroglutamic acid salt (10.0 g, 32.8 mmol), N,N-dimethylformamide (200 mL) and triethylamine (12 mL, 86.1 mmol) were added, giving a mixture which was heated to 120° C. To the resulting solution was added trityl chloride (9.04 g, 32.4 mmol). The reaction was then cooled to 60° C., maintained at 60° C. for 4 hours, and then allowed to slowly cool to room temperature. After 18 hours, the reaction mixture was diluted with diethyl ether (300 mL) and washed first with 400 mL 1:1 H2O:saturated aqueous NaCl solution, then with 2×100 mL H2O. The aqueous washes were combined and extracted with diethyl ether (100 mL). The organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo to give an oil which that purified via flash chromatography on silica gel (25% ethyl acetate/hexanes) to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1.B.C(=O)([O-])[O-:23].[Na+].[Na+].OO>C1COCC1.C(OCC)(=O)C>[OH:23][CH2:10][CH2:9][C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:16]=2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: C=Cc1ccc(-c2ccc(C(=O)OC)cc2)c(OC)c1
Reactant: O=C([O-])[O-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(CCO)cc2OC)cc1
Temperature: 60 °C

Procedure:
A solution of Example 445A (228 mg) and 1M borane in THF (1.2 mL) in THF (2 mL) at room temperature was stirred for 5 hours, and treated sequentially with 2M sodium carbonate (1 mL) and 33% hydrogen peroxide (1 mL). The mixture was heated to 60° C. for 1 hour, diluted with ethyl acetate (100 mL), washed with water (45 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20-40% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([N:12]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)[CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24](O)=[O:25])[CH:22]=2)[NH:17][C:16]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)[N:63]2[CH2:67][CH2:66][CH2:65][CH2:64]2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(NCC)C>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:11])[N:12]([CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24](=[O:25])[N:63]([CH2:67][CH3:66])[CH2:64][CH3:65])[CH:22]=2)[NH:17][C:16]=1[C:27]1[CH:28]=[C:29]([CH3:34])[CH:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)O)cc3c2CCN(CCCCc2ccncc2)C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCNCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccncc3)C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 846 mg (1.38 mmol) of 3-[2-[benzyloxycarbonyl-[4-(pyridin-4-yl)butyl]amino]ethyl]-2-(3,5-dirnethylphenyl)-1H-indole-5-carboxylic acid hydrochloride, 862 mg (1.66 mmol) of benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), and 8.5 mL of dry methylene chloride was treated with 1.16 mL (839 mg; 8.29 mmol) of triethylamine, followed after a few minutes by 0.715 mL (505 mg, 6.91 mmol) of diethylamine. The resulting solution was stirred under nitrogen at room temperature overnight and then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient elution with 1-5% methanol in methylene chloride) afforded a quantitative yield of the desired product; homogeneous by TLC in 95:5 CH2Cl2 -MeOH. 500 MHz 1H NMR (CDCl3) was complex, owing to rotamers, but was consistent with the assigned structure. Mass spectrum (ESI): m/e=631.5 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10]I)([CH3:4])([CH3:3])[CH3:2].[I-].[CH2:14]([O:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[CH:24][C:23]=1[N:29]1[S:33](=[O:35])(=[O:34])[N:32]([CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:31](=[O:42])[CH2:30]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CCOC(C)=O.[Zn]>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][C:26]1[CH:25]=[CH:24][C:23]([N:29]2[CH2:30][C:31](=[O:42])[N:32]([CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[S:33]2(=[O:35])=[O:34])=[C:22]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCI
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [I-]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Zinc dust (3.6 g, 55 mmol) is placed in a flask and heated under vacuum to remove traces of water. DMF (30 mL) is then added under nitrogen atmosphere. Dibromoethane (cat. 0.5 mL) is added and the mixture heated until effervescence occurs. The reaction is allowed to cool to RT over 30 min and chlorotrimethylsilane (cat 0.5 mL) is added, followed after 30 min with (3-iodopropyl)-carbamic acid tert-butyl ester (4.0 g, 14 mmol) dissolved in 10 mL of DMF. After 30 min, TLC indicates the iodide has been consumed and Pd2(dba)3 (0.6 g) and tri-o-tolylphosphine (0.5 g) are added, followed by the dropwise addition of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (5 g, 9.2 mmol) dissolved in 25 mL of DMF. The reaction mixture is stirred for 14 h and then diluted with EtOAc and filtered through Celite. The filtrate is washed with 1M HCl, brine and water, dried over MgSO4, filtered through a short plug of silica and concentrated to afford the title compound as a light yellow oil.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[NH:5])#[N:2].Cl.C(CC(=N)OCC)#N.Br[CH:17]1[C:26](=O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:19][CH2:18]1>C(O)C>[NH2:5][C:4]1[NH:6][C:26]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:19][CH2:18][C:17]=2[C:3]=1[C:1]#[N:2]
Reactant: N#CCC(=N)N
Reactant: O=C1c2ccccc2OCC1Br
Agent: CCOC(=N)CC#N
Agent: Cl
Solvent: CCO
Product: N#Cc1c(N)[nH]c2c1COc1ccccc1-2

Procedure:
To an ethanolic solution of 2-cyanoacetamidine prepared from ethyl 2-cyanoacetimidate hydrochloride (4.0 g) as in Reference Example 2 was added a solution of 3-bromo-4-chromanone (3.0 g) in ethanol dropwise under ice-cooling with stirring. The mixture was stirred at room temperature overnight and, then, concentrated under reduced pressure. The resulting crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: 2% methanol/chloroform) and recrystallized from acetone/isopropyl ether to provide the title compound as light-brown crystals (0.31 g). m.p. 216-217° C.
Reaction SMILES: [OH:1][C@H:2]1[C@H:9]2[C@:5]([C:12]([O:14]C)=[O:13])([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@H:3]1[CH2:16][NH:17][C:18](=[O:60])[CH2:19][NH:20][C:21](=[O:59])[CH2:22][N:23]1[CH2:34][CH2:33][N:32]([CH2:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][CH2:30][N:29]([CH2:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:28][CH2:27][N:26]([CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:25][CH2:24]1.O[Li].O>CO>[OH:1][C@H:2]1[C@H:9]2[C@:5]([C:12]([OH:14])=[O:13])([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@H:3]1[CH2:16][NH:17][C:18](=[O:60])[CH2:19][NH:20][C:21](=[O:59])[CH2:22][N:23]1[CH2:34][CH2:33][N:32]([CH2:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[CH2:31][CH2:30][N:29]([CH2:43][C:44](=[O:50])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])[CH2:28][CH2:27][N:26]([CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:25][CH2:24]1
Reactant: COC(=O)[C@@]12O[C@@H](CNC(=O)CNC(=O)CN3CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC3)[C@@H](O)[C@@H]1OC(C)(C)O2
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)NCC(=O)NC[C@@H]2O[C@@]3(C(=O)O)OC(C)(C)O[C@H]3[C@@H]2O)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
To a solution of 19a (1.0 g, 1.17 mmol) in MeOH (2 mL) was added a solution of LiOH.H2O (48.5 mg, 1.17 mmol, Aldrich). The resulting solution was stirred at room temperature for 4 h. Solvents were evaporated and the residue was purified by silica column chromatography. Product 20a was obtained as a white solid (0.8 g; yield 81%).