Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@H:15]([C:19](O)=[O:20])[CH2:14]2)=[CH:9][CH:8]=1.C[N:26]1CCOCC1.ClC(OCC)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@H:15]([C:19]([NH2:26])=[O:20])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: O=C(O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: CN1CCOCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.8 %

Procedure:
To (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (2.0 g, 6.07 mmol; enantiomeric purity (S):(R)>99.9:0.1) in tetrahydrofuran (40 mL), N-methylmorpholine (676 mg, 6.68 mmol) was added at 0° C. After stirring for 20 min, a solution of ethyl chloroformate (725 mg, 6.68 mmol) was added dropwise over 10 min, and stirring at 0° C. was continued for another 20 min. Ammonia (excess) was then bubbled for 15 min through the resulting suspension. The reaction mixture was warmed up to room temperature and stirred for 15 min. Water (50 mL) was added, and the tetrahydrofuran was evaporated in vacuo. The product, which precipitated, was collected by filtration, washed with water and tert-butyl methyl ether and dried at 45° C. in vacuo to afford (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid amide (1.75 g, 88%). The purity of the product by HPLC was 98.9% (area) and the enantiomeric ratio (S):(R) was determined as 99.8:0.2.
Reaction SMILES: C[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].I[CH2:14][CH2:15][CH3:16].O1C[CH2:20][CH2:19][CH2:18]1>>[C:15]1([N:6]2[C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=[CH:2]2)[CH:16]=[CH:20][CH:19]=[CH:18][CH:14]=1
Reactant: CCCI
Reactant: Cc1nc2ccccc2[nH]1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: c1ccc(-n2cnc3ccccc32)cc1
Reaction time: 0.33 h

Procedure:
To a flask were added 2.0 g 2-methylbenzimidazole and 40 ml tetrahydrofuran and the mixture was cooled to 10 C under nitrogen. 0.9 g Sodium hydride were added in portions and the reaction mixture was stirred for 20 minutes. 3.9 g 1-iodopropane were added and the mixture was heated to 45 C for 6 hours. The mixture was quenched slowly with 40 ml water, extracted twice with ethyl acetate and washed with water. Following solvent removal, the product was purified by silica gel chromatography using pure ethyl acetate to 5% methanol in ethyl acetate. A pale yellow oil was obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:13]([Mg]Br)=[CH2:14]>O1CCCC1.[Cu]I>[CH2:1]([O:8][CH2:9][C@H:10]([OH:11])[CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: C=C[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CC[C@@H](O)COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of (2R)-2-[(benzyloxy)methyl]oxirane (167 g, 1.02 mol) in tetrahydrofuran (2 L) was added copper(I) iodide (11.62 g, 61.02 mmol) at room temperature. The mixture was stirred for 5 minutes, then cooled to −78° C. A solution of vinylmagnesium bromide (1 M in tetrahydrofuran, 1.12 L, 1.12 mol) was added drop-wise over 1 hour while the reaction temperature was maintained below −70° C. Upon completion of the addition, the cooling bath was removed and the reaction mixture was left to stir at room temperature for 1 hour, then quenched by slow addition of aqueous ammonium chloride solution (200 mL). After dilution with additional aqueous ammonium chloride solution (1.5 L) and ethyl acetate (1.5 L), the aqueous layer was extracted with ethyl acetate (1 L) and the combined organic layers were washed with aqueous ammonium chloride solution (1.5 L), dried over magnesium sulfate, filtered, and concentrated in vacuo. Three batches of this reaction were carried out and combined to give the product as an orange oil. Yield: 600 g, 3.1 mmol, quantitative. 1H NMR (400 MHz, CDCl3) δ 7.28-7.40 (m, 5H), 5.78-5.90 (m, 1H), 5.08-5.17 (m, 2H), 4.57 (s, 2H), 3.86-3.94 (m, 1H), 3.53 (dd, J=9.6, 3.3 Hz, 1H), 3.39 (dd, J=9.6, 7.4 Hz, 1H), 2.26-2.34 (m, 3H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([Br:10])[CH:4]=1.CN(C)[CH:13]=[O:14]>C(Cl)Cl>[Br:10][C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([Br:9])[CH:6]=1)[CH:13]=[O:14]
Reactant: CN(C)C=O
Reactant: Brc1cc(Br)cc(Br)c1
Agent: [Mg]
Solvent: ClCCl
Product: O=Cc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
1.344G (56 mM) of magnesium was added to a solution of 15-7G(50 mM) of 1,3,5-tribromobenzene and the mixture was stirred at room temperature after 5 hours, most of the metal was digested. To the resulting brown Grignard solution was added 7.5 mL (0.1M) of N,N-dimethylformamide at 0° under nitrogen. The resulting mixture was stirred overnight at room temperature. Solvent was removed in vacuo at room temperature. The residue was taken up in 200 mL of ethyl acetate and washed with 6×50 mL of saturated sodium chloride solution, dried over anhydrous MgSO4. Solvent was removed to give a crude solid, which was dissolved in minimum amount of CH2Cl2 and applied on silica gel. Elution with 1:9 mixture of ether:hexane containing methylene chloride gave 45% yield of the desired aldehyde as white solid.
Reaction SMILES: Cl[C:2](Cl)(Cl)[S:3]Cl.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1>C(Cl)(Cl)Cl.CO>[S:23]1[CH:24]=[CH:25][N:26]=[C:22]1[N:21]=[C:2]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][S:3]1
Reactant: Nc1nccs1
Reactant: ClSC(Cl)(Cl)Cl
Reactant: Nc1ccccn1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: c1ccn2c(=Nc3nccs3)snc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
To a solution of 6.6 ml. (60 mmol) trichloromethanesulphenic acid chloride in 900 ml chloroform one adds dropwise at 0° C. a solution of 5.6 g (60 mmol) 2-aminopyridine and 8.3 ml triethylamine in 50 ml chloroform. One after-stirs for 10 min. and adds dropwise thereto a solution of 6.0 g (60 mmol) 2-aminothiazole and 25 ml triethylamine in 100 ml chloroform. After 3 h stirring at room temperature, one evapovates and washes the precipitate with methanol. There remain 8.9 g of title compound (63% of theory) of the m.p. 169°-171° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10](OCC)=[O:11])[N:5]=[C:4]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:3]=1.O.[NH2:25][NH2:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:5]=[C:6]([S:8][CH2:9][C:10]([NH:25][NH2:26])=[O:11])[N:7]=1
Reactant: CCOC(=O)CSc1nc(Cl)cc(NCc2ccc(Cl)cc2)n1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NNC(=O)CSc1nc(Cl)cc(NCc2ccc(Cl)cc2)n1

Procedure:
A stirred mixture of 1.1 g of (6-chloro-4-p-chlorobenzylamino-2pyrimidinylthio)acetic acid, ethyl ester 0.18 g of hydrazine hydrate (98%) and 0.3 g of sodium carbonate in 15 ml. of ethanol was heated under reflux for 3 hr. The reaction mixture was filtered and the filtrate diluted with water until a precipitate appeared. The solid was washed with aqueous (10%) sodium carbonate then recrystallized from ethanol to a mp. of 178-182°C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:35][CH2:36][CH:37]([OH:50])[CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:49])[CH3:48])=[CH:42][CH:41]=1>>[C:47]([NH:46][C:43]1[CH:44]=[CH:45][C:40]([O:39][CH2:38][CH:37]([OH:50])[CH2:36][NH:35][C:16]([C@@H:9]2[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]2[S:25]([C:22]2[CH:23]=[CH:24][C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][CH:21]=2)(=[O:27])=[O:26])=[O:18])=[CH:41][CH:42]=1)(=[O:49])[CH3:48]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Nc1ccc(OCC(O)CN)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)COc2ccc(NC(C)=O)cc2)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and N-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy}phenyl) acetamide, the title compound was obtained in 62% purity by HPLC. MS(ESI+): m/z=581.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:9][CH:8](O)[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4]1.[Cl-:15].[Cl-].[Cl-].[Al+3]>COCCOC>[ClH:15].[CH3:1][NH:2][CH:3]1[CH:9]=[CH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4]1
Reactant: CNC1COc2ccccc2C(O)C1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: COCCOC
Product: CNC1C=Cc2ccccc2OC1
Product: Cl
Yield: 89.9 %

Procedure:
1.93 g of 3-methylamino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol were added to 25 ml of ethylene glycol dimethyl ether and reacted with 1.5 g aluminum trichloride while cooling with ice. Subsequently, the reaction mixture was heated for 18 hours at boiling temperature. Thereafter, the solvent was evaporated; the residue was dissolved in water, and the solution was reacted with diluted sodium hydroxide solution and extracted with methylene chloride. The methylene chloride extract was evaporated, and the 3-methylamino-2,3-dihydro-1-benzoxepine which remained as a residue was converted to its hydrochloride as described in Example 1, and this was recrystallized from a methanol/ether mixture. 1.9 g of 3-methylamino-2,3-dihydro-1-benzoxepine hydrochloride were obtained. Melting point: 168°-170 degrees C.
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[C:21]([Cl:57])[CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[Cl:57][C:21]1[CH:20]=[C:19]([OH:18])[CH:56]=[CH:55][C:22]=1[O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:53]=[CH:52][C:33]([NH:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:42])[CH2:37][CH2:36]2)=[CH:32][CH:31]=1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3Cl)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3Cl)cc2)CC1
Yield: 39.1 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}-2-chlorophenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-octyl-1-piperidinecarboxamide(0.185 g, 0.23 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.053 g, 0.09 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:37]=[C:36]([C:38]2[CH:39]([CH3:45])[NH:40][C:41](=[O:44])[NH:42][N:43]=2)[CH:35]=[CH:34][C:20]=1[O:21][CH2:22][C:23]([NH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:24]>O1CCCC1>[Cl:18][C:19]1[CH:37]=[C:36]([C:38]2[CH:39]([CH3:45])[NH:40][C:41](=[O:44])[NH:42][N:43]=2)[CH:35]=[CH:34][C:20]=1[O:21][CH2:22][C:23]([NH:25][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][N:31]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:32][CH2:33]1)=[O:24]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC1NC(=O)NN=C1c1ccc(OCC(=O)NCCN2CCNCC2)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1NC(=O)NN=C1c1ccc(OCC(=O)NCCN2CCN(C(=O)c3ccc(Cl)cc3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
0.43 g of p-chlorobenzoyl chloride and 0.25 g of triethylamine were added to a suspension of 0.5 g of α-[2-chloro-4-(2,3,4,5-tetrahydro-5-methyl-3-oxo-1,2,4-triazin-6-yl)phenoxy-N-[2-(1-piperazinyl)ethyl]acetamide (prepared as described in Example 10) in 10 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour. The tetrahydrofuran used as the solvent was removed by evaporation under reduced pressure, and the residue was extracted with methylene chloride. The extract was washed with water and dried over anhydrous magnesium sulfate, after which the residue was purified by column chromatography through silica gel, eluted with a 98:2 by volume mixture of methylene chloride and ethanol, to give 0.2 g of a colorless oil. This oil was crystallized from ethanol and then recrystallized, also from ethanol, to give 0.16 g of the title compound as colorless fine crystals melting at 186°-188° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc(C#N)cc3)CC2)cc1
Yield: 89.6 %

Procedure:
A solution of N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (180 mg, 0.510 mmol) and α-bromo-p-tolunitrile (104 mg, 0.530 mmol) in acetonitrile (5 mL) was treated with potassium carbonate and the resulting mixture was heated at reflux for 2 h. The mixture was poured into a mixture of ethyl acetate and water. The organic layer was concentrated in vacuo, the residue dissolved in 10% acetic acid/methanol, and the resulting solution loaded onto an ion exchange resin (SCX, Varian). Elution with methanol (4 column volumes) followed by 2 N ammonia in methanol (2 column volumes) and concentration of the appropriate fractions yielded 214 mg (90%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.I[CH2:16][C:17](=[O:39])[C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C:32](=[CH:33][CH2:34]2)[C@:30]2([CH3:31])[C:25](=[CH:26][C:27](=[O:37])[CH:28]=[CH:29]2)[CH2:24][CH2:23]3)[CH2:20][C@H:19]1[CH3:38]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:16][C:17](=[O:39])[C@@H:18]3[C@:35]4([CH3:36])[C@H:21]([C@H:22]5[C:32](=[CH:33][CH2:34]4)[C@:30]4([CH3:31])[C:25](=[CH:26][C:27](=[O:37])[CH:28]=[CH:29]4)[CH2:24][CH2:23]5)[CH2:20][C@H:19]3[CH3:38])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CI
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(CC(=O)[C@H]3[C@H](C)C[C@H]4[C@@H]5CCC6=CC(=O)C=C[C@]6(C)C5=CC[C@@]43C)CC2)cc1

Procedure:
Following the general procedure of EXAMPLES 1.6A, 7, 8, 11-19, 83, 126 and 139 and making non-critical variations but starting with 4 -(4-methoxyphenyl)piperazine (PREPARATION A-31) and 21-iodo-16α-methylpregna-1,4,9(11)-triene-3,20-dione (PREPARATION S-22), the title compound is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([O-:26])=[O:25])[Se:21][C:22]=1[CH3:23].O.[CH:28](O)(C)C>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[C:4]([CH3:16])[N:3]=[C:2]2[NH:17][C:18]1[CH:19]=[C:20]([C:24]([O:26][CH3:28])=[O:25])[Se:21][C:22]=1[CH3:23]
Reactant: COc1cc2nc(C)nc(Cl)c2cc1OC
Reactant: CC(C)O
Reactant: Cc1[se]c(C(=O)[O-])cc1N
Solvent: O
Product: COC(=O)c1cc(Nc2nc(C)nc3cc(OC)c(OC)cc23)c(C)[se]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
To a solution of 4-chloro-6,7-dimethoxy-2-methylquinazoline (From example 24; 700 mg, 2.93 mmol) in isopropanol (20 mL) was added 4-amino-5-methylselenophene-2-carboxylate (1.3 g, 5.8 mmol) at rt and the mixture was stirred at rt for 16 h. The mixture was poured into ice cooled water and stirred for 10 min. The solution was extracted with EtOAc (3×100 mL) and the combined layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (98:2) as eluents to give the product (700 mg, 57%) as a brown color solid, mp 200-204° C. 1H NMR (400 MHz, CDCl3): δ 8.18 (1H, s), 7.19 (1H, s), 7.00 (1H, s), 3.98 (3H, s), 3.92 (3H, s), 3.85 (3H, s), 2.58 (3H, s), 2.46 (3H, s); 13C NMR (100 MHz, CDCl3): δ 163.5, 162.8, 156.9, 154.8, 148.7, 148.2, 144.0, 135.3, 135.1, 131.8, 107.3, 106.4, 99.8, 56.2, 56.1, 52.2, 26.2, 15.5; LC-MS (positive ion mode): m/z 420, 422 (M+H)+.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[NH2:16])(=[O:4])[CH3:3].[C:17]([O:20][CH:21]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:22](O)=[O:23])(=[O:19])[CH3:18].C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.O1CCOCC1>[C:2]([NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[NH:16][C:22](=[O:23])[CH:21]([O:20][C:17](=[O:19])[CH3:18])[CH2:25][O:26][C:27](=[O:29])[CH3:28])(=[O:4])[CH3:3]
Reactant: CC(=O)OCC(OC(C)=O)C(=O)O
Reactant: COC(=O)c1ccc(NC(C)=O)c(N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(NC(C)=O)c(NC(=O)C(COC(C)=O)OC(C)=O)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
Compound 16 (0.12 g, 0.57 mmol) was dissolved in a mixture of DMF (2 mL) and dioxane (3 mL) and cooled to 0° C. A solution of 2,3-diacetoxypropionic acid (0.220 g, 1.15 mmol) in dioxane (3 mL) was added followed by the addition of dicyclohexylcarbodiimide (0.195 mL, 0.183 g, 0,870 mmol). The resulting reaction mixture was stirred for 3 hours, initially at 0° C. with slow warming to room temperature. The solid dicyclohexylurea which separated was filtered and the filtrate was concentrated to dryness on a rotary evaporator. The solid residue was filtered and washed on the filter with 5% HCl (5 mL), water (5 mL), 5% NaHCO3 (5 mL), and again with water (2×10 mL). This was dried under vacuum to give 18 (200 mg, 91.3%) as a white solid: mp 130°-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH:21](O)([CH3:23])[CH3:22].S(=O)(=O)(O)O>C1C=CC=CC=1>[CH3:22][CH:21]([O:19][C:18](=[O:20])[CH2:17][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:23]
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC(C)OC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 56 %

Procedure:
A solution of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.1 g, 0.0108 mole), isopropanol (50 ml), benzene (50 ml), and concentrated sulfuric acid (5 ml) was refluxed under a Dean-Stark trap for 24 hrs. The reaction mixture was concentrated and the residue partitioned between 5% potassium hydroxide solution (50 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous portion extracted with ethyl acetate (2×25 ml). The organic layers were combined and washed with 5% potassium hydroxide (25 ml), water (25 ml), dried over sodium sulfate, and concentrated in vacuo to give 2.0 g (56%) of a solid, mp 118°-120° C. Recrystallization from isopropyl ether gave 1.7 g of off-white needles, mp 117.5°-119° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.BrC1C=CC(Cl)=NC=1.O>CS(C)=O>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]([O:17][C:14]2[CH:13]=[CH:12][C:11]([CH2:10][C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[CH:23][CH:24]=1
Reactant: Clc1ccnc2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Clc1ccc(Br)cn1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Oc2ccnc3ccccc23)cc1)C(=O)O
Reaction time: 0.25 h
Yield: 68 %

Procedure:
N-Boc-L-Tyrosine (0.844 g, 3 mmol) and KOBu-t (0.727 g, 6.5 mmol) are dissolved in dry DMSO (2.9 mL) under argon atmosphere in a tightly closed glass reaction tube and stirred for 15 min, then 4-chloroquinoline (0.491 g, 3 mmol) is added. The mixture is stirred for 6 days at 30° C. When only traces of 5-bromo-2-chloropyridine are detected (LC-MS control), the reaction mixture is poured into water (40 mL) and the aqueous phase is washed with diethyl ether (2×20 mL). The pH of aqueous phase is adjusted to ˜4 by adding 20% aqueous citric acid. The product precipitated is collected on filter and washed with water (50 mL) to give the title compound (0.833 g, 68%) as a grey solid.
Reaction SMILES: [C:1](=[NH:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:22]([CH:24]([CH2:29][C:30]1[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1)[C:25](OC)=O)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:25]=[C:24]([CH2:29][C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=4)[C:22](=[O:23])[N:21]=3)=[CH:11][CH:10]=2)=[CH:14][C:15]=1[CH3:20]
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Reactant: Cc1cc(Oc2ccc(CCOC(=N)N)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C)c4)cc3)nc2=O)cn1
Temperature: 130 °C
Yield: 7.9 %

Procedure:
To the solution of 2-{4-[(4-chloro-3-methylphenyl)oxy]phenyl}ethyl imidocarbamate (100 mg, 0.239 mmol) and methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (64.4 mg, 0.287 mmol) in NMP (1 mL) was added K2CO3 (132 mg, 0.957 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (9 mg, 7.85% yield). LCMS: rt=3.54 min, [M+H+]=479
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:10]([OH:13])[CH:11]=[CH2:12])=O)(C)(C)C.[H-].[Na+].CCCCCC>CN(C)C=O>[CH:15]1([CH2:14][C@H:9]2[CH:10]([CH:11]=[CH2:12])[O:13][C:6](=[O:5])[NH:8]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C=CC(O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=CC1OC(=O)N[C@H]1CC1CCCCC1
Reaction time: 3 h

Procedure:
The resultant product of Example 1 (2.80 g, 9.88 mmol) in dry dimethylformamide (DMF) (50 ml) was added to a stirred suspension of NaH (593 mg of a 60% dispersion in oil, 14.8 mmol, hexane washed) in dry DMF (50 ml). After 3 h, the mixture was quenched (750 ml water+100 ml brine) and extracted with ether (5×100 ml). The combined organic phase was washed with brine (3×50 ml), dried (MgSO4), filtered and evaporated to an oil (2.23 g). The NMR spectrum of the crude product revealed an 82:18 mixture of 5S:5R diastereomers. Silica gel chromatography gave 80% recovery of pure diastereomers. 5S: