Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]([CH2:10][CH2:11][OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([Cl:23])([Cl:22])[Cl:21])[CH:17]=[C:16](Cl)[N:15]=1>O>[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([Cl:21])([Cl:22])[Cl:23])[CH:17]=[C:16]([O:12][CH2:11][CH2:10][O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:15]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Reactant: OCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Clc1cc(C(Cl)(Cl)Cl)cc(OCCOc2ccccc2)n1

Procedure:
A solution was prepared by dissolving 5.28 grams (0.11 mole) of sodium hydride (as a 50 percent oil mixture) in 15.20 grams (0.11 mole) of 2-phenoxyethanol. To this solution was added, over a 30 minute period, 26.54 grams (0.1 mole) of 2,6-dichloro-4-(trichloromethyl)pyridine. The mixture was heated and refluxed for 4 hours. The reaction mixture was diluted with 700 ml of water and extracted with methylene chloride. The extract was washed with water, dried with sodium sulfate and filtered. The methylene chloride and other volatile impurities were removed by distillation under reduced pressure. The 2-chloro-6-(2-phenoxyethoxy)-4-(trichloromethyl)pyridine product which was recovered distilled at 95° C. under0.05 mm of pressure. The product was recovered in a yield of 27 grams (73.5 percent of theoretical). The product solidified upon standing at 60°-62° C. Upon analysis, the product was found to have carbon, hydrogen, nitrogen, and chlorine contents of 46.22, 3.15, 3.94 and 37.92 percent, respectively, as compared with the theoretical contents of 45.81, 3.02, 3.82 and 38.64 percent, respectively, calculated for the above named compound.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][CH:35]=[CH2:36])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)=O>O1CCCC1>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][CH:35]=[CH2:36])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1
Reactant: C=CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Solvent: C1CCOC1
Product: C=CCON=C(C(=O)OCC)c1csc(N)n1
Yield: 82.9 %

Procedure:
A solution of ethyl 2-(2-tritylaminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer, 8.7 g), 50% formic acid (42.5 ml) and tetrahydrofuran (42.5 ml) was stirred at 60° C. for 40 minutes. After concentrating the resultant solution in vacuo, the residue was dissolved in ethyl acetate, washed with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. After concentrating the resultant solution in vacuo, the residue was subjected to column chromatography on silica gel with benzene and ethyl acetate in turn, to give ethyl 2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer, 3.7 g), mp. 102° to 104° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[C:11]2[C:12](=[O:24])[N:13]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][C:10]=2[NH:9][CH:8]=1.O.[OH-].[Na+].CN(C)[CH:30]=[O:31]>>[CH3:6][C:7]1[C:11]2[C:12](=[O:24])[N:13]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][C:10]=2[NH:9][C:8]=1[CH:30]=[O:31]
Reactant: Cc1c[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31.7 %

Procedure:
A stirred solution of N,N-dimethylformamide (1.68 ml) was added dropwise slowly with phosphorus oxychloride (0.9 ml, 9.65 mmol) under an argon atmosphere while maintaining the temperature at 0° C. Upon completion of the addition, the mixture was stirred for 15 minutes at room temperature, and cooled down to 0˜5° C. in an ice-water bath. A mixture of 3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (2.29 g, 8.77 mmol) in 10.5 ml of N,N-dimethylformamide was added dropwise to the above solution. Upon completion of the addition, the mixture was stirred for 2 hours at 0° C., added with cold water (5 ml), stirred for 5 minutes. The resulting mixture was adjusted to pH 12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (30 ml×3). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane:methanol (10:1) as eluents to give 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (989 mg, 3 steps 31.7%) as a red oil which was used as such.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.C1C(=O)N([Br:18])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CC(O)=O.C1C=CC=CC=1.C(OCC)(=O)C>[Br:18][CH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CBr)nc1
Temperature: 120 °C

Procedure:
6-methylnicotinic acid (100 mg 0.14 mmol) was dissolved in 10% AcOH/benzene (1 mL) and treated with NBS (117 mg, 0.18 mmol) and benzoylperoxide (18 mg, 0.07 mmol). The reaction mixture was heated in a sealed microwave reactor at 120° C. for 1 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, dried (MgSO4), concentrated and purified by silica gel chromatography to yield 6-(bromomethyl)pyridine-3-carboxylic acid.
Reaction SMILES: C1COCC1.[C:6]1([CH2:12][OH:13])[CH:11]=[CH:10][CH:9]=[CH:8]C=1.[OH-].[Na+].[Cl:16][C:17]1[C:22]([O:23][CH2:24][CH:25]2[CH2:27][O:26]2)=[CH:21][CH:20]=[CH:19][N:18]=1>O>[Cl:16][C:17]1[C:22]([O:23][CH2:24][CH:25]([OH:26])[CH2:27][O:13][CH2:12][CH2:6]/[CH:11]=[CH:10]\[CH:9]=[CH2:8])=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: Clc1ncccc1OCC1CO1
Reactant: OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=C/C=C\CCOCC(O)COc1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
A mixture of THF (915 ml), benzenemethanol (2.96 mol) and NaOH (2.36 mol) was stirred at room temperature for 30 minutes (cooling was required to keep the temperature below 25° C.). Intermediate (19) (1.97 mol) was added. The reaction mixture was stirred at room temperature for 4 days. Water was added dropwise (cooling required) and the mixture was extracted with ethyl acetate. The organic layer was dried, filtered and the solvent was evaporated. The residue was combined with analogously obtained fraction, then purified by HPLC over silica gel (eluent: hexane/ethyl acetate (60/40)). The desired fractions were collected and the solvent was evaporated, yielding 38% of 1-[(2-chloro-3-pyridinyl)oxy]-3-[(3Z)-3,5-hexadienyloxy]-2-propanol (intermediate 20).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][N:12]1[C:16](=[O:17])[C:15]2([CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19][CH2:18]2)[N:14]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[O:17]=[C:16]1[C:15]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:14]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:13][N:12]1[CH2:11][C:10]1[CH:9]=[C:8]([CH:41]=[CH:40][CH:39]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A solution of benzyl 3-(3-(tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (5 g, 9.0 mmol, 1 equiv) in a mixture of ethyl acetate and ethanol was charged with 10% palladium on carbon (1 g, 20%/wt) and the resulting mixture was stabilized to a hydrogen atmosphere. The reaction was stirred as such for 2 h, filtered through Celite and the filtrate was concentrated in vacuo to afford the title compound as a grey foam (3.69 g, 97%); 1H NMR (400 MHz, DMSO-d6): δ 1.52 (s, 9H); 1.54-1.56 (m, 2H); 2.43-2.49 (m, 2H); 2.88-2.93 (m, 2H); 3.18-3.24 (m, 2H); 4.58 (s, 2H); 4.62 (s, 2H); 6.74 (t, 2H, J=6.8 and 7.6 Hz); 6.88 (d, 2H, J=8 Hz); 7.18-7.22 (m, 2H); 7.49-7.55 (m, 2H); 7.79-7.85 (m, 2H); MS for C25H31N3O3 m/z 422.24 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]C)[C:9]1=[N:15][CH:16]=[C:17]([C:20]([O:22]CC)=[O:21])[C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2.Br>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[C:9]1=[N:15][CH:16]=[C:17]([C:20]([OH:22])=[O:21])[C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: CCOC(=O)c1cnc2n(c1=O)CCc1cc(OC)c(OC)cc1-2
Agent: Br
Product: O=C(O)c1cnc2n(c1=O)CCc1cc(O)c(O)cc1-2
Yield: 82 %

Procedure:
Ethyl 6,7-dihydro-9,10-dimethoxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate was treated with 48% hydrogen bromide as described in Example 19 to give a 82% yield of the title acid, m.p. 308°-314°. Recrystallization from N,N-dimethylformamide gave the analytical sample, m.p. 321°-323°.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([B:8]([OH:10])[OH:9])=[CH:5][CH:4]=1)=O.[CH3:11][NH:12][CH3:13]>COCCOC.C1COCC1>[CH3:11][N:12]([CH2:1][C:3]1[O:7][C:6]([B:8]([OH:10])[OH:9])=[CH:5][CH:4]=1)[CH3:13]
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: CNC
Solvent: C1CCOC1
Solvent: COCCOC
Product: CN(C)Cc1ccc(B(O)O)o1
Reaction time: 0.08 h

Procedure:
To a solution of (5-formyl-2-furyl)boronic acid (50 mg, 0.36 mmol) in DME (1.0 mL) was added a 2.0M solution of dimethylamine in THF (0.53 mL, 1.0 mmol). The reaction mixture stirred for 5 minutes before resin bound MP-BH(OAc)3 (2.2 mmol/g, 0.33 g, 0.714 mmol) was added. The reaction mixture was stirred at room temperature for five hours and an additional 1 equivalent of dimethylamine in THF was added and stirring continued overnight. The reaction mixture was filtered through a plug of glass wool and the resin was washed with DME. The THF/DME filtrate solution containing the desired compound was used immediately in subsequent reactions.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[N:28]=[C:27]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[NH:26][C:25]=3[C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=3)=[CH:23][C:18]=2[O:17][CH2:16]1>C1COCC1>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[N:28]=[C:27]([CH:29]4[CH2:30][CH2:31][N:32]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:33][CH2:34]4)[NH:26][C:25]=3[C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: Cc1cccc(-c2[nH]c(C3CCNCC3)nc2-c2ccc3c(c2)OCO3)n1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2[nH]c(C3CCN(S(C)(=O)=O)CC3)nc2-c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
Methanesulfonyl chloride (0.009 mL, 0.12 mmol) and diisopropylethylamine (0.026 mL, 0.15 mmol) were added to a solution of 2-(5-benzo[1,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-6-methyl-pyridine (0.036 g, 0.10 mmol; see Example 9) in anhydrous THF (3 mL). The reaction mixture was stirred at room temperature for 3 hours. Solvent was removed under reduced pressure, and the residue was dissolved in 1 mL DMSO. The DMSO solution was filtered and injected onto preparative HPLC. HPLC purification eluting with acetonitrile:water gave 0.011 g (25%) of the title compound as a yellow solid. MS (ESP+) m/z 441.2 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.74 (t, 1H, J=7.9 Hz), 7.34 (m, 1H), 7.28 (m, 1H), 7.03 (m, 3H), 6.08 (s, 2H), 3.92 (m, 2H), 3.25 (m, 1H), 2.94 (m, 2H), 2.90 (s, 3H), 2.66 (s, 3H), 2.23 (m, 2H), 2.03 (m, 2H).
Reaction SMILES: [O-]CC.[Na+].C([O:8][CH2:9][C:10]1[N:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[N:41]([C:42]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:40]=[N:39][N:38]=3)=[CH:27][CH:26]=2)[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:13]([C:15]([OH:18])([CH3:17])[CH3:16])[N:14]=1)(=O)C>C(O)C>[OH:8][CH2:9][C:10]1[N:11]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[N:41]([C:42]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[N:40]=[N:39][N:38]=3)=[CH:29][CH:30]=2)[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:13]([C:15]([OH:18])([CH3:16])[CH3:17])[N:14]=1
Reactant: CCOC(=O)c1c(C(C)(C)O)nc(COC(C)=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(C(C)(C)O)nc(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.2 %

Procedure:
0.75 ml of a 0.15N solution of sodium ethoxide in ethanol was added to a solution of 1.69 g of ethyl 2-acetoxymethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 102(a)] in 15 ml of ethanol, and the mixture was stirred at room temperature for 5 minutes. The reaction solution was then concentrated by evaporation under reduced pressure, ethyl acetate and water were added to the residue, and the ethyl acetate layer was separated. This ethyl acetate layer was washed with an aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate, after which it was concentrated by evaporation under reduced pressure. The resulting residue was purified by recrystallization from a mixture of diethyl ether and diisopropyl ether, to give 1.47 g of the title compound as crystals, melting at 151°-152° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([NH:15][CH:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=2[S:18][CH2:17]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:5])[CH3:2]>Cl.O1CCOCC1>[C:25]([CH2:24][N:21]1[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=2[S:18][CH2:17][CH:16]([NH:15][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:22]1=[O:23])([OH:27])=[O:26]
Reactant: CCCCCCCCC(NC1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O)C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCCC(NC1CSc2ccccc2N(CC(=O)O)C1=O)C(=O)OCC
Yield: 72.8 %

Procedure:
1.7 g of the 3-(1-ethoxycarbonylnonylamino)-5-t-butoxycarbonylmethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one obtained in Example 17 was dissolved in 12 ml of a 6N solution of hydrogen chloride in dioxane and then reacted at room temperature for an hour. After this solution was concentrated under reduced pressure, 0.6 ml of triethylamine was added to the residue. This product was purified by silica gel column chromatography using a 5:2 mixture of benzene and acetic acid as the eluent. Thus, there was obtained 1.1 g of the desired compound in the form of a colorless, transparent oily material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.I[CH2:10][CH3:11].C(N(CC)CC)C>O1CCCC1>[CH2:10]([S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: CCI
Reactant: Fc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSc1ccc(F)cc1
Yield: 86.2 %

Procedure:
A solution of 4-fluorobenzenethiol (10 g, 78 mmol) and iodoethane (7.57 mL, 94 mmol) in tetrahydrofuran (100 mL) was treated with triethylamine (13.05 mL, 94 mmol) at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated, washed with hexane and dried under vacuum to provide the title compound (10.5 g, 81%).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[C:12]([C:17]4[CH:18]=[N:19][C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:13]=[CH:14][CH:15]=3)[C:10]3([C:38]4[C:29](=[CH:30][C:31]5[O:36][CH2:35][CH2:34][O:33][C:32]=5[CH:37]=4)[O:28][CH2:27]3)[C:9]2=[O:39])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[C:10]2([C:38]4[C:29](=[CH:30][C:31]5[O:36][CH2:35][CH2:34][O:33][C:32]=5[CH:37]=4)[O:28][CH2:27]2)[C:9](=[O:39])[NH:8]3)[CH:18]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(-c3cnc4ccccc4c3)c2C12COc1cc3c(cc12)OCCO3
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2cccc(-c3cnc4ccccc4c3)c2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1H)-one was obtained (99%) as a light yellow solid: mp 221-224° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.41 (d, J=2.2 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.75-7.68 (m, 1H), 7.58-7.53 (m, 2H), 7.40-7.33 (m, 2H), 7.04-7.00 (m, 1H), 6.93-6.88 (m, 1H), 6.36 (s, 1H), 5.84 (s, 1H), 4.42 (d, J=9.5 Hz, 1H), 4.25 (d, J=9.5 Hz, 1H), 4.25-4.05 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 179.0, 155.1, 150.5, 146.9, 144.6, 142.6, 138.3, 136.4, 135.5, 131.8, 130.1, 129.5, 129.1, 128.6, 127.3, 127.0, 124.8, 123.0, 111.2, 110.4, 98.9, 78.27, 64.7, 64.2, 58.4; MS (ES+) m/z 422.8 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:22]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=1)=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:21])[NH2:20])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C[C:35]([OH:37])=[O:36]>>[NH:1]([C:35]([O:37][C:4]([CH3:6])([CH3:5])[CH3:3])=[O:36])[C@@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:22]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([N+:29]([O-:31])=[O:30])=[CH:32][CH:33]=1)=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:20])[NH2:21])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(=O)O
Reactant: CC(C)C[C@@H](N)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
MM-D-Leu-Gly-L-Arg-pNA.AcOH
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[CH3:15][C:16]1[O:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:19]([C:21](O)=[O:22])[N:20]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:21]([C:19]2[N:20]=[C:16]([CH3:15])[O:17][C:18]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])[CH:9]=[N:8]1
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Product: Cc1nc(C(=O)Nc2cnn(CCCCC(C)(F)F)c2)c(-c2ccccc2)o1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=389.28.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH:2]1[C:6]([OH:8])=[O:7].Cl[Si](C)(C)[CH3:11]>CO>[CH3:11][O:7][C:6]([CH:2]1[NH:3][CH2:4][CH2:5][S:1]1)=[O:8]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)C1NCCS1
Solvent: CO
Product: COC(=O)C1NCCS1
Yield: 125 %

Procedure:
A mixture of (±)-thiazolidine-2-carboxylic acid (1.58 g, 11.9 mmol) and chlorotrimethylsilane (5.1 g, 47 mmol) in methanol (22 mL) was heated at reflux for 5 hours, cooled, and concentrated giving a solid (2.19 g, 100%).
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11]C2C=CC(Cl)=CC=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][Si:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][O:32]CCl>CN(C=O)C>[Br:1][C:2]1[N:10]([CH2:11][O:32][CH2:31][CH2:30][Si:29]([CH3:36])([CH3:35])[CH3:28])[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
To a solution of 8-bromo-3-methyl-1H-purine-2,6(3H,7H)-dione (3.5 g, 14.3 mmol, intermediate 8 step 1) in DMF (30 mL) was added potassium carbonate (3.9 g, 28.6 mmol). Then 2-(trimethylsilyl)ethoxymethyl chloride (2.37 g, 14.3 mmol) was added dropwise 0° C., it was stirred room temperature for 3 h. The mixture was partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give a crude product which was washed with ethanol and dried in vacuo to give 8-bromo-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (4.0 g, 74.9%) as a white solid. LCMS retention time 1.458 min, LCMS MH+ 377.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.C(OCC)(=O)C.ClCCl.ClCCl.CO>[CH3:39][O:38][C:34]1[CH:33]=[C:29]([CH:28]=[C:27]([O:26][CH3:25])[C:35]=1[O:36][CH3:37])[C:30]([N:13]1[CH2:14][CH2:15][C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([CH2:16][CH2:17][OH:18])[CH2:12]1)=[O:31]
Reactant: COc1ccc(C2(CCO)CCNC2)cc1OC
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1ccc(C2(CCO)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine (5.34 g, 21.2 mmol) and sodium carbonate (1.24 g, 11.7 mmol) in ethyl acetate/water (4/1) (120 mL). Cool the reaction mixture to −5° C. with an salt-ice bath. Slowly, add 3,4,5-trimethoxybenzoyl chloride (5.14 g, 22.3 mmol) as a solution in ethyl acetate (60 mL) at a rate such that the temperature of the reaction mixture does not rise above 0° C. Maintain the reaction temperature at about 0° C. After 18 hours, separate the organic layer. Extract the organic layer twice with 1 M aqueous hydrochloric acid solution, saturated solution of sodium bicarbonate, water and a saturated solution of sodium chloride. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Combine the aqueous layers and neutralize with a saturated solution of sodium bicarbonate. Extract the neutralized aqueous layers with dichloromethane. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain another residue. Combine the residues and chromatograph on silica gel eluting with 10/1 dichloromethane/methanol to obtain a residue. Combine the residue and dichloromethane (100 mL), and extract 3 times with 1M hydrochloric acid solution and saturated solution of potassium carbonate. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the title compound: Rf=0.23 (silica gel, 10/1 ethyl acetate/methanol).