Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15]CC)=[O:14])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cc1cccc(OCc2ccc(C)cc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(COc2cccc(CC(=O)O)c2)c(C)c1
Reaction time: 3 h

Procedure:
To a stirred solution Ethyl 2-(3-(2,4-dimethylbenzyloxy)phenyl)acetate (Step A, 0.900 g, 3.0 mmol) in absolute ethanol (25 ml) was added 1N NaOH (10 ml) at room temperature. The reaction mixture was stirred for 3 hours, or until all the starting material is gone, concentrated and diluted with chloroform and acidified by 1M HCl to bring the pH to 3.5-4. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to give the title compound as white solid.
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][N:6]1[CH2:10][C@H:9]([O:11][CH3:12])[C@@H:8]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:7]1)C.[C:23]([O:27][C:28]([C:30]1[CH2:35][CH2:34][C:33]2[S:36][C:37]([NH2:39])=[N:38][C:32]=2[N:31]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([C:30]1[CH2:35][CH2:34][C:33]2[S:36][C:37]([NH:39][C:4](=[O:22])[CH2:5][N:6]3[CH2:10][C@H:9]([O:11][CH3:12])[C@@H:8]([NH:13][C:14]([C:16]4[S:17][C:18]([Cl:21])=[CH:19][CH:20]=4)=[O:15])[CH2:7]3)=[N:38][C:32]=2[N:31]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)C1=Nc2nc(N)sc2CC1
Reactant: CCOC(=O)CN1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OC)C1
Product: CO[C@H]1CN(CC(=O)Nc2nc3c(s2)CCC(C(=O)OC(C)(C)C)=N3)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
94.1 In analogy to example 25.3 {(3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-pyrrolidin-1-yl}-acetic acid ethyl ester (example 25.2) was reacted with 2-amino-6,7-dihydro-thiazolo[5,4]pyridine-5-carboxylic acid tert-butyl ester (CAS 365996-05-0) to give 2-(2-{(3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-pyrrolidin-1-yl}-acetylamino)-6,7-dihydro-thiazolo[5,4-]pyridine-5-carboxylic acid tert-butyl ester as off-white solid. MS 556.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:13][CH:12]([O:14][CH3:15])[CH2:11]2)[C:5]([O:16][CH2:17][CH3:18])=[C:4]([CH:19](O)[CH3:20])[CH:3]=1.CN(C)C=O.S(Cl)([Cl:29])=O>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:13][CH:12]([O:14][CH3:15])[CH2:11]2)[C:5]([O:16][CH2:17][CH3:18])=[C:4]([CH:19]([Cl:29])[CH3:20])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOc1c(C(C)O)cc(Cl)c(C#N)c1N1CC(OC)C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1c(C(C)Cl)cc(Cl)c(C#N)c1N1CC(OC)C1
Reaction time: 2 h
Yield: 91.1 %

Procedure:
6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-(3-methoxyazetidin-1-yl)benzonitrile (30 mg, 0.1 mmol) (racemic mixture) was dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (100 μL, 1 mmol). Thionyl chloride (18 μL, 0.24 mmol) was added dropwise at room temperature and the reaction was stirred for 2 hrs. The reaction was diluted with EtOAc, washed with water and saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give the crude 6-chloro-4-(1-chloroethyl)-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile (0.030 g, 100%). LCMS calculated for C15H19Cl2N2O3(M+H)+: m/z=329.1; found: 329.1.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([O-])=[O:4].[O-]CC.[Mg+2].[O-]CC.[CH:16]1(C(O)=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CO.O1CCCC1>[CH:16]1([C:3]([CH2:2][C:1]([O:7][CH3:8])=[O:6])=[O:4])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(O)C1CCCC1
Reactant: COC(=O)CC(=O)[O-]
Agent: CC[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+2]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CC(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
In 200 mL of methanol, was dissolved 8.91 g (75.4 mmol) of monomethyl malonate, and the resulting solution was mixed with 4.30 g (37.5 mmol) of magnesium ethoxide, and stirred for 4 hours at room temperature. The reaction solution was concentrated and the residue was dried under reduced pressure. In 120 mL of tetrahydrofuran, was dissolved 4.10 mL (37.7 mmol) of cyclopentanecarboxylic acid, and the resulting solution was mixed with 6.69 g (41.2 mmol) of carbonyldiimidazole, followed by stirring for 2.5 hours. The reaction solution was added to a dry magnesium salt and the resulting mixture was stirred at room temperature for 221 hours. The reaction solution was concentrated; the residue was mixed with 150 mL of 2 N hydrochloric acid, extracted with ethyl acetate, and washed with an aqueous sodium hydrogencarbonate solution and then saturated sodium chloride water. The resultant was dried over sodium sulfate anhydride, filtered, and concentrated. The residue was distilled (0.15 mmHg, 51 to 55° C.) to give 5.72 g (33.4 mmol, 88.8%) of methyl 2-cyclopentanecarbonylacetate as an anhydrous liquid. Similarly to Example 133, 2.32 g (8.39 mmol, 57.0%) of pale yellow crystals were obtained from 5.72 g (33.4 mmol) of methyl 2-cyclopentanecarbonylacetate.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[C:7]=1[C:8]([O:10]C)=[O:9].Cl>>[CH3:1][C:2]1[O:3][C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1c(C)oc2ccccc2c1=O
Agent: Cl
Product: Cc1oc2ccccc2c(=O)c1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 10.0 g. (0.0458 mole) of methyl 2-methyl-4-oxo-4H-1-benzopyran-3-carboxylate in 100 ml. of conc. hydrochloric acid was maintained at 80°-90° for 20 minutes. Ice (400 g.) was added and the separated tacky solid was filtered and washed well with water. The crude product was dissolved in 300 ml. of 5% sodium bicarbonate and the insoluble portion was extracted away with 300 ml. of ether. The aqueous phase was acidified with conc. hydrochloric acid to give 6.4 g. (68.3%) of white acid; m.p. 120°-135°. Recrystallization from 2-propanol gave pure product; m.p. 145°-147°.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[CH:27](O)=[O:28].C(OC(=O)C)(=O)C>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][N:18]([CH:27]=[O:28])[CH:17]([CH3:21])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=CO
Reactant: Cc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1c(N2CCN(C=O)C(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 80 °C

Procedure:
1-Cyclopropyl-7-(3-methyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.4 g) is added to a mixture of formic acid (1.7 ml) and acetic anhydride (2.2 ml) at 0° C. After the addition, the mixture is heated at 80° C. for 2 hours. To the reaction mixture is added water, and the mixture is extracted with dichloromethane. After removing the solvent by concentration, the resulting residue is recrystallized from methanol to give 1-cyclopropyl-7-(4-formyl-3-methyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.13 g), as white powder, m.p. 236°-239° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][C:32](OC)=[O:33])(=[O:30])=[O:29])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[BH4-].[Na+].CO>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][CH2:32][OH:33])(=[O:29])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: COC(=O)CS(=O)(=O)N[C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NS(=O)(=O)CCO)no2)cc1C#N
Temperature: 75 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
Prepared using General Procedure 18: To a stirred solution of (R)-methyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl) sulfamoyl)acetate (0.72 g, 1.5 mmol) in THF (25 mL) was added sodium borohydride (0.24 g, 6.2 mmol) at room temperature. The reaction was heated to 75° C. and methanol (0.06 mL, 1.5 mmol) was added dropwise. After 1 h, the reaction was cooled and concentrated. The residue was partitioned between DCM and 0.5N HCl. The organic layer was dried over MgSO4, concentrated, and recrystallized from methanol to give 0.40 g (60%) of (R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide 186. LCMS-ESI (m/z) calculated for C23H24N4O5S: 468.2; found 491.1 [M÷Na]+, tR=8.64 min (Method 2). Elemental Analysis determined for C23H24N4O5S; C calculated=58.96%; found=58.86%; H calculated=5.16%; found=5.08%; N calculated=11.96%; found=11.78%. 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J=2.2 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 8.10 (d, J=7.7 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.42 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.1 Hz, 1H), 5.05 (q, J=7.9 Hz, 1H), 4.94-4.69 (m, 2H), 4.30-3.91 (m, 2H), 3.49 (ddd, J=17.4, 8.8, 3.5 Hz, 1H), 3.39 (td, J=4.8, 1.6 Hz, 2H), 3.25-3.07 (m, 1H), 2.71 (dtd, J=11.5, 8.0, 3.6 Hz, 1H), 2.11-1.95 (m, 1H), 1.48 (d, J=6.1 Hz, 6H). 13C NMR. (101 MHz, CDCl3) δ 173.30, 168.79, 162.95, 143.72, 142.80, 134.25, 134.04, 129.06, 127.76, 127.23, 123.52, 116.84, 115.41, 113.72, 104.06, 72.94, 59.01, 57.56, 55.84, 34.85, 31.61, 21.88. Chiral HPLC: (R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide was eluted with methanol (Chiral Method 2): 99.9% ee, tR=8.59 min. (S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide 187 was synthesized in an analogous fashion from (S)-methyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl) sulfamoyl)acetate: >99.9% ee, tR for (S)-enantiomer=6.62 min (Chiral Method 2).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7].[Br-].[Li+].CN(C=O)C.Cl>O>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1O
Agent: Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(O)c(O)c1
Temperature: 180 °C
Yield: 66.9 %

Procedure:
To a 4-necked 1 L round bottom flask equipped with a mechanical stirrer and a condenser, 3-methoxy-4-hydroxybenzonitrile 2a (70.7 g, 0.47 mole), lithium bromide (81.3 g, 0.94 mole), and N,N′-dimethylformamide (220 mL) were added successively at 25° C., followed by heating in an oil bath at 180° C. for 10 hours. The reaction mixture was allowed to cool to 85° C. Water (285 mL) was then added, and upon cooling to 25° C., and treatment with concentrated hydrochloric acid proceed. The resulting mixture was extracted with ethyl acetate (300 mL×2). The extract was concentrated under reduced pressure to give a pale brown solid. Water (430 mL) was added and the mixture was then heated till the mixture became homogeneous. After the reaction mixture was cooled down to approximately 40° C., 3,4-Dihydroxybenzonitrile was precipitated out and the reaction mixture was further cooled to 10° C. so as to ensure complete precipitation. The resulting solid was isolated by filtration and dried under reduced pressure. 3,4-Dihydroxybenzonitrile (42.5 g) was obtained as a white solid with a yield of 67% and a purity of greater than 99% as indicated by HPLC analysis.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7](=[N:9][C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH3:8])[CH2:5][CH2:4][O:3]1.C(N(CC)CC)C.Cl.C(=O)([O-])O.[Na+]>O>[OH:3][CH2:4][CH2:5][C:6]1[C:2](=[O:1])[N:11]2[N:12]=[CH:13][CH:14]=[C:10]2[NH:9][C:7]=1[CH3:8]
Reactant: CC(=Nc1cc[nH]n1)C1CCOC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1[nH]c2ccnn2c(=O)c1CCO
Temperature: 100 °C
Yield: 90.8 %

Procedure:
In 7.5 ml of water were suspended 1.17 g (6.04 mmol) of 3-{[1-(tetrahydro-2-oxo-3-furyl)ethylidene]amino}-pyrazole, and 0.73 g (7.23 mmol) of triethylamine were added to the suspension. The resultant mixture was stirred for 2 hours in an oil bath heated to 100° C. Thereafter, the reaction mixture was cooled with ice water, and concentrated hydrochloric acid was added thereto with stirring to adjust the pH of the reaction mixture to about 2 (deposit solids). Furthermore, a saturated aqueous solution of sodium hydrogencarbonate was added to adjust the pH of the mixture to about 4. Insoluble solids were collected by filtration, washed several times with water and air-dried to obtain 1.06 g (yield: 90.6%) of the intended product.
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][NH:15][CH2:16]3)[C:12]2=[O:19])=[CH:7][CH:6]=1.[N:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)=[C:23]=[O:24].CCN(CC)CC>ClCCl>[F:33][C:32]([F:34])([F:35])[O:31][C:28]1[CH:27]=[CH:26][C:25]([NH:22][C:23]([N:15]2[CH2:14][CH:13]3[CH:17]([CH2:18][N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][C:3]([F:2])([F:20])[F:21])=[CH:6][CH:7]=4)[C:12]3=[O:19])[CH2:16]2)=[O:24])=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C1C2CNCC2CN1c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)N1CC2CN(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
2-(4-Trifluoromethoxy-phenyl)-hexahydro-pyrrolo[3,4-c]pyrrol-1-one, hydrochloride (0.11 g, 0.36 mmol), 1-isocyanato-4-(trifluoromethoxy)benzene (0.15 g, 0.72 mmol) and Et3N (0.15 g, 1.44 mmol) were added to dichloromethane (2 mL), the mixture was stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure, purified by prep-HPLC to yield the title compound (50 mg, 28%) as white solid. 1H NMR (300 MHz, CDCl3): δ 7.68-7.65 (m, 2H), 7.42-7.40 (m, 2H), 7.39-7.13 (m, 4H), 4.18-4.03 (m, 3H), 3.79-3.69 (m, 2H), 3.45-3.38 (m, 2H), 3.22-3.20 (m, 1H); LC-MS: 489.8 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH3:24]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH3:24]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3cc(Cl)ccc3Cl)c(=O)c12
Reactant: CI
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1-c1cc(Cl)ccc1Cl)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 70.3 %

Procedure:
A mixture of (4S,7R)-2-(2,5-dichloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 44; 12.55 g, 37.2 mmol) and iodomethane (12 mL, 193 mmol) in dimethylformamide (75 mL) was heated at 100° C. for 3 h and then cooled to room temperature. The solvent was evaporated, dichloromethane (300 mL) was added and the solution was washed with saturated aqueous sodium thiosulfate (100 mL), water (2×100 mL), and brine (100 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by flash column chromatography, eluting with 50-100% ethyl acetate/petroleum ether. Fractions homogeneous for the product were evaporated and ethyl acetate (100 mL) was added. The mixture was stirred at room temperature for 10 min and then hexane (300 mL) was added. The mixture was stirred at room temperature for 10 min and then cooled to 0° C. and filtered. The filter cake was washed with hexane and dried. The solid was dissolved in ethanol (100 mL) and treated with activated charcoal (0.8 g). The mixture was stirred at room temperature for 30 min, filtered through celite, and then evaporated. The residue was dried at 70° C. overnight to give (4S,7R)-2-(2,5-dichloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (9.18 g, 70%) as a white solid. ES(+)-MS (M+H) 351.
Reaction SMILES: [Br:1][C:2]1[N:10](C(OC(C)(C)C)=O)[C:9]2[C:4](=[N:5][C:6]([O:18][CH3:19])=[CH:7][CH:8]=2)[C:3]=1[CH2:20][C:21]([O:23]CC)=[O:22].O[Li].O>C1COCC1.CO.O>[Br:1][C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([O:18][CH3:19])=[CH:7][CH:8]=2)[C:3]=1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)Cc1c(Br)n(C(=O)OC(C)(C)C)c2ccc(OC)nc12
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc2[nH]c(Br)c(CC(=O)O)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
tert-Butyl 2-bromo-3-(2-ethoxy-2-oxoethyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (380 mg, 0.9 mmol) was dissolved in 12 mL of THF/MeOH/H2O (3/2/1) and to it was added LiOH.H2O (116 mg, 2.7 mmol). The reaction mixture was allowed to stir at ambient temperature for 3 hours and then purified by RP HPLC eluting with acetonitrile/water to afford 220 mg of 2-(2-bromo-5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetic acid. Dissolved 200 mg of the above acid (0.7 mmol) and (S)-methyl 3-(3-allylphenyl)-2-aminopropanoate hydrochloride (197 mg, 0.77 mmol) in 5 mL of DMF and to it was added N,N-diisopropylethylamine (366 μL, 2.1 mmol). The reaction mixture was cooled down to 0° C. and to it was added HATU (319 mg, 8.4 mmol), and then it was allowed to stir at ambient temperature for 20 minutes. The reaction mixture was purified by RP HPLC eluting with acetonitrile/water (with 0.1% TFA) to afford 210 mg (0.43 mmol) of (S)-methyl 3-(3-allylphenyl)-2-(2-(2-bromo-5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamido)propanoate which was dissolved in 5 mL of CH2Cl2 and cooled down to 0° C. To it were added N,N-diisopropylethylamine (0.15 mL, 0.86 mmol), di-tert-butyl carbonate (113 mg, 0.86 mmol) and 4-dimethylaminopyridine (5.2 mg, 0.04 mmol). The resulting mixture was allowed to stir for 5 minutes and then partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over MgSO4, filtered and the filtrate was concentrated to dryness. It was purified by silica gel chromatography eluting with EtOAc/hexanes) to afford 230 mg of (S)-tert-butyl 3-(2-(3-(3-allylphenyl)-1-methoxy-1-oxopropan-2-ylamino)-2-oxoethyl)-2-bromo-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate MS (m/z): 586.0 [M+H]+; HPLC retention time 4.86 min (5-99% acetonitrile:water with 0.05% formic acid).
Reaction SMILES: [C@@H:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:21](Cl)(=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:21]([C@@:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3])(=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC(=O)[C@@]1(n2cnc3c(=O)[nH]c(N)nc32)O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 100 mL flask was added guanosine (2.0 g, 7.06 mmol) and N,N-dimethyl-4-aminopyridine (0.017 g, 0.14 mmol). N,N-dimethylformamide (25 mL) was added via cannula with stirring, the flask was purged with argon gas and pyridine (14 mL) was added via cannula. The slurry was allowed to cool 10 min. in an ice/NaCl bath and lauroyl chloride (2.12 mL, 9.2 mmol) was added dropwise. The mixture was allowed to stir while it slowly warmed to 25° C. After 18 h, the mixture was poured into 300 mL of ice-cold 0.1 M sodium bicarbonate solution giving a white solid which was isolated by suction filtration, washed with 3×100 mL hot water, air dried, and recrystallized from hot methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@@:8](O)([CH3:23])[CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]2([CH3:23])[CH2:9][N@:10]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[CH:7]=1
Reactant: C[C@@](O)(CNS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F
Agent: CC1(c2cc(Br)ccc2F)C[N@@]1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(c2cc(Br)ccc2F)C[N@]1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N—[(S)-2-(5-bromo-2-fluoro-phenyl)-2-hydroxy-propyl]-2-nitro-benzenesulfonamide (20.8 g, 48 mmol) in CH2Cl2 (400 ml) was added PPh3 (19.2 g, 72.4 mmol) at 0-5° C. and diethyl azodicarboxylate (11.6 ml, 72.4 mmol). The reaction mixture was stirred for 24 h at 25° C. and concentrated. The title compound was obtained after chromatographic purification over silica gel (hexane-EtOAc 20:1 to 2:1) as yellow crystals: TLC (toluene-EtOAc 3:1): Rf=0.69; HPLC RtH5=1.308 min; 1H NMR (360 MHz, CDCl3): δ 8.31 (m, 1H), 7.28 (m, 3H), 7.60 (dd, 1H), 7.42 (m, 1H), 6.91 (dd, 1H), 3.24 (s, 1H), 2.81 (s, 1H), 2.06 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[OH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C)C=O>[CH3:2][O:3][C:4]([C:6]1([NH:11][C:23]([C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]=2[OH:12])=[O:24])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: COC(=O)C1(N)CCCC1
Reactant: O=C(O)c1ccc2ccccc2c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(NC(=O)c2ccc3ccccc3c2O)CCCC1
Reaction time: 48 h
Yield: 43 %

Procedure:
1.00 g 1-amino-cyclopentanecarboxylic acid methyl ester hydrochloride, 0.698 g 1-hydroxy-2-naphthoic acid, 2.12 g HATU and 1.94 ml N,N′diisopropyl-ethylamine in 40 ml of dimethylformamide were stirred at 65° C. for 1 hour, followed by room temperature for 2 days. Water was added and the mixture was extracted with diethyl ether three times. The combined organic layers were dried with magnesium sulfate and concentrated in vacuo. Purification by flash chromatography on silica with heptane/ethyl acetate afforded 0.5 g of 1-[(1-Hydroxy-naphthalene-2-carbonyl)-amino]-cyclopentanecarboxylic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[Br:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=1>>[Br:34][C:35]1[CH:43]=[CH:42][C:38]([CH2:39][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[CH3:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]3[OH:13])[CH:5]=2)=[CH:37][CH:36]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: Cc1cccc2c1c(Cc1ccc(Br)cc1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
4-Methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 23-(1) and 4-bromobenzoyl chloride were treated in a manner similar to Example 27 to give the titled compound as a colorless powder. APCI-Mass m/Z 462/464 (M−H). 1H-NMR (DMSO-d6) δ 2.38 (s, 3H), 3.24 (m, 1H), 3.30-3.47 (m, 4H), 3.68 (m, 1H), 4.18 (s, 2H), 4.52 (t, J=5.5 Hz, 1H), 5.08 (d, J=5.3 Hz, 1H), 5.15 (d, J=5.0 Hz, 1H), 5.17 (d, J=5.8 Hz, 1H), 5.34 (d, J=9.2 Hz, 1H), 6.71 (d, J=7.1 Hz, 1H), 6.98 (t, J=7.7 Hz, 1H), 7.13 (d, J=8.3 Hz, 2H), 7.15 (s, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H).