Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7]1[S:11][C:10]([NH2:12])=[N:9][N:8]=1>C(OCC)(=O)C>[CH3:5][O:6][C:7]1[S:11][C:10]([N:12]=[C:1]=[O:2])=[N:9][N:8]=1
Reactant: COc1nnc(N)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-methoxy-2-amino-1,3,4-thiadiazole (40 grams) in ethyl acetate (300 ml) is added to the reaction vessel, and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-methoxy-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([SH:13])[CH:10]=[CH:11][CH:12]=1.[F:14][C:15]1[C:20](F)=[CH:19][C:18]([CH2:22][OH:23])=[C:17]([N+:24]([O-:26])=[O:25])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([S:13][C:20]2[C:15]([F:14])=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([CH2:22][OH:23])[CH:19]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Sc1cccc(C2OCCCO2)c1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1CO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(Sc2cccc(C3OCCCO3)c2)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[1,3]Dioxan-2-yl-benzenethiol (2.57 g, 14.02 mmol), prepared as described in Example 1, Step C, (4,5-difluoro-2-nitro-phenyl)-methanol (2.65 g, 14.02 mmol), and cesium carbonate (9.1 g, 28 mmol) were combined in DMF (100 mL). The resulting mixture was stirred overnight at room temperature. Water was added, and the resulting mixture was then extracted with ethyl acetate. The organic layer was dried with Na2SO4 and filtered, and the solvent was removed to yield an oil, which was purified via silica column chromatography (50% EtOAc/heptane) to yield a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:24]([O-])=O)[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1C=CC=CC=1.C(OC1C=C(C=C([N+]([O-])=O)C=1C1C=CC=CC=1)C(O)=O)C>>[NH2:24][C:16]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([O:8][CH2:1][CH3:2])[CH:10]=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: CCOc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Product: CCOc1cc(C(=O)O)cc(N)c1-c1ccccc1

Procedure:
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenylbenzoic acid with 3-ethoxy-5-nitro-4-phenylbenzoic acid, and following the procedure described, 5-amino-3-ethoxy-4-phenylbenzoic acid is obtained with a melting point of 137.5°-138.5° C.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([B:16]([OH:18])[OH:17])[CH:13]=[N:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([B:16]([OH:18])[OH:17])[CH:13]=[N:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Nc2cncc(B(O)O)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Nc1cncc(B(O)O)c1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.4 %

Procedure:
(5-(4-Methoxybenzamido)pyridin-3-yl)boronic acid (300 mg, 0.79 mmol) was dissolved in dichloromethane (15 ml). A solution of boron tribromide (1M in dichloromethane, 3.93 mL, 3.93 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with a solution of 4% sodium bicarbonate, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 225 mg (100% yield) of the title compound. Purity 98%.
Reaction SMILES: BrC1C=CC(COC2C=NN(C3CCCCO3)C(=O)C=2)=NC=1.[OH:23][C:24]1[CH:29]=[N:28][N:27]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C:26](=[O:36])[CH:25]=1.Cl[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1>>[F:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][O:23][C:24]2[CH:29]=[N:28][N:27]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)[C:26](=[O:36])[CH:25]=2)=[CH:40][CH:41]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=c1cc(O)cnn1C1CCCCO1
Agent: O=c1cc(OCc2ccc(Br)cn2)cnn1C1CCCCO1
Product: O=c1cc(OCc2ccc(F)cc2)cnn1C1CCCCO1

Procedure:
5-(4-Fluoro-benzyloxy)-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one is prepared following preparation 25a from 8.00 g (40.8 mmol) 5-hydroxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (preparation 5a) and 5.4 mL (44.9 mmol) 1-chloromethyl-4-fluoro-benzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[CH2:22][O:21][C:20](=[O:24])[NH:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:23]3[CH2:22][O:21][C:20](=[O:24])[N:19]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2COC(=O)N3)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2COC(=O)N3Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.9 %

Procedure:
To a solution of 4-(2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (43 m g, 0.13 mmol) in 2 ml anhydrous dimethylformanide was added sodium hydride (8 mg of a 60% suspension in mineral oil, 0.2 mmol) portion-wise at 0° C. The solution was stirred with a magnetic stirrer at 0° C. for 20 minutes, at which time the initial off-gassing ended. Benzyl bromide (0.02 ml, 0.17 mmol) was added in one portion and the reaction mixture was stirred at 0° C. for an hour. The solution was allowed to warm to room temperature and the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by prep TLC to give 33 mg of 4-(1-benzyl-2-oxo-1,4-dihydro-2H-benzo[d] [1,3]oxazin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester as a white solid (60%). MS: 424 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:29]1[CH:34]=[C:33]([CH2:35]OS(C)(=O)=O)[CH:32]=[N:31][CH:30]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: CS(=O)(=O)OCc1cncnc1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cncnc4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with methanesulfonic acid pyrimidin-5-ylmethyl ester gave the title compound. ES-MS m/e (%): 491.0(M+H+).
Reaction SMILES: O=[C:2]1CN[C:5](=[O:8])[CH2:4][NH:3]1.C=O.[OH:11][PH:12]([OH:14])=[O:13].P(Cl)(Cl)Cl.[OH:19]P(O)=O>C(O)(=O)C>[P:12]([CH2:2][NH:3][CH2:4][C:5]([OH:8])=[O:19])([OH:14])([OH:11])=[O:13]
Reactant: O=[PH](O)O
Reactant: O=C1CNC(=O)CN1
Agent: C=O
Solvent: CC(=O)O
Solvent: ClP(Cl)Cl
Product: O=C(O)CNCP(=O)(O)O

Procedure:
The sequence of reactions in Reaction Scheme 9a is comparable to those set forth in Reaction Scheme 9 except that N-acetylglycine XVIII is deacylated to form 2,5-diketopiperazine XXX. 2,5-diketopiperazine XXX is then reacted with formaldehyde and H3PO3 PCl3 or other H3PO3 source to produce N-(phosphonomethyl)glycine I and acetic acid. Acetic acid which is produced in the hydrolysis step can be reacted with ammonia to generate acetamide for the carboxymethylation step.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19](CC4C=CC=CC=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1OC.Cl.C1(=O)C2C(=CC=CC=2)CC1>>[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:13]2[CH2:14][C:5]3[C:6](=[CH:7][CH:8]=[CH:3][CH:4]=3)[C:11]2=[O:12])=[CH:17][CH:18]=1
Reactant: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Agent: Cl
Agent: O=C1CCc2ccccc21
Product: O=C1c2ccccc2CC1Cc1ccncc1

Procedure:
U.S. Pat. No. 6,252,081 teaches the preparation of Donepezil HCl by the reaction of 1-indanone derivative with carbonate ester. The resulting 2-alkoxycarbonyl-1-indanone derivative is halogenated with (4-pyridyl) methyl or a salt thereof and decarboxylated successively to give 2-(4-pyridyl)methyl-1-indanone derivative. On reacting the 2-(4-pyridyl) methyl-1-indanone derivative with benzyl bromide, their quaternary ammonium salts are formed, which on reduction with platinum oxide catalyst gives Donepezil HCl (Examples 1 to 3). Overall yield of Donepezil HCl 82% (98%×85%×100%×99%).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:19])[NH2:18])=O)C1C=CC=CC=1.[CH:23]1([S:27]([Cl:30])(=[O:29])=[O:28])[CH2:26][CH2:25][CH2:24]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[ClH:30].[NH:19]=[C:17]([NH:18][S:27]([CH:23]1[CH2:26][CH2:25][CH2:24]1)(=[O:29])=[O:28])[NH:16][CH2:15][CH2:14][CH2:13][C@@H:12]([C:20]([N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:22])[NH2:11]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=S(=O)(Cl)C1CCC1
Reactant: C1CCNC1
Product: Cl
Product: N=C(NCCC[C@H](N)C(=O)N1CCCC1)NS(=O)(=O)C1CCC1

Procedure:
Starting from (S)-N2-(benzyloxycarbonyl)-arginine, cyclobutanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 1.
Reaction SMILES: [N:1]1[N:2]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:4][CH:5]=1.[F:10][C:11]1[CH:39]=[CH:38][CH:37]=[CH:36][C:12]=1[CH2:13][C@H:14]1[CH2:18][NH:17][C@H:16]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[O:20])[CH2:15]1>>[N:3]1[N:2]([CH2:6][C:7]([N:17]2[CH2:18][C@H:14]([CH2:13][C:12]3[CH:36]=[CH:37][CH:38]=[CH:39][C:11]=3[F:10])[CH2:15][C@H:16]2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[CH:24][CH:23]=2)=[O:20])=[O:9])[N:1]=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2F)CN1
Reactant: O=C(O)Cn1nccn1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2F)CN1C(=O)Cn1nccn1

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid and (2S,4R)-4-(2-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 107, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, CDCl3): δ 9.14 (s, 1H), 7.71 (s, 2H), 7.44-7.40 (m, 2H), 7.27-7.17 (m, 3H), 7.12-6.86 (m, 7H), 5.30 (d, 2H), 4.83 (d, 1H), 3.59-3.53 (m, 1H), 3.23 (t, 1H), 2.98-2.76 (m, 3H), 2.62 (dd, 1H), 1.78-1.69 (m, 1H). MS (EI) for C28H25F2N5O3 found 518 (MH+).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:6]=1[N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)([CH3:3])[CH3:2]>C(O)C.[Pd]>[CH:1]([O:4][C:5]1[C:6]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:7][CH:8]=[CH:9][C:10]=1[NH2:11])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1c(N2CCN(C)CC2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)Oc1c(N)cccc1N1CCN(C)CC1
Reaction time: 22 h
Yield: 84 %

Procedure:
A mixture of 0.80 g of 1-(2-isopropoxy-3-nitrophenyl)-4-methylpiperazine and 91 mg of 10% palladium-on-carbon in 300 ml of ethanol is hydrogenated at 25° C. under 1 bar for 22 h. The mixture is filtered on Clarcel and the Clarcel is rinsed with ethanol. The filtrate is concentrated to dryness under reduced pressure and the residue is purified by chromatography on a 50 g silica cartridge, elution being carried out with pure dichloromethane and then successively with 98/2 and 95/5 v/v dichloromethane/methanol mixtures at a flow rate of 30 ml/min, so as to obtain 0.60 g of 2-isopropoxy-3-(4-methylpiperazine-1-yl)phenylamine in the form of a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:24])=[CH:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1
Reactant: Cc1cc(-c2ccc(C(=O)O)cc2)ccn1
Reactant: Nc1ccc2cccnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(=O)Nc3ccc4cccnc4c3)cc2)ccn1
Temperature: 25 °C

Procedure:
To a solution of 7-aminoquinoline (D55) (338 mg, 0.26 mmol) in DCM (3 ml) was added 4-(2-methylpyrid-4-yl)-benzoic acid (D72) (62 mg, 0.29 mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (74 mg, 0.39 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) and the reaction stirred at room temperature until complete by tlc. The resultant precipitate was filtered off to give the title compound as an off-white solid. MS(ES): MH+ 340, M-H+ 338
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:21](O)=O)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([NH2:35])[CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[C:21]1[NH:34][C:31]2[CH:32]=[CH:33][C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:29][C:30]=2[N:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCOCc1ccccc1)C(=O)O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Product: CC(C)(C)OC(=O)N[C@@H](CCCOCc1ccccc1)c1nc2cc(C(C)(C)C)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 Steps 1 and 2 using 5-(benzyloxy)-N-(tert-butoxycarbonyl)-L-norvaline and 4-tert-butyl-1,2-diaminobenzene. The crude product was purified by silica gel column chromatography eluting with 30-40% EtOAc in petroleum ether (430 mg, 52%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([NH:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:24].[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([NH:16][C:11]2([C:14]#[N:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:25])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(NC(=O)c2ccc(Cl)cc2)CCNCC1

Procedure:
A solution of 4-(4-chloro-benzoylamino)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (0.23 g, 0.63 mmol) in 4 M HCl in dioxane (30 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the hydrochloride salt. Note: The product is contaminated with some primary amide (partial hydrolysis of the nitrile). MS (ISP): 264.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)#[N:23].[Na+]>>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:32])=[O:31])=[CH:28][CH:29]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Reactant: N#Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4ccc(C#N)cc4)cc3c2C1
Yield: 34 %

Procedure:
The product of Example 29, step B and sodium 4-cyanobenzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 3:2 hexane/ethyl acetate) provided tert-butyl 8-(4-cyanophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (107 mg, 34%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.09-8.03 (m, 3H), 7.84 (dd, J=5.7, 3.9 Hz, 1H), 7.80-7.76 (m, 2H), 7.55 (d, J=8.4 Hz, 1H), 4.58 (s, 2H), 3.84 (t, J=5.7 Hz, 2H), 2.91-2.82 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:19]([O:20][C:21](=[O:25])[CH2:22][CH2:23][CH3:24])[C@H:18]([CH3:26])[O:17][C@@H:9](SC2C=CC=CC=2)[C@@H:8]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Br:35]Br>C(Cl)Cl>[C:1]([O:6][C@@H:7]1[C@@H:19]([O:20][C:21](=[O:25])[CH2:22][CH2:23][CH3:24])[C@H:18]([CH3:26])[O:17][C@@H:9]([Br:35])[C@@H:8]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: BrBr
Reactant: CCCC(=O)O[C@@H]1[C@@H](OC(=O)CCC)[C@H](C)O[C@@H](Sc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: ClCCl
Product: CCCC(=O)O[C@@H]1[C@@H](OC(=O)CCC)[C@H](C)O[C@@H](Br)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution containing 0.54 g (1.12 mmol) of 2 in 5 mL of anhydrous CH2Cl2 at 0° C. under argon was added 0.21 g (0.07 mL, 1.34 mmol) of Br2. The reaction mixture was stirred at 0° C. for 20 min then diluted with 20 mL of CH2Cl2 and washed with 3% aq NaHSO3. The organic layer was separated, dried (MgSO4) and concentrated under diminished pressure. The crude residue was then purified by flash chromatography on a silica gel column (26×4 cm). Elution with 2:1 hexanes-ethyl acetate gave 3 as a colorless oil: yield 0.49 g (96%); silica gel TLC Rf 0.21 (2:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 0.94 (q, 6H, J=7.5 Hz), 1.25 (d, 3H, J=6.3 Hz), 1.62 (m, 4H), 2.23 (m, 4H), 4.04 (m, 1H), 4.11 (dd, 1H, J=3.3 and 1.8 Hz), 4.64 (q, 2H, J=12.3 Hz), 5.30 (t, 1H, J=9.9 Hz), 5.57 (dd, 1H, J=10.2 and 3.3 Hz), 6.34 (d, 1H, J=0.6 Hz) and 7.33 (m, 5H); 13C NMR (CDCl3) δ 13.71, 17.11, 18.31, 18.47, 35.99, 36.11, 69.67, 70.27, 71.26, 73.37, 79.20, 86.35, 127.96, 128.18, 128.57, 137.18, 172.31 and 172.68. Note: this compound must be used promptly; product decomposes rather rapidly (1-2 days).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([OH:19])=[O:18])[C@@H:14]([NH:20][C:21](=[O:51])[C@H:22]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[NH:23][C:24](=[O:41])[C@@H:25]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[NH:26]C(OC(C)(C)C)=O)[C@H:12]1[OH:13]>C(O)=O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([OH:19])=[O:18])[C@@H:14]([NH:20][C:21](=[O:51])[C@H:22]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[NH:23][C:24](=[O:41])[C@@H:25]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[NH2:26])[C@H:12]1[OH:13]
Reactant: COc1ccc(C[C@H](NC(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Solvent: O=CO
Product: COc1ccc(C[C@H](NC(=O)[C@H](N)Cc2ccccc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Yield: 66.6 %

Procedure:
1-(6-Amino-9H-purin-9-yl)-1,3-dideoxy-3-[N-(β-phenyl-D-alanyl)-O-methyl-L-tyrosylamino]-β-D-ribofuranuronic acid (240 mg) was prepared by reacting 1-(6-amino-9H-purin-9-yl)-3-[N-(N-tert-butoxycarbonyl-β-phenyl-D-alanyl-O-methyl-L-tyrosylamino]-1,3-dideoxy-β-D-ribofuranuronic acid (420 mg) prepared in Example 84 with formic acid (6.7 ml) according to a similar manner to that of Example 45, mp. 175°-182° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=O)=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25]([NH:28][C:29](=[O:32])[CH2:30]Cl)[CH2:26][CH3:27].CN(C)C=[O:36]>>[Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH:30]([OH:36])[C:29]([NH:28][CH2:25][CH2:26][CH3:27])=[O:32])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCCNC(=O)CCl
Reactant: CN(C)C=O
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Br)nc2n1
Agent: [H-]
Agent: [Na+]
Product: CCCNC(=O)C(O)C1c2ccccc2C(=O)N1c1ccc2ccc(Br)nc2n1

Procedure:
The procedure is as in Example 26, but starting with 2-(7-bromo-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (12 g) in anhydrous dimethylformamide (300 cc), an oily suspension (50% by weight; 2.4 g) of sodium hydride and N-(propyl)chloroacetamide (6.9 g). After recrystallization in acetonitrile, [2-(7-bromo-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl]-N-propylglycolamide (2.1 g), m.p. 174° C., is obtained.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH:4]([OH:8])[CH2:5][CH:6]=[CH2:7].I[CH3:10].[H-].[Na+]>O1CCCC1>[CH3:10][O:8][CH:4]([CH2:5][CH:6]=[CH2:7])[CH2:3][CH:2]=[CH2:1]
Reactant: CI
Reactant: C=CCC(O)CC=C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(CC=C)OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Into a round-bottom flask, was placed a solution of hepta-1,6-dien-4-ol (2.00 g, 17.8 mmol, 1.00 equiv) and iodomethane (5.00 g, 35.2 mmol, 2.00 equiv) in tetrahydrofuran (30 mL). The solution was cooled to 0° C. and sodium hydride (1.00 g, 25.0 mmol, 1.50 equiv, 60% in mineral oil) was added to the reaction in portions. The resulting mixture was stirred overnight at room temperature, then carefully quenched with water (5 mL) and diluted with of ether (30 mL). The organics was washed with brine (2×20 mL), dried (Na2SO4), filtered and concentrated in vacuo to obtain the title compound as a colorless oil (2.00 g, 84%).
Reaction SMILES: [OH-].[Na+].C(O[C:6]([C:8](C)([C:17](=[O:19])[CH3:18])[CH2:9][CH2:10][CH2:11][CH2:12][S:13]([OH:16])(=[O:15])=[O:14])=O)C>O.CO>[CH3:6][CH:8]([C:17](=[O:19])[CH3:18])[CH2:9][CH2:10][CH2:11][CH2:12][S:13]([OH:16])(=[O:14])=[O:15]
Reactant: CCOC(=O)C(C)(CCCCS(=O)(=O)O)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)C(C)CCCCS(=O)(=O)O
Temperature: 50 °C
Reaction time: 15 h

Procedure:
A solution of 290 mg of NaOH in 3 ml water was added to the mixture of 710 mg (2.53 mmol) of 5-ethyloxycarbonyl-5-methyl-6-oxo-1-heptanesulfonic acid in 15 ml of methanol. The obtained mixture was stirred for 15 hours at 50° C. Methanol was removed by a rotary evaporator, residue was acidified to pH 1 and then solvent was removed until dry to yield 5-methyl-6-oxo-1-heptanesulfonic acid. The product thus obtained (940 mg, 4.5 mmol), 1.02 g (5.4 mmol) of 4-hydrazinobenzenesulfonic acid, and 15 ml of acetic acid was refluxing for 16 hours. The insoluble precipitate was filtered and the filtrate was evaporated. The obtained residue was column purified (RP-18, water) to yield 840 mg of the 2,3-dimethyl-3-(4-sulfobutyl)-3H-5-indolesulfonic acid (IVd). δH (200 MHz, DMSO-d6): 7.66 (1H, s, arom H), 7.6 (1H, d, 8.0 Hz, arom H), 7.4 (1H, d, 7.8 Hz arom H), 2.66 (2H, t, 6.8 Hz, CH2SO3H), 2.32 (3H, s, 2-CH3), 2.10-1.78 (2H, m, CH2), 1.53-1.26 (2H, m, CH2), 1.31 (3H, s, 3-CH3), 0.83-0.41 (2H, m, CH2).