Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])[CH:8]=1)[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:15]2[CH:20]=[C:19]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)[CH:18]=[CH:17][C:16]=2[F:22])=[O:23])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Reactant: OB(O)c1ccc(F)cc1
Product: CCOC(=O)COc1cccc(NC(=O)c2cc(-c3ccc(F)cc3)ccc2F)c1

Procedure:
The phenyl bromide (139) (100 mg, 0.25 mmol) was coupled to 4-fluoro-phenylboronic acid (33 mg, 0.23 mmol) using Method E. During this reaction, partial hydrolysis occurred. The residue was extracted using Work-up E1 to give a mixture of acid and ester, which was used without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[O:8]=[C:3]1[CH:2]([O:1][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:7][CH2:6][CH2:5][NH:4]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NCCCC1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCCNC1=O
Reaction time: 0.5 h

Procedure:
To a suspension of 3-hydroxy-piperidin-2-one (500 mg, 4.34 mmol, 1.0 eq) and triethylamine (0.908 mL, 6.51 mmol, 1.5 eq) in dichloromethane (3 mL) at 0° C. was added dropwise methanesulfonyl chloride (497 mg, 4.34 mmol, 1.0 eq) dissolved in dichloromethane (1 mL). The reaction was complete within 30 min as judged by LCMS. An orange precipitate was filtered, redissolved in dichloromethane and purified by column chromatography (MeOH/CH2Cl2) to give the title compound as a white waxy solid (204 mg, 1.056 mmol, 24.3% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 5.78 (br. s, 1H) 4.94-5.05 (m, 1H) 3.30-3.44 (m, 2H) 3.27 (s, 3H) 2.24-2.37 (m, 1H) 2.08-2.21 (m, 1H) 1.98-2.08 (m, 1H) 1.79-1.96 (m, 1H). MS (m/z, MH+): 193.7
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+]=[N-])[CH2:10][C@H:9]1[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>O1CCOCC1.[Pd]>[C:1]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@H:9]1[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1COCCO1
Product: CN(C)C(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 98.4 %

Procedure:
To a solution of (2S,4S)-1-Boc-4-azido[(dimethylamino)carbonyl]pyrrolidine (9 g, 32 mmol) prepared in Step B in dioxane (30 mL) was added dropwise Pd/C (900 mg). The reaction mixture was stirred under hydrogen condition for 24 h, filtered through Celite, and concentrated in vacuo to give the title compound as an oil (8.1 g, 98.5%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[N:10]([O-])=O.[Na+].O.O.Cl[Sn]Cl.[OH-].[K+]>Cl.O>[NH:1]([C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[NH2:10]
Reactant: O=N[O-]
Reactant: COc1ncccc1N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Solvent: O
Product: COc1ncccc1NN
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a stirred solution of 3-amino-2-methoxypyridine (5 g, 40.3 mmol) in 6N HCl (80 mL) was added dropwise a solution of NaNO2 (2.78 g, 40.3 mmol) in water (50 mL) at 0° C. After 30 min at this temperature, a solution of SnCl2.2H2O (22.72 g, 101 mmol) in 6N HCl (80 mL) was added dropwise at 0° C. The reaction mixture was stirred 90 min at 0° C. The reaction mixture was adjusted to pH˜10-11 with a solution of KOH 40% in water and extracted with EtOAc. The combined organic layers were washed with water, dried over Na2SO4 and evaporated under reduced pressure to afford the title product (4.97 g, 33.9 mmol, 84% yield) as red oil. tR: 0.31 min (LC-MS 2); ESI-MS: 140 [M+H]+ (LC-MS 2).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([CH3:17])([CH3:16])[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:8]=2[CH:25]=1)(=O)[CH3:2].Cl.[NH2:27][OH:28]>N1C=CC=CC=1>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[C:8]2[CH:25]=[C:4]([C:1](=[N:27][OH:28])[CH3:2])[CH:5]=[CH:6][C:7]=2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([CH3:17])([CH3:16])[N:10]=1
Reactant: CC(=O)c1ccc2c(c1)C(c1ccccc1F)=NC(C)(C)C(=O)N2C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1ccc2c(c1)C(c1ccccc1F)=NC(C)(C)C(=O)N2C

Procedure:
A solution of 13.66 g (40.37 mmol) of 7-acetyl-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one and 13.6 g (0.196 mol) of hydroxylamine hydrochloride in 50 ml of pyridine is stirred at room temperature for 18 hours, then poured on to ice and extracted with methylene chloride/ethanol (9:1). The organic phase is washed successively with 3 N hydrochloric acid and water, dried and evaporated. The residue is chromatographed on 150 g of silica gel using methylene chloride as the elution agent and there is obtained, from ether, 5-(o-fluorophenyl)-1,3-dihydro-7-[1-(hydroxyimino)-ethyl]-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one of melting point 199°.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[N:4](COCC[Si](C)(C)C)[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:21]=1.ClC1C2C(=O)NN=CC=2N(COCC[Si](C)(C)C)C=1C1C=CC(OC(F)F)=C(OC2CCC2)C=1>>[Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[NH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:21]=1
Reactant: COc1ccc(-c2c(Cl)c3c(=O)[nH]ncc3n2COCC[Si](C)(C)C)cc1OCC1CC1
Agent: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CCC3)c2)c(Cl)c2c(=O)[nH]ncc21
Product: COc1ccc(-c2[nH]c3cn[nH]c(=O)c3c2Cl)cc1OCC1CC1
Yield: 54.6 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 32-(b) except for using 340 mg (0.71 mmol) of 3-chloro-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 47-(a) in place of 3-chloro-2-(3-cyclobutoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 134 mg of the title compound was obtained as a white solid. (Yield: 55%)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[O:7])[O:4][C:3]=1[CH2:8]I.[O:10]=[C:11]1[CH:15]([S:16][C:17]2[C@H:18]([CH3:31])[C@@H:19]3[C@@H:26]([C@H:27]([OH:29])[CH3:28])[C:25](=[O:30])[N:20]3[C:21]=2[C:22]([O-:24])=[O:23])[CH2:14][CH2:13][NH:12]1.[Na+].CN(C)C=O>C(Cl)(Cl)Cl.C(OCC)(=O)C>[O:10]=[C:11]1[CH:15]([S:16][C:17]2[C@H:18]([CH3:31])[C@@H:19]3[C@@H:26]([C@H:27]([OH:29])[CH3:28])[C:25](=[O:30])[N:20]3[C:21]=2[C:22]([O:24][CH2:8][C:3]2[O:4][C:5](=[O:7])[O:6][C:2]=2[CH3:1])=[O:23])[CH2:14][CH2:13][NH:12]1
Reactant: Cc1oc(=O)oc1CI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(SC3CCNC3=O)[C@H](C)[C@H]12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1oc(=O)oc1COC(=O)C1=C(SC2CCNC2=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 45.7 %

Procedure:
A solution of 66 mg of 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl iodide (prepared by heating 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl bromide and sodium iodide under reflux in acetone) in chloroform was added to a mixture of 47.6 mg of sodium (1R, 5S, 6S)-2-(2-oxo-3-pyrrolidinylthio)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate and 0.4 ml of dry dimethylformamide. The mixture was stirred at room temperature for 80 minutes and then at 30°-45° C. for 4.5 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed four times with an aqueous solution of sodium chloride. The extract was dried and the solvent was distilled off under reduced pressure. The residue was purified by Lobar column chromatography (Merck, LiChroprep Si60, size A), eluted with a 10:1 by volume mixture of ethyl acetate and methanol, to give 27.4 mg of the title compound in the form of a colorless powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li][C:11](C)(C)[CH3:12].ICC>C1COCC1>[CH2:11]([C:5]1[S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)[CH3:12]
Reactant: c1ccc2sccc2c1
Reactant: [Li]C(C)(C)C
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cc2ccccc2s1

Procedure:
2-Ethylbenzo[b]thiophene was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 8.9 mmoles, 5.3 ml), iodoethane (8.9 mmoles, 0.72 ml) and THF (20 ml). 1.2 g (99%) of a yellow liquid was isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[CH3:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:15])=[C:9]([OH:13])[CH:8]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CCc1cccc(O)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1ccc(Br)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
To a −10° C. solution of 3-(3-hydroxy-phenyl)-propionic acid ethyl ester (2.0 g, 10.31 mmol) in chloroform (0.2 M, 51 mL) was added N-bromosuccinimide (1.93 g, 10.83 mmol). After stirring at RT overnight, the solution was concentrated in vacuo and purified by flash column chromatography (SiO2, 5% to 15% ethyl acetate/hexanes) to give the product as a colorless oil (0.45 g, 16%).
Reaction SMILES: C([O:9][C@H:10]1[C@H:14]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:13][C@H:12]([CH2:24][O:25][S:26]([NH2:29])(=[O:28])=[O:27])[C@H:11]1[O:30]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.N.CO>>[S:26](=[O:28])(=[O:27])([O:25][CH2:24][C@H:12]1[CH2:13][C@@H:14]([NH:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)[C@H:10]([OH:9])[C@@H:11]1[OH:30])[NH2:29]
Reactant: NS(=O)(=O)OC[C@H]1C[C@@H](NC(=O)c2ccncc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: N
Solvent: CO
Product: NS(=O)(=O)OC[C@H]1C[C@@H](NC(=O)c2ccncc2)[C@H](O)[C@@H]1O
Yield: 40.1 %

Procedure:
A solution of (1S,2R,3R,5R)-3-{[(aminosulfonyl)oxy]methyl}-5-(isonicotinoylamino)cyclopentane-1,2-diyl dibenzoate (61.1 mg, 0.113 mmol) in a 7.00 M solution of ammonia in MeOH (1.50 mL, 10.5 mmol) was stirred for 2 days. The reaction mixture was then concentrated in vacuo and purified via reverse phase C18 preparative HPLC eluting with a gradient of 5 to 70% of 0.1% FA/95% ACN/5% H2O in 0.1% FA/99% H2O/1% ACN over 16 min to afford the title compound (15.0 mg, 40%). 1H NMR (CD3OD, 300 MHz) δ: 8.67 (m, 2H), 7.78 (m, 2H), 4.34-4.32 (m, 1H), 4.19-4.17 (m, 2H), 3.93-3.92 (m, 2H), 2.38-2.31 (m, 1H), 1.76-1.72 (m, 1H), 1.43-1.38 (m, 1H) ppm. LC/MS: Rt=0.76 min, ES+ 332 (FA standard).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](C1NC=CN=1)([C:20]1[NH:21]C=CN=1)=[O:19].C(CN)O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:21][CH2:20][CH2:18][OH:19])=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Solvent: NCCO
Solvent: CN(C)C=O
Product: O=C(NCCO)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 94.6 %

Procedure:
A solution of 4-benzyloxy benzoic acid (20 g, 87.6 mmol), 1,1,-carbonyl-diimidazole (14.9 g, 91.8 mmol) and DMF (80 ml) was stirred at 50° C. for 1 h. The solution is cooled to 0° C., and ethanolamine (25% in water, 81.2 g) is added. After 45 min., the precipitate was filtered to give 4-benzyloxy-N-(2-hydroxy-ethyl)-benzamide (22.49 g, 94.5%) as a white solid. MS: me/e=271 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH:16](SC)[C:17]#[N:18]>O1CCCC1.[Ni]>[NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]#[N:18]
Reactant: CSC(C#N)c1cccc(C(=O)c2ccccc2)c1N
Agent: [Ni]
Solvent: C1CCOC1
Product: N#CCc1cccc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
To a solution of 19.4 g (0.069 mole) of 2-amino-3-benzoyl-α-(methylthio)benzeneacetonitrile in 200 ml of tetrahydrofuran was added 160 g of commercial Raney nickel which had been washed three times with water and three times with tetrahydrofuran. The mixture was stirred at ambient temperature for 10 minutes and then filtered. The filtrate obtained was concentrated to give a solid residue. This residue was recrystallized from 2-propanol to yield 11.7 g (72%) of the titled compound as bronze needles, m.p. 137.5°-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:24][O:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH2:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)([OH:22])=[O:21]
Reactant: COC(=O)CCCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(O)CCCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 136.5 %

Procedure:
The procedure described in Example 115 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-methoxycarbonylbutyl)-3-(pyridin-3-yloxy)propanamide (41.4 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(4-carboxybutyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride (29.6 mg).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:43]1[CH:44]=[C:45]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:48])=[CH:47][C:42]=1[O:41][C@H:40]2[OH:58])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:59]1(C)C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>CO.COC(OC)OC>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:43]1[CH:44]=[C:45]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:48])=[CH:47][C:42]=1[O:41][C@H:40]2[O:58][CH3:59])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)O[C@@H](O)[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: COC(OC)OC
Solvent: CO
Product: CCc1ccc(Cc2cc3c(cc2Cl)O[C@@H](OC)[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 70 °C
Yield: 70 %

Procedure:
To a solution of 27 (35 mg, 44 μmol) in anhydrous MeOH (1 mL) and trimethylorthoformate (0.5 mL) was added 4-toluenesulfonic acid (15 mg). The mixture was heated in a closed vial at 70° C. overnight, cooled to ambient temperature, loaded onto a preparatory TLC plate, and developed using 15% EtOAc in petroleum ether to give 54 (25 mg, 70% yield). LC/MS m/z 834 (M+Na).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.II.CSC.C(=O)(O)[O-:16].[Na+]>CS(C)=O>[CH:1]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)=[O:16]
Reactant: O=C([O-])O
Reactant: Cc1ccc(C#N)cn1
Agent: II
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CSC
Product: N#Cc1ccc(C=O)nc1
Temperature: 150 °C
Yield: 50 %

Procedure:
A mixture of 6-methylnicotinonitrile (10.0 g, 84.6 mmol) and iodine (20.0 g, 78.8 mmol) in dimethylsulfoxide (150 mL) was heated at 150° C. under nitrogen for 20 minutes (reaction exhaust was scrubbed with bleach to remove dimethyl sulfide). After cooling to room temperature saturated aqueous sodium bicarbonate (200 mL) was added carefully and the resulting mixture was extracted with toluene (3×100 mL). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to give the desired product as an orange oil (5.65 g, 50%) which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 8.06 (1H, d), 8.17 (1H, dd), 9.05 (1H, d), 10.12 (1H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5]C=[CH:3][CH:2]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.C(NCC)C>O>[CH2:2]([N:1]([CH2:6][CH3:5])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1)[CH3:3]
Reactant: c1ccncc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: O
Solvent: CCNCC
Product: CCN(CC)c1ccc([N+](=O)[O-])cn1
Temperature: 120 °C
Yield: 86 %

Procedure:
The pyridine derivative of the present invention is represented by the general formula A or B. For example, 50 g of 2-chloro-5-nitropyridine and 150 ml of diethylamine were placed in a sealed tube and heated at 120° C. for 7 hr. Pure water was added to the precipitated crystal, and the crystal was collected by filtration and recrystallized from 300 ml of methanol to give 53 g of 2-diethylamino-5-nitropyridine (yield: 86%, melting point: 75° to 76° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]23[CH2:16][O:15][C@@H:14]([CH:17]4[CH2:19][CH2:18]4)[CH2:13][C@H:12]2[CH2:11][O:10][NH:9]3)[CH:7]=1>C(O)(=O)C.[Zn]>[NH2:9][C@@:8]1([C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:20])[CH2:16][O:15][C@@H:14]([CH:17]2[CH2:18][CH2:19]2)[CH2:13][C@H:12]1[CH2:11][OH:10]
Reactant: Fc1ccc(Br)cc1[C@]12CO[C@@H](C3CC3)C[C@H]1CON2
Agent: [Zn]
Solvent: CC(=O)O
Product: N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](C2CC2)C[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
Zinc dust (1.06 g, 16.2 mmol) was added to a solution of (3aR,5R,7aS)-7a-(5-bromo-2-fluorophenyl)-5-cyclopropylhexahydro-1H-pyrano[3,4-c][1,2]oxazole (C55) (311 mg, 1.08 mmol) in acetic acid (56 mL). The reaction mixture was allowed to stir at room temperature overnight. The reaction was filtered through an empty Bakerbond cartridge, eluting with ethyl acetate to remove the zinc. The filtrate was concentrated and then passed through a 4 g methanol-conditioned MCX cartridge. This was washed with methanol (4×15 mL), dichloromethane (4×15 mL) and 2 N ammonia in methanol (40 mL). The filtrate was concentrated in vacuo to give the product (225 mg), which was taken directly to the following step. LCMS m/z 291.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22](Cl)=[O:23])[CH2:17][CH2:16]1)(=[O:14])[CH3:13].Cl>>[C:12]([N:15]1[CH2:16][CH2:17][CH:18]([CH2:21][C:22]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:23])[CH2:19][CH2:20]1)(=[O:14])[CH3:13]
Reactant: Fc1ccccc1
Reactant: CC(=O)N1CCC(CC(=O)Cl)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)N1CCC(CC(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirred mixture of 50 parts of fluorobenzene and 32 parts of aluminium trichloride is added dropwise (slowly) a solution of 26.5 parts of 1-acetyl-4-piperidineacetyl chloride in 50 parts of fluorobenzene. Upon completion, stirring is continued for 2 hours at reflux temperature. The reaction mixture is cooled to room temperature and poured onto a mixture of crushed ice and a hydrochloric acid solution. The aqueous phase is separated and extracted with methylbenzene. The combined organic phases are dried, filtered and evaporated, yielding 31 parts (90%) of 2-(1-acetyl-4-piperidinyl)-1-(4-fluorophenyl)ethanone as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[O:15][C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH:9]=2)=[C:4]([CH3:31])[CH:3]=1.[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[O:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:21])=[CH:18][CH:17]=3)[CH:9]=2)=[C:4]([CH3:31])[CH:3]=1
Reactant: CCOC(=O)CCNC
Reactant: Cc1cc(Cl)ccc1-c1cc(C(Oc2ccc(C(=O)O)cc2)C2CCCCC2)c(C)o1
Product: Cc1cc(Cl)ccc1-c1cc(C(Oc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)c(C)o1
Yield: 100.3 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-{[5-(4-chloro-2-methylphenyl)-2-methyl-3-furyl](cyclohexyl)methoxy}benzoic acid (162 mg) as well as ethyl 3-(methylamino)propanoate (59 mg) to give the title compound (194 mg, 99%) as an amorphous compound.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[CH:22][C:23]5[O:24][CH2:25][CH2:26][O:27][C:28]=5[C:19]=4[O:18][CH2:17]3)[C:9]2=[O:29])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>>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2([C:20]3[CH:21]=[CH:22][C:23]4[O:24][CH2:25][CH2:26][O:27][C:28]=4[C:19]=3[O:18][CH2:17]2)[C:9]1=[O:29]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1c2ccc2c1OCCO2
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2ccccc2C12COc1c2ccc2c1OCCO2

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one was obtained (30%) as a colorless solid: mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.23 (ddd, J=7.7, 7.7, 0.5 Hz, 1H), 7.13 (d, J=7.2 Hz, 1H), 6.99-6.90 (m, 2H), 6.21 (ABq, 2H), 4.76 (ABq, 2H), 4.26 (s, 4H); 13C NMR (75 MHz, DMSO-d6) δ 178.3, 148.7, 144.5, 141.8, 132.3, 129.2, 128.6, 123.8, 122.5, 122.2, 114.1, 109.7, 80.2, 64.1, 63.9, 57.7; MS (ES+) m/z 295.9 (M+1).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH3:42])=[CH:36][CH:35]=2)([F:33])[CH3:32])[CH:25]=1)(=O)C.ClC1C=CC([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)=CC=1C(F)CC1C=CC(OCC)=CC=1>CO.C[O-].[Na+]>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C@@H:6]2[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]2[OH:4])=[CH:25][C:26]=1[C:31]([C:34]1[CH:35]=[CH:36][C:37]([O:40][CH2:41][CH3:42])=[CH:38][CH:39]=1)([F:33])[CH3:32]
Reactant: CCOc1ccc(C(C)(F)c2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Agent: CCOc1ccc(CC(F)c2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOc1ccc(C(C)(F)c2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.98 g of the 2,3,4,6-tetra-O-acetyl-1-{4-chloro-3-[1-(4-ethyoxyphenyl)-1-fluoroethyl]phenyl}-1-deoxy-β-D-glucopyranose prepared as above was dissolved in 7 ml of anhydrous methanol containing 0.11 g of sodium methoxide, and stirred for 5 hours at room temperature, and then 1 g of dried strongly acidic resin was added, and stirred overnight at room temperature. The resin was removed by filtration, and the resulting filtrate was evaporated to dryness on a rotary evaporator to afford a white solid, which was 1-{4-chloro-3-[(4-ethyoxyphenyl)-1-fluoroethyl]phenyl}-1-deoxy-β-D-glucopyranose. ESI-MS, m/z=441.2 ([M+1]).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][NH2:20])([CH3:16])[CH3:15]>>[CH3:15][CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][NH:20][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH3:16]
Reactant: CC(C)N(CCN)C(C)C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)N(CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(C)C

Procedure:
Following the procedure of Example 1, p-nitrobenzenesulfonyl chloride was reacted with N,N-diisopropyl ethylene diamine to give the free base, m.r. 86°-88° C.