Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][C@@H:31]([C:40](O)=[O:41])[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:40](=[O:41])[C@H:31]([CH2:30][CH2:29][CH2:28][CH2:27][NH:26][C:24]([O:23][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:25])[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of 0.73 g (5.26 mmol) of glycine ethyl ester hydrochloride and 0.74 mL (5.26 mmol) of triethylamine in 42 mL of chloroform were added successively, at 0° C., 2.0 g (5.26 mmol) of Nε -benzyloxycarbonyl-Nα -(tert-butoxycarbonyl)-L-lysine and 1.09 g (5.26 mmol) of dicyclohexylcarbodiimide. The reaction mixture was stirred overnight at room temperature. The resulting precipitate was removed by filtration and the filtrate was washed successively with 0.5N hydrochloric acid, water, 3% aqueous sodium bicarbonate solution and water, then dried over anhydrous sodium sulfate. Evaporation of the solvent afforded a residue which was triturated with ethyl acetate. Insoluble materials were removed by filtration and the filtrate was evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and isopropyl ether to give 1.15 g (48%) of the title compound as colorless crystals. The mother liquor was concentrated under reduced pressure and the residue was crystallized as before to give a second crop of crystals (0.77 g, 32.1%). Total yield 80.1%, melting point 69°-70° C. NMR and IR spectral analyses confirmed the identity of the product, which has the formula: ##STR102##
Reaction SMILES: [C:1]([N:8]1CCC(N)C[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:16]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18][N:17]=1.C([N:26]([CH2:30][CH3:31])[CH:27]([CH3:29])C)(C)C>O1CCOCC1.O>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]1[CH2:29][CH2:27][N:26]([C:16]2[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18][N:17]=2)[CH2:30][CH2:31]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(Cl)ncn1
Reactant: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)ncn1
Temperature: 150 °C

Procedure:
A suspension of Boc-4-aminopiperidine (613 mg, 3 mmol), 4-chloro-6-methylpyrimidine (433 mg, 3.3 mmol) and N,N-diisopropylethyl amine (771 L, 4.5 mmol) in dioxane (12 mL) was heated to 150° C. in the microwave for 30 minutes. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient from AcOEt to AcOEt/EtOH 9:1 as eluent. The title compound was obtained as a light yellow solid (693 mg, 79%).
Reaction SMILES: CS(C)=O.[C:5](=O)([O-])[O-].[K+].[K+].[C:11]1([C:17]2[NH:18][C:19]3[C:24]([C:25]=2[C:26](=[O:28])[CH3:27])=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.IC>O>[CH3:5][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]([C:26](=[O:28])[CH3:27])=[C:17]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1c(-c2ccccc2)n(C)c2ccccc12
Reaction time: 0.67 h
Yield: 85 %

Procedure:
Dimethylsulphoxide (12 ml) and potassium carbonate (3.31 g) were stirred for 10 min. and then 1-(2-phenyl-1H-indol-3-yl)-1-ethanone (1.41 g) was added and stirring was continued for a further 40 min. Iodomethane (0.75 ml) was added and the mixture was stirred for 2.75 h. Water (30 ml) was added and the mixture was extracted with ether (3×40 ml). The combined organic extracts were washed with water (4×40 ml), dried, and evaporated to leave an oil which was crystallised from cyclohexane to give the title compound (1.27 g), m.p. 76°-77°.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:16].[OH:17]OS([O-])=O.[K+]>C(#N)C>[C:1]1([S:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)(=[O:17])=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ccc(Sc2ccccc2)cc1F
Reactant: O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3,4-difluoroaniline (3.5 g), acetonitrile (60 ml), diphenyldisulfide (6 g) and isoamyl nitrite (8 ml) were charged to a flask and heated at 60° C. for 2 h then evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent isohexane) to give the subtitle compound. The product (3,4-difluorophenyl phenyl sulfide) was dissolved in acetonitrile (60 ml). Water (10 ml) and oxone (20 g) were added and stirred for 72 h at RT. The reaction mixture was partitioned between ether/water, the organics were separated, washed with water, then dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent 5-10% ethyl acetate/isohexane) to give the subtitle compound (2.14 g).
Reaction SMILES: [O-2:1].[Mg+2:2].[O-2].[Ca+2].[C:5](=[O:7])=[O:6]>O>[C:5](=[O:1])([OH:7])[O-:6].[Mg+2:2].[C:5](=[O:1])([OH:7])[O-:6]
Reactant: [O-2]
Reactant: O=C=O
Agent: [Ca+2]
Agent: [Mg+2]
Solvent: O
Product: O=C([O-])O

Procedure:
The second method of preparation of the aqueous solution of magnesium bicarbonate in technical solution is to add water to magnesium oxide to digest at 50˜95° C. for 0.5˜5 hours, with the weight ratio of the liquid to solid: 1˜5:1 (calculated by the weight of water and magnesium oxide). Water is added to form slurry or magnesium hydroxide and water is mixed directly based on the weight ratio of the liquid to solid: 10˜200:1 (calculated by weight of water and magnesium oxide and/or calcium oxide). Then the slurry is carbonized by carbon dioxide gas, with reaction temperature controlled at 0˜50° C. and reaction time 0.1˜5 hour. Pure aqueous solution of magnesium bicarbonate is obtained by filtration.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-])=O.[H][H]>C(O)C.[Pd]>[N:8]1([CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:16]=[CH:15][CH:14]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1cccc(CN2CCOCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CN2CCOCC2)c1
Yield: 96.6 %

Procedure:
A solution of 4-(3-nitrobenzyl)morpholine (3.0 g, 14 mmol) in ethanol (40 ml) was treated with 10% palladium on charcoal (150 mg) and hydrogenated at 50 psi until hydrogen uptake ceased (ca. 2 hours). The mixture was filtered through a glass microfibre filter paper (Whatman GF/A) and evaporated to dryness to give 3-(morpholin-4-ylmethyl)phenylamine as a colourless oil (2.6 g, 100%) which was used without purification. m/z (ES+) 193 (M++H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1cccc(F)c1
Agent: Cl
Product: O=C(CNC(=O)c1cccc(F)c1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 3-fluorobenzoic acid.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:12]([N:19]1[C:31]2[C:30]([S:32][CH3:33])=[C:29]([CH2:34][C:35]([NH2:37])=O)[CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>N1C=CC=CC=1>[CH2:12]([N:19]1[C:31]2[C:30]([S:32][CH3:33])=[C:29]([CH2:34][C:35]#[N:37])[CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CSc1c(CC(N)=O)ccc2c3ccccc3n(Cc3ccccc3)c12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CSc1c(CC#N)ccc2c3ccccc3n(Cc3ccccc3)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
32 mg of p-toluene sulfonyl chloride was added to a solution of 20 mg of 9-benzyl-1-methylthiocarbazole-2-acetamide, as obtained in Example 75, in 0.6 ml of pyridine at room temperature. The reaction mixture was then heated to 60° C. and stirred for 2 hours. The reaction mixture was then cooled to room temperature and water was added. The aqueous layer was extracted with ethyl acetate, and the organic extract was washed with a 0.5N aqueous solution of hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 50 mg of silica gel using, as eluent, a 4:1 by volume mixture of hexane and ethyl acetate to yield 18 mg of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.Cl.[NH2:24][CH2:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([NH:24][CH2:25][C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cc(N)nc1-c1ccco1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(NCc2ncc(C(F)(F)F)cc2Cl)cc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 6-amino-3-cyano-2-furan-2-yl-pyridin-4-yl ester, 2-aminomethyl-3-chloro-5-(trifluoromethyl)pyridine hydrochloride and DBU in DME. ES-MS m/e (%): 396 (M{37Cl}+H+, 40), 394 (M{35C}+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:10]([NH:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(Cl)nc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Nc1nc(Cl)ccc1NCc1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of 6-chloro-2,3-diaminopyridine (2.00 g, 13.9 mmol, Combi-Blocks) and benzaldehyde (1.48 g, 13.9 mmol, Aldrich) in 1,2-dichloroethane (50 mL) was treated with acetic acid (0.2 mL, 3 mmol) and the mixture was allowed to stir for 30 minutes. Na(OAc)3BH (8.8 g, 42 mmol) was added and the reaction was stirred overnight. The reaction was quenched with water, then poured into saturated NaHCO3 solution. The product was extracted with three portions of DCM, and the combined extracts were washed with saturated NaHCO3 solution and brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-75% EtOAc in hexanes was used to afford purified product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[OH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CN1CCC(O)CC1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CN1CCC(Oc2nc(N)nc(-c3ccco3)c2C#N)CC1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-hydroxy-1-methylpiperidine and DBU in DME. ES-MS m/e (%): 300 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5]2.[NH:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.BrC1C=C2C(=CC=1)C[C:34](=[O:39])CC2.C(N)CCC>>[CH2:13]([NH:12][CH:7]1[CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([C:34]([N:17]3[CH2:21][CH2:20][CH2:19][CH:18]3[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:39])[CH:11]=[CH:10][C:9]=2[CH2:8]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCNC1CCc2cc(Br)ccc2C1
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: C1CN[C@H](CN2CCCC2)C1
Solvent: CCCCN
Product: CCCCNC1CCc2cc(C(=O)N3CCCC3CN3CCCC3)ccc2C1

Procedure:
(6-Butylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone is prepared from (6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-butyl-amine and (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine in a manner substantially analogous to Procedure A. (See herein Example 1). Starting material, (6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-butyl-amine, was prepared from 6-bromo-2-tetralone and n-butylamine in a manner substantially analogous to Preparation 1. Mass spectrum (APCI) 384 (M++1).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:5]([C:16]([O:18]CC)=[O:17])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]1)#[N:2].[OH-].[Na+].CCO.O>>[C:1]([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:5]([C:16]([OH:18])=[O:17])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][F:15])[CH2:9]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOC(CF)C2)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1c(N2CCOC(CF)C2)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A mixture of ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-(2-(fluoromethyl)morpholino)thiophene-2-carboxylate (300 mg, 0.00054 mol), Sodium hydroxide (0.12 g, 0.0030 mol) in EtOH (10.0 mL, 0.171 mol) and water (3.0 mL, 0.17 mol) was stirred at rt until completion by LCMS. The mixture was concentrated and the residue was acidified by 1NHCl. The precipitate was collected and dried in air and vacuum to afford 4-cyano-3-(2,4-dichlorophenyl)-5-(2-(fluoromethyl)morpholino)thiophene-2-carboxylic acid (225 mg, 99%). LCMS: (FA) ES+ 415, ES− 413.
Reaction SMILES: C1(C)C=CC(S([O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.[N:31]12[C:37](=[O:38])[CH2:36][CH:35]1[CH2:34][C:33](=O)[CH:32]2[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>C(Cl)Cl>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([S:11]([O:10][C:33]2[CH2:34][CH:35]3[N:31]([C:37](=[O:38])[CH2:36]3)[C:32]=2[C:40]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:41])(=[O:12])=[O:13])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OCc3ccccc3)N3C(=O)CC3C2)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 66.8 %

Procedure:
p-Toluenesulfonic anhydride (326 mg, 1 mμol) and N,N-diisopropylethylamine (192 μl, 1.1 mμol) are added to an ice-cold, stirring solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (259 mg, 1 mμol) in anhydrous methylene chloride (10 ml). The resulting solution is stirred in the cold and under a nitrogen atmosphere for 2.5 hours. The solution is diluted with methylene chloride (20 ml), washed with water (10 ml). 1 M pH 3 phosphate buffer (10 ml) and 5% aqueous sodium bicarbonate (2×10 ml) dried with magnesium sulfate, filtered, and evaporated under vacuum to a semi-solid. This material is triturated with ice-cold ethyl acetate (2×2 ml) and diethyl ether (2×5 ml) to provide benzyl 3-(p-toluenesulfonyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (276 mg, 67%) as a white powder. Recrystallization from methylene chloridediethyl ether gives analytically pure product as small white needles: mp 103°-105°; IR (CH2Cl2) 1786, 1723, 1382, and 1190 cm-1 ; NMR (CDCl3) 8 2.44 (s,3,ArCh3) 3.03 (dd,1,J=3.0 and 17.0, HGβ), 3.16 (dd,1,J=8.5 and 18.7,H4a), 3.32 (dd,1,J=10.0 and 18.7,H46), 3.55 (dd,1,J=5.5 and 17.0,HG), 4.21 (m,1,H5), 5.14 (ABq,2,J=12,CH2Ar), 7.35 (S,5,ArHO, 7.26 and 7.75 (two d's,4, J=9,ArH); UV(dioxane) 283 (E6600) and 277 (E6500) nm.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:29][CH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[N:35]([CH:41]1[CH2:46][CH2:45][C:44](=[O:47])[NH:43][C:42]1=[O:48])[C:34]2=[O:49].CCOC(C)=O>CN(C)C=O>[O:48]=[C:42]1[CH:41]([N:35]2[C:34](=[O:49])[C:33]3[C:37](=[CH:38][CH:39]=[C:31]([CH2:30][NH:29][C:9]([C:6]4[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=4)=[O:11])[CH:32]=3)[C:36]2=[O:40])[CH2:46][CH2:45][C:44](=[O:47])[NH:43]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CSc1ccc(C(=O)O)nc1
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
A stirred mixture or 5-methylsulfanyl-pyridine-2-carboxylic acid (0.34 g, 2.00 mmol) and CDI (0.34 g, 2.10 mmol) in N,N-dimethylformamide (15 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (0.77 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×75 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (EtOAc/hexanes, gradient, product eluted at 90% EtOAc). The product fractions were combined and concentrated to give 5-methylsulfanyl-pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.55 g, 63% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 2.89 min (98.58%); mp: 185-187° C.; 1H NMR (DMSO-d6) δ 1.83-2.18 (m, 1H), 2.52-2.68 (m, 5H), 2.78-3.02 (m, 1H), 4.64 (d, J=6.4 Hz, 2H), 5.14 (dd, J=5.4, 12.9 Hz, 1H), 7.76-7.91 (m, 4H), 7.92-8.00 (m, 1H), 8.53 (d, J=1.9 Hz, 1H), 9.52 (t, J=6.3 Hz, 1H), 11.11 (s, 1H); 13C NMR (DMSO-d6) δ 13.93, 21.99, 30.93, 42.36, 48.99, 122.08, 123.51, 129.78, 131.56, 133.56, 133.83, 139.66, 145.03, 145.90, 147.57, 164.11, 166.99, 167.13, 169.80, 172.72; LCMS: MH=439; Anal Calcd for C21H18N4O5S: C, 57.53; H, 4.14; N, 12.78. Found: C, 57.17; H, 4.04; N, 12.54.
Reaction SMILES: Br[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][Cl:15])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C[Si]([C:21]#[N:22])(C)C.[Sn](Cl)(Cl)(Cl)Cl.O>C(Cl)Cl>[Cl:15][CH2:14][CH2:13][CH2:12][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:2]([CH3:4])([CH3:3])[C:21]#[N:22])=[CH:10][CH:9]=1)=[O:16]
Reactant: CC(C)(Br)c1ccc(C(=O)CCCCl)cc1
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(C(=O)CCCCl)cc1

Procedure:
Dissolve 1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (2.00 g, 6.59 mmol) in anhydrous methylene chloride (20 mL) and place under an argon atmosphere. Add trimethylsilyl cyanide (1.10 mL, 8.25 mmol) followed by tin (IV) chloride (0.20 mL, 1.7 mmol) via syringe. Stir at reflux for 1 hour, add water (20 mL) and stir for an additional ½ hour. Separate the layers and extract the aqueous layer with methylene chloride. Combine the organic layers, wash with brine, dry (MgSO4), filter and evaporate the solvent in vacuo. Purify by silica gel chromatography (15% ethyl acetate/hexane) to give the title compound as a white solid; mp 79-80° C.
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:8]=[C:9]2[CH:15]=[N:14][NH:13][C:10]2=[CH:11][N:12]=1.CN([CH:19]=[O:20])C>C1COCC1>[NH:13]1[C:10]2=[CH:11][N:12]=[C:7]([CH:19]=[O:20])[CH:8]=[C:9]2[CH:15]=[N:14]1
Reactant: Brc1cc2cn[nH]c2cn1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=Cc1cc2cn[nH]c2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
t-BuLi (27 mL, 1.7 M in pentane) was added to 100 mL of THF at −78° C. 5-bromo-1H-pyrazolo[3,4-c]pyridine (3.0 g, 15 imol) was added dropwise to the solution in 50 ml of THF via addition funnel. The resulting mixture was stirred for 1 h, at which point DMF (6.0 mL, 76 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred 2 h. The reaction was then carefully quenched with aq. NH4Cl and diluted with EtOAc. The resulting biphasic mixture was partitioned in a separatory funnel. The aqueous portion was extracted three tines with EtOAc, and the combined organic extracts were washed with brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (100% CH2Cl2 to 7.5% MeOH/CH2Cl2), afforded the desired 1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (1.1 g, 50% yield) as a white solid. H1 NMR (MeOD, 400 MHz) keto tautomer: 10.17 (s, 1H), 9.19 (s, 1H), 8.56 (s, 1H), 8.46 (s, 1H); enol tautomer: 9.00 (s, 1H), 8.25 (s, 1H), 8.05 (s, 2H), 5.73 (s, 1H). MS (API-ES) m/z (%): 141 (100%, M++1).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:27]([C:31]1[CH:32]=[C:33]([C:42]2[N:43]=[C:44]([CH:47]=O)[S:45][CH:46]=2)[CH:34]=[C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:36]=1[OH:37])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>C(OC(=O)C)(=O)C>[C:27]([C:31]1[CH:32]=[C:33]([C:42]2[N:43]=[C:44]([CH:47]=[C:2]3[CH2:6][CH2:5][NH:4][C:3]3=[O:7])[S:45][CH:46]=2)[CH:34]=[C:35]([C:38]([CH3:39])([CH3:40])[CH3:41])[C:36]=1[OH:37])([CH3:28])([CH3:29])[CH3:30]
Reactant: O=C1NCCC1Br
Reactant: CC(C)(C)c1cc(-c2csc(C=O)n2)cc(C(C)(C)C)c1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)c1cc(-c2csc(C=C3CCNC3=O)n2)cc(C(C)(C)C)c1O
Temperature: 70 °C

Procedure:
16.0 g (91 mmol) of 3-bromopyrrolidin-2-one were heated to boiling in 30 ml of acetic anhydride for 1 hour. After evaporating the reaction mixture t dryness under reduced pressure, the residue was dissolved in 50 ml of tetrahydrofuran and, after adding 26.2 g (0.1 mol) of triphenylphosphine, heated under reflux for 5 hours. It was then concentrated again, the residue was dissolved in 300 ml of ethanol and 24.7 g (78 mmol) of the aldehyde from Example 2 b1) and 27 ml (0.36 mol) of triethylamine were added. After heating the mixture at 70° C. for 2 hours, the yellow precipitate was filtered off and washed with ethanol. The crystal magma is dissolved in about 2 1 of chloroform, the solution is washed several times with saturated sodium chloride solution and dried over Na2SO4, and the chloroform phase is concentrated to a third. Yellow crystals deposit on allowing to stand for a relatively long time.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:10])[CH2:5][CH:6]([OH:9])CO.O>ClCCl>[OH:10][C:4]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH2:3][O:2][CH3:1])[CH2:5][CH:6]=[O:9]
Reactant: COCC(O)(CC(O)CO)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: COCC(O)(CC=O)c1ccccc1
Temperature: 25 °C

Procedure:
NalO4 (5.20 g) was added to a mixture of 5-methoxy-4-phenyl-pentane-1,2,4-triol (1.10 g), dichloromethane (10 mL), and water (5 mL) chilled in an ice bath. The mixture was stirred vigorously while warming to ambient temperature in the cooling bath and further stirred at this temperature overnight. Then, water (20 mL) and dichloromethane (50 mL) were added, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic phases were washed with water and dried (MgSO4). After removal of the solvent, the title compound was yielded which was directly submitted to the next reaction step (glycol cleavage).