Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[OH:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([N:26]1[CH2:27][CH2:28][CH2:29][CH:24]([OH:23])[CH2:25]1)=[O:6]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Reactant: OC1CCCNC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)N1CCCC(O)C1
Yield: 95.3 %

Procedure:
The procedure of Example 1 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid and 3.0 g of 3-hydroxypiperidine were used as starting materials. 7.4 g (yield 96%) of the title compound was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][C:40]([C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:19]4[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=2)[C:32]([CH3:44])=[C:33]3[CH3:43])=[O:41])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@@H](N)c1cccc(Cl)c1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3cccc(Cl)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(3-chlorophenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 537/538/539 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH2:4][CH2:3]1.[Cl:16][S:17](O)(=[O:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+].CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1>ClCCl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[C:12]([S:17]([Cl:16])(=[O:19])=[O:18])[CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH2:6][CH2:7]1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1N1CCN(C)CC1
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
2-(4-Methylpiperazin-1-yl)anisole (200 mg, 1 mmol) was added in portions over ten minutes to ice-cooled, stirred chlorosulfonic acid (1.2 ml) under argon. The resulting brown solution was stirred at 0° C. for 0.25 h and then at ambient temperature for a further 1.25 h. The solution was slowly poured onto crushed ice (50 g). Dichloromethane (50 ml) was added to the mixture followed by saturated sodium carbonate solution until pH10 was attained in the aqueous phase. The layers were separated and the aqueous phase further extracted with dicholoromethane. The combined organic phases were dried (Na2SO4) and concentrated to an oil. The oil was stirred with hexane (4 ml) to give the title compound as a cream solid (210 mg, 71%).
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[CH2:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15].O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][OH:37])[CH:31]=1)[NH2:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O.C1COCC1.[Cl-].[Na+].O.CN(C=O)C>[CH2:13]([C:17]1[CH:18]=[CH:19][C:20]([C:21]2[O:23][N:29]=[C:28]([C:30]3[CH:31]=[C:32]([CH2:36][OH:37])[CH:33]=[CH:34][CH:35]=3)[N:27]=2)=[CH:24][CH:25]=1)[CH:14]([CH3:15])[CH3:16]
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Reactant: NC(=NO)c1cccc(CO)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cc1ccc(-c2nc(-c3cccc(CO)c3)no2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.8 %

Procedure:
Carbonyl diimidazole (421 mg, 2.60 mmol) was added to a solution of 4-isobutyl benzoic acid (386 mg, 2.17 mmol) and DMF (10 mL) and stirred for 2 hours at room temperature. N′-hydroxy-3-(hydroxymethyl)benzenecarboximidamide (360 mg, 2.17 mmol) was added to the reaction mixture and stirred for 18 hours at ambient temperature. The reaction was diluted with water and extracted with ethyl acetate (2×) and the combined organic extracts were washed with 0.25 N sodium hydroxide, water and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give a crude residue. The crude residue was dissolved in THF (6 mL) and treated with tetrabutyl ammonium fluoride (1M in THF, 2.4 mL, 2.38 mmol). The solution was stirred at ambient temperature for 18 hours, diluted with brine and extracted with ethyl acetate. The combined organic layers were concentrated in vacuo. Purification by flash chromatography (silica, 1:9 to 2:3 EtOAc:hexanes) provided the title compound (193 mg, 29% yield) as a solid.
Reaction SMILES: CO.[CH3:3][C:4]1[N:5]([CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[C:6]2[C:11]([C:12]=1[C:13]([O:15]CC)=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[OH-].[K+]>O>[CH3:3][C:4]1[N:5]([CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[C:6]2[C:11]([C:12]=1[C:13]([OH:15])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CCOC(=O)c1c(C)n(C(C)c2ccccc2)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)c2ccccc2n1C(C)c1ccccc1
Reaction time: 4 h
Yield: 54.8 %

Procedure:
To a mixed solution of methanol and water (4 mL), ethyl 2-methyl-1-(1-phenylethyl)-1H-indole-3-carboxylate (300 mg, 0.98 mmol) and potassium hydroxide (546 mg, 9.76 mmol) was added. The mixture was refluxed with stirring for 4 hours. The reaction mixture was concentrated to give a residue. To the residue, water (10 mL) was added and the mixture was extracted with dichloromethane (20 mL×3). The organic phase was concentrated to give crude product 2-methyl-1-(1-phenylethyl)-1H-indole-3-carboxylic acid (150 mg). LRMS (M−H)− m/z: calcd 279.13. found 279.
Reaction SMILES: [NH2:1][C:2]([CH2:10][OH:11])=[CH:3][C:4](=[O:9])[C:5]([O:7][CH3:8])=[O:6].[Cl:12][C:13]1[C:14]([NH:19]N)=[N:15][CH:16]=[CH:17][CH:18]=1.Cl>C(#N)C>[Cl:12][C:13]1[C:14]([N:19]2[C:4]([OH:9])([C:5]([O:7][CH3:8])=[O:6])[CH2:3][C:2]([CH2:10][OH:11])=[N:1]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C(=O)C=C(N)CO
Reactant: NNc1ncccc1Cl
Agent: Cl
Solvent: CC#N
Product: COC(=O)C1(O)CC(CO)=NN1c1ncccc1Cl

Procedure:
A mixture of methyl 4-amino-5-hydroxy-2-oxopent-3-enoate (1.59 g, 10 mmol), 3-chloropyridin-2-ylhydrazine (1.43 g, 10 mmol and HCl (1 g, 10 mmol, 37% solution in water) was stirred in 15 ml of acetonitrile at 25° C. for 20 hours. The solution was concentrated under reduced pressure and the residue was washed with water and isopropanol. This gave 2.13 g (75%) of the product, with a melting point of 111-113° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5]O)#[N:2].C1(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:1]([C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][N:27]=[N+:28]=[N-:29])#[N:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C#N)c(CO)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc(C#N)c(CN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-cyano-5-methoxybenzyl alcohol (1.8 g, 11 mmol) in THF (50 mL) was cooled to 0° C. and then treated sequentially with diphenylphosphoryl azide (2.8 mL, 13 mmol) and DBU 1.9 mL, 13 mmol), the former added in one portion and the latter dropwise. The reaction mixture was allowed to warm gradually to room temperature and to then stir there overnight. The solvent was removed and the residue partitioned between ethyl acetate and water. The organic phase was washed with dilute citric acid, then brine and dried (Na2SO4). The solvent was removed in vacuo and the residue purified by column chromatography eluting with 4:1:1 hexane/chloroform/ethyl acetate to give the product as a yellow oil: 1H NMR (CDCl3) δ7.62 (d, J=8.6 Hz, 1H), 7.02 (d, J=2.6 Hz, 1H), 6.92 (dd, J=2.6, 8.6 Hz, 1H), 4.59 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[CH3:17].[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].ClCCl.O>[CH3:17][C:3]1[CH:4]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:18]=[O:19])[CH:25]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1Br
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
2-Bromo-1,3-dimethyl-5-[3-(methylsulfonyl)propoxy]benzene (0.10 g), 3-formylphenylboronic acid (0.05 g, 1.05 eq), potassium phosphate (0.13 g, 2.0 eq) and 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride-dichloromethane complex (PdCl2(dppf)) (5 mg, 2 mol %) were charged in a glass tube, and N,N-dimethylformamide (1 mL) and water (0.5 mL) were added thereto. After argon substitution, the mixture was stirred at 60° C. for 3 hr. The obtained reaction mixture was analyzed by high performance liquid chromatography to find the title compound (81.8% peak area).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(CC)CC)C>ClCCl>[N:28]1([C:14]([C@@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:16])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C([C@@H]1CCCNC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(3R)-Piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (2.64 g, 11.5 mmol), benzotriazo-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 1.1 eq., 5.61 g) and 1-hydroxybenzotriazole hydrate (0.1 eq., 180 mg) were dissolved in anhydrous dichloromethane (30 mL) under nitrogen and morpholine (1.1 eq., 1.11 mL) was added followed by triethylamine (3 eq., 4.82 mL). The solution briefly came to reflux and was then allowed to stir for 16 hr at ambient temperature. The solution was washed with 0.2M sodium hydroxide solution (×2), dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The residue was dissolved in anhydrous toluene and the solvent again removed under vacuum. The product was purified by chromatography on silica gel eluting with a 5% to 10% methanol in dichloromethane gradient. The product was dissolved in ethyl acetate (30 mL), saturated with hydrogen chloride at −78° C. then stirred at room temperature for 1 hr. The solvent was evaporated in a stream of dry nitrogen. The solid residue was dissolved in water (˜5 mL) followed by sodium hydroxide (1 g). Xylene was added and the solvent was removed under vacuum. The residue was extracted with dichloromethane, the organic solution was filtered through Celite® and the solvent was evaporated under vacuum to give the title compound as a colorless oil which crystallized on refrigeration (2.25 g, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][CH2:11][CH2:10][S:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[Cl:14][CH2:15][CH2:16][CH2:17]I.[OH-].[Na+]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:14][CH2:15][CH2:16][CH2:17][N:12]1[CH2:11][CH2:10][S:9][C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]1=2
Reactant: ClCCCI
Reactant: O=[N+]([O-])c1ccc2c(c1)SCCN2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)SCCN2CCCCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.7 %

Procedure:
A solution of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (1.0 g, 5.10 mmol) and 1-chloro-3-iodopropane (1.075 mL, 10.19 mmol) in CH2Cl2 (10 mL) was treated with 50% NaOH solution (10 mL), followed by tetrabutylammonium bromide (0.082 g, 0.255 mmol) at room temperature. The resulting mixture was stirred overnight (16 hours) at room temperature and then refluxed for 4 hours. The reaction was brought to room temperature and diluted with water (50 mL), and the product was extracted into CH2Cl2 (3×25 mL). The combined CH2Cl2 layers were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (1:4 to 2:3 EtOAc:hexanes) to obtain the title compound (0.65 g, 47%) as a solid. 1H NMR (CDCl3) δ 7.96 (d, 1H, J=2.7 Hz), 7.88 (dd, 1H, J=2.7, 9.3 Hz), 6.64 (d, 1H, J=9.3 Hz), 3.84-3.80 (m, 2H), 3.65-3.60 (m, 4H), 3.05-3.02 (m, 2H), 2.16-2.08 (m, 2H); ESI-MS (m/z, %): 273 (MH+, 100).
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[C:9](=[CH2:12])[C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1.[CH3:17][S:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])=[O:19]>>[CH3:1][C:2]1[S:11][C:10]2[C:9](=[CH:12][C:26]3[CH:27]=[C:22]([NH:21][S:18]([CH3:17])(=[O:19])=[O:20])[CH:23]=[CH:24][CH:25]=3)[C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: C=C1c2ccccc2CCc2nc(C)sc21
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Product: Cc1nc2c(s1)C(=Cc1cccc(NS(C)(=O)=O)c1)c1ccccc1CC2

Procedure:
Following procedures essentially as described in Preparation 24 followed by procedures essentially as described in Example 219, and using 2-methyl-4-methylene-9,10-dihydro-4H-3-thia-1-aza-benzo[f]azulene and 3-methanesulfonylaminophenylboronic acid, the title compounds are made.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH:8]1([NH2:11])[CH2:10][CH2:9]1>>[CH:8]1([N:11]([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:10][CH2:9]1
Reactant: NC1CC1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCN(CCC(=O)OCC)C1CC1

Procedure:
A mixture of 400 g. of ethyl acrylate (containing 0.75% hydroquinone inhibitor) and 114 g. of cyclopropylamine is heated in a bomb in an oil bath at 175° C. for 10 hours. The reaction mixture is then removed and distilled in vacuo to give N-cyclopropyl-N,N-di(β-carbethoxyethyl)amine.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15](=[O:18])[CH:16]=[CH2:17])=[O:5])C.CS(C)=O.[OH-].[K+]>O.[OH-].[Na+]>[O:18]=[C:15]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH:6]1[C:4]([OH:5])=[O:3])[CH:16]=[CH2:17]
Reactant: C=CC(=O)N1c2ccccc2CC1C(=O)OCC
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=CC(=O)N1c2ccccc2CC1C(=O)O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 2,3-dihydro-1-(1-oxo-2-propenyl)-1H-indole-2-carboxylic acid ethyl ester (14.4 g.), 80% aqueous dimethylsulfoxide (200 ml.) and potassium hydroxide (86% pellets, 3.85 g.) was stirred under nitrogen atmosphere for 2.5 days at room temperature, then evaporated under reduced pressure on a rotary evaporator to give an oily residue. The residue was dissolved in water with the aide of a small amount of dilute sodium hydroxide solution. The aqueous solution was washed with ether twice, then made acidic by addition of dilute hydrochloric acid to pH ca. 2. The oil thus separated was extracted with ether three times. The combined ether extract was washed with water, then with saline, and dried over anhydrous magnesium sulfate. Evaporation of the ether on a rotary evaporator under reduced pressure gave a solid residue which melted at 158°-160°, and weighed 9.2 g. Recrystallization from ethyl acetate improved the melting point to 167°-169°.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C@@H:5]([C@H:7]([C@@H:9]([C@@H:11]([CH2:13][OH:14])O)[OH:10])[OH:8])[OH:6])[CH3:2].Cl.C(NC[C@@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O)C>O>[CH3:2][CH2:1][N:3]1[C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@@H:5]([OH:6])[CH2:4]1
Reactant: CCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCNC[C@@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: O
Product: CCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO
Reaction time: 48 h
Yield: 60 %

Procedure:
1.0 gram of N-ethylglucamine is suspended in 50 mL water and titrated to pH 5.0 with concentrated HCl (simultaneously dissolving the aminosugar). This solution is placed in a 500 ml, shaker flask. To this solution is added 2.0 grams (wet weight) of washed Gluconobacter oxydans cells and the solution agitated at 100-120 rpm. Afar 24 hours, HPLC analysis indicates that 70% of the initial charge of N-ethylglucamine has been converted to 6-ethylamino-6-deoxy-α-L-sorbofuranose, and after 48 hours, at least 90% has been converted. After 72 hours, the supernatant is separated from the cells and sterile filtered. An aliquot (10 mL) of the supernatant is adjusted to pH 9.0 with concentrated NH4OH, chilled in an ice bath, and 100 mg NaBH4 is added. After standing in the ice bath overnight, the samples are acetylated and assayed by gas chromatography (GC)-mass spectroscopy. GC-mass spectroscopy indicates a 60% yield of N-ethyl-1-deoxynojirimycin from 6-ethylamino-6-deoxy-α-L-sorbofuranose (Chemical ionization mass spectroscopy of the acetylated product indicates that the GC peak corresponding to the reduced cyclized product has a parent peak mass of 360 (M+H), corresponding to tetra-acetylated N-ethyl- 1-deoxynojirimycin).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[OH:13][NH:14][C:15](=N)[C:16]([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:15]1[N:12]=[C:11]([N:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)[O:13][N:14]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: N#CN1CCC2(CC1)OCCO2
Reactant: CC(C)(C)C(=N)NO
Product: CC(C)(C)c1noc(N2CCC3(CC2)OCCO3)n1

Procedure:
The title compound is prepared from 1,4-dioxa-8-aza-spiro[4.5]decane-8-carbonitrile and N-hydroxy-2,2-dimethyl-propionamidine following a procedure analogous to that described in Intermediate 2. LC (method 8): tR=1.53 min; Mass spectrum (ESI+): m/z=268 [M+H]+.
Reaction SMILES: B([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([C:20]1[C:24]([CH3:25])=[C:23]([CH3:26])[O:22][N:21]=1)[CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])(=[O:12])=[O:11])(O)O.Br[C:28]1[CH:35]=[CH:34][C:33]([C:36]2[O:37][CH:38]=[CH:39][N:40]=2)=[CH:32][C:29]=1[CH:30]=[O:31]>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C:24]1[C:20]([N:13]([CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[S:10]([C:5]2[C:4]([C:28]3[CH:35]=[CH:34][C:33]([C:36]4[O:37][CH:38]=[CH:39][N:40]=4)=[CH:32][C:29]=3[CH:30]=[O:31])=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:12])=[O:11])=[N:21][O:22][C:23]=1[CH3:26]
Reactant: O=Cc1cc(-c2ncco2)ccc1Br
Reactant: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1C=O
Temperature: 85 °C

Procedure:
To the 2-borono-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide and 2-bromo-5-(2-oxazolyl)benzaldehyde (13.32 g, 58.14 mmol, prepared as described in Example 21 of European Patent Application No. 702,012) in 264 ml of toluene and 132 ml of 95% ethanol ("EtOH"), 106 ml 2M aqueous sodium carbonate and tetrakis(triphenylphosphine)palladium(0) (6.11 g, 5.29 mmol) were added and the reaction mixture heated under argon at 85° C. for 4 hrs, cooled and diluted with 250 ml of EtOAc. The organic layer was separated and washed with 100 ml H2O and 50 ml brine, dried and concentrated. The residue was chromatographed on silica gel using 1:1 hexane/EtOAc to afford the title product of this step (16.95 g, 62.7% for two steps) as a colorless gum.
Reaction SMILES: ClC1C=CC(N(C2CCNCC2)C(=O)C2C=CC=C(OC)C=2)=CC=1.C(OC([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)[CH2:34][CH2:33]1)=O)(C)(C)C.[CH3:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([S:54](Cl)(=[O:56])=[O:55])=[CH:50][CH:49]=1>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[F:45][C:42]1[CH:41]=[CH:40][C:39]([N:38]([CH:35]2[CH2:34][CH2:33][NH:32][CH2:37][CH2:36]2)[S:54]([C:51]2[CH:50]=[CH:49][C:48]([O:47][CH3:46])=[CH:53][CH:52]=2)(=[O:56])=[O:55])=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: COc1cccc(C(=O)N(c2ccc(Cl)cc2)C2CCNCC2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N(c2ccc(F)cc2)C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
The title compound was prepared as in example 98, steps (A) to (C). Step (B) (acylation) was substituted by the following sulphonylation procedure. To a solution of 4-(4-fluoro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (4.00 g, 13.6 mmol) in dichloromethane (60 ml) and pyridine (32 ml) was added 4-methoxybenzenesulfonyl chloride (3.40 g, 16.3 mmol). After 40 hours stirring at room temperature, the reaction mixture was diluted with ethyl acetate (80 ml), washed with chlorhydric acid (2×50 ml, 0.5 N) and with saturated sodium hydrogencarbonate (50 ml), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was taken in ether to provide a precipitate. Filtration led to 4-[(4-fluoro-phenyl)-(4-methoxy-benzenesulfonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (4.70 g, 74%) as a off white solid, MS (ISP): m/e=465.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[Li+].[Cl-]>C1(C)C=CC=CC=1>[CH2:14]([C:2]1[CH:9]=[C:8]([F:10])[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1)[CH:13]=[CH2:12]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1c(F)cc(Br)cc1F
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1cc(F)c(C#N)c(F)c1

Procedure:
A mixture of 4-bromo-2,6-difluorobenzonitrile (2.0 g, 9.2 mmol), allyl-tributyl-stannane (3.65 g, 11.0 mmol), LiCl (1.17 mg, 28 mmol) and Pd(PPh)4 (0.2 g) in 70 mL of anhydrous toluene was refluxed under N2 overnight. Checked the reaction with TLC and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product 4-allyl-2,6-difluorobenzonitrile. MS m/z: 180 (M+1)+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-])=[C:7](C#N)[C:6](=[O:15])[NH:5]2.S(S([O-])=O)([O-])=O.[Na+].[Na+].C#N.Cl.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[C:3]([CH3:16])=[C:4]2[C:9]([N:8]=[CH:7][C:6](=[O:15])[NH:5]2)=[CH:10][CH:11]=1
Reactant: Cc1c(F)ccc2c1[nH]c(=O)c(C#N)[n+]2[O-]
Agent: C#N
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Solvent: CCO
Solvent: O
Product: Cc1c(F)ccc2ncc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.1 %

Procedure:
A mixture of 6-fluoro-5-methyl-3-oxo-3,4-dihydro-2-quinoxalinecarbonitrile 1-oxide (15.9 g, 71.8 mmol) and sodium dithionite (36.7 g, 179.6 mmol) in ethanol (200 ml) and water (400 ml) was heated under reflux for 1 h, with a flow of argon over the top of the condenser leading to a bleach-filled bottle to trap HCN. The cooled mixture was carefully acidified to pH1 with dilute HCl and the mixture was stirred for 45 min at RT. Sodium hydroxide (50% aqueous) was then added to give pH˜11 and the mixture was evaporated to remove approx. 500 ml. The residue was acidified to pH 6 with dilute HCl (caution: cyanide still present!) and the precipitate was filtered off, washed with water and dried to give a solid (10.37 g, 81%). Extraction of the aqueous liquor with 10% methanol/dichloromethane and evaporation of the extracts gave a further small amount of product (0.8 g). Total yield 11.2 g, 88%.