Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NCCN1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.[NH2:23][CH2:24][C@H:25]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:26]([O:28][CH3:29])=[O:27].C(N(CC)CC)C>CO>[CH2:34]([O:33][C:31]([NH:30][CH:25]([CH2:24][N:23]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1)[C:26]([O:28][CH3:29])=[O:27])=[O:32])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(Cn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C)NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate A Step 3) (1.342 g, 3.98 mmol), (S)-methyl 3-amino-2-(((benzyloxy)carbonyl)amino)propanoate (1.207 g, 4.18 mmol) and triethylamine (1.665 ml, 11.94 mmol) were suspended in methanol (20 ml). The mixture was heated to reflux for 16 hours then cooled to room temperature and filtered. The residue was rinsed with methanol (20 ml) to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]([OH:18])[CH:10]=1)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]([O:18][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc(C(N)=O)c(O)c1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C(N)=O)c(OCC2CCCCC2)c1
Temperature: 60 °C

Procedure:
To 4-(4-carbamoyl-3-hydroxy-phenoxy)-butyric acid ethyl ester (3.0 g, 11.22 mmol) in DMF (25 mL) was added Cs2CO3 (5.11 g, 15.71 mmol) followed by (bromomethyl)cyclohexane (1.72 mL, 12.34 mmol). The mixture was heated to 60° C. for 6 h, then dumped onto ice/H2O. The formed solids were collected by filtration (H2O wash)and dried in vacuuo (3.74 g, 92%). MS [M+H]+ 364. m.p. 98-99° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([S:13](Cl)(=[O:15])=[O:14])=[CH:5][CH:4]=1.[CH2:17]([O:19][C:20](=[O:31])[CH2:21][CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH2:23]1)[CH3:18].C(N(CC)CC)C>ClCCl.O>[CH2:17]([O:19][C:20](=[O:31])[CH2:21][CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([S:13]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:15])=[O:14])[CH2:23]1)[CH3:18]
Reactant: CCOC(=O)CC1CNc2ccccc21
Reactant: COc1ccc(S(=O)(=O)Cl)c2ccccc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC1CN(S(=O)(=O)c2ccc(OC)c3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
4-Methoxynaphthylsulfonyl chloride (1.25 g, 5 mmol.) was added portionwise to ethyl-2,3-dihydro-1H indole-3-acetate (1 g, 5 mmol) in dichloromethane (20 cm3), containing triethylamine (1 cm3, 7 mmol) at 0° C. After stirring at room temperature for 4 h, the reaction was diluted with water and the organic layer was separated, dried and concentrated to give ethyl-1-(4-methoxynaphthylsulfonyl)-2,3-dihydroindole-3-acetate as an oil (2 g, 4.7 mmol, 94%). This was then taken up in ethyl alcohol (20 cm3) and aqueous sodium hydroxide (4N, 7 cm3, 28 mmol) was added and the resulting mixture was stirred and heated together at reflux for 2 h. The reaction mixture was then cooled and the ethyl alcohol was removed under reduced pressure. The residue was taken up in water and extracted once with diethyl ether to remove any unreacted ester. The aqueous mixture was then acidified and the product extracted into ethyl acetate. The organic layer was separated, dried and concentrated to provide 1-(4-methoxynaphthylsulfonyl)-2,3-dihydro-indole-3-acetic acid as a solid (1.17 g, 3.00 mmol, 64%).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16].[CH2:18](C([Sn])=C(CCCC)CCCC)[CH2:19]CC>C(OCC)(=O)C.CCCCCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:15]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:7]=1[CH:18]=[CH2:19])[C:11]#[N:12])([O-:17])=[O:16]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=Cc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 82.5 %

Procedure:
To N,N-dimethylformamide (50 ml) were added 4-chloro-3-nitrobenzonitrile (2.81 g, 15.39 mmol), tri-n-butylvinyltin (5.23 g, 16.49 mmol) and bis(triphenylphosphine)palladium(II) dichloride (701 mg, 0.999 mmol), and the mixture was stirred with heating at 100° C. for 160 min. The reaction mixture was cooled, diluted with an ethyl acetate-hexane=1:1 mixed solvent, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (2.21 g, yield 82%) as a yellow solid.
Reaction SMILES: [CH2:1]([CH:8]([CH2:11][OH:12])[CH2:9][OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C1(C)C=CC=CC=1>[F:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]1[O:10][CH2:9][CH:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:11][O:12]1
Reactant: O=Cc1cccc(F)c1F
Reactant: CCCCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CCCCCCCC1COC(c2cccc(F)c2F)OC1

Procedure:
Quantities: compound from Example 8 (27 g, 0.155 mol), 2,3-difluorobenzaldehyde (21.5 g, 0.15 mol) and 4-toluenesulphonic acid (100 mg). The experimental procedure was as described in Example 11 except using dry benzene instead of dry toluene.
Reaction SMILES: [C:1]1([C:11]([O:13][C:14]([CH3:18])(C)[C:15]#[CH:16])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:19]1(C(O)=O)C2C(=CC=CC=2)C=CC=1.CC(O)(C)C#C>>[C:1]1([C:11]([O:13][CH:14]([CH2:15][CH3:16])[C:18]#[CH:19])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C#CC(C)(C)OC(=O)c1cccc2ccccc12
Reactant: O=C(O)c1cccc2ccccc12
Agent: C#CC(C)(C)O
Product: C#CC(CC)OC(=O)c1cccc2ccccc12

Procedure:
1,1-dimethyl-2-propynyl 1-naphthoate, nD20 =1.5765, is prepared from 1-naphthoic acid and 3-methyl-1-butyn-3-ol.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12.[H-].[Na+].Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:3]=12.[I:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Ic1ccnc2cn[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc3nccc(I)c3n2)cc1
Product: COc1ccc(Cn2ncc3nccc(I)c32)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
7-Iodo-1H-pyrazolo[4,3-b]pyridine (500 mg, 2.041 mmol) and NaH (103 mg, 60% in oil, 4.08 mmol) were combined in DMF (10 mL) at 25° C. After 10 minutes, the mixture was cooled to 0° C. and 1-(chloromethyl)-4-methoxybenzene (0.297 mL, 2.143 mmol) was added and the mixture stirred for a further 15 minutes. The ice bath was removed and the mixture stirred for 1 hour then diluted with water (150 mL) and saturated ammonium chloride solution (50 mL). The product was extracted into EtOAc. The organic layers were combined, dried over magnesium sulfate, filtered and evaporated in vacuo onto silica and subjected to chromatography on silica eluted with EtOAc in hexanes (0-50%) to give 7-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine and 7-iodo-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridine which was used without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[F:9][C:10]([F:14])([F:13])[CH2:11][NH2:12]>C(OCC)(=O)C>[F:9][C:10]([F:14])([F:13])[CH2:11][NH:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NCC(F)(F)F
Reactant: Fc1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Product: FC(F)(F)CNc1ccccn1
Temperature: 220 °C
Yield: 468.5 %

Procedure:
A mixture of 2-fluoropyridine (2.00 g, 20.6 mmol) and 2,2,2-trifluoroethylamine hydrogen chloride (5.00 g, 36.9 mmol) was heated to 220° C. for 30 min in a microwave reactor. The same reaction was repeated 5 times. The reaction mixtures from all 6 reactions were cooled, combined and diluted with ethyl acetate (150 mL). The organic mixture was neutralized by washing with saturated aqueous sodium bicarbonate, water (30 mL) and brine (30 mL). The organic phase was dried over Na2SO4 and concentrated, and the resulting residue was purified by chromatography on silica gel using 80% ethyl acetate/hexane as eluant to give the title compound as a white solid (17.0 g).
Reaction SMILES: C(N=C(N)N)#N.ClC1C=C(NC(N(C)C)=[O:17])C=CC=1C.[C:21]([O:30]OC(C)(C)C)([C:24]1[CH:29]=CC=C[CH:25]=1)(C)C.CN(C)C1C=CC(C)=CC=1.C1C=[C:50]2[C:52](NS(=O)(=O)[C:49]2=CC=1)=[O:53].P(NN)(=O)(OCC)OCC>>[C:21]([O:30][CH2:49][CH:50]1[O:53][CH2:52]1)(=[O:17])[C:24]([CH3:25])=[CH2:29]
Reactant: Cc1ccc(NC(=O)N(C)C)cc1Cl
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: CC(C)(C)OOC(C)(C)c1ccccc1
Agent: CCOP(=O)(NN)OCC
Agent: N#CN=C(N)N
Solvent: Cc1ccc(N(C)C)cc1
Product: C=C(C)C(=O)OCC1CO1

Procedure:
Mixture A (20.0 g) is mixed with dicyandiamide (0.4 g) and N-(3-chloro-4-methylphenyl)-N',N'-dimethylurea (0.4 g) and the mixture milled in a triple-roll mill until homogeneous. The milled product is then treated with tert.butyl cumyl peroxide (0.5 g), N,N-dimethyl-p-toluidine (0.1 g), o-benzoic sulphimide (0.1 g) and diethyl phosphoro hydrazidate (0.2 g) and mixed until homogeneous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17](=O)[CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:13][CH2:12]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:15][CH2:16]1
Reactant: O=C(COCc1ccccc1Oc1ccccc1)N1CCN(CCCc2ccccc2Cl)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cl
Product: Clc1ccccc1CCCN1CCN(CCOCc2ccccc2Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4.1 g (8.5 mmol) of 1-[3-(2-chlorophenyl)propyl]-4-[1-oxo-2-[(2-phenoxyphenyl)methoxy]ethyl]piperazine in 95 ml of dry ether was added dropwise, under nitrogen and with stirring, to a suspension of 1.26 g (33.1 mmol) of lithium aluminium hydride in 63 ml of dry ether. The reaction mixture was stirred at room temperature for 2 hours and cooled to 5° C., after which 5 ml of water were added dropwise. The precipitate was filtered off and the filtrate evaporated. The crude product was dissolved in 15 ml of ethanol, to which 4 ml of 5 N HCl in ethanol was added. The precipitate was filtered off and recrystallized from 20 ml of ethanol. Yield 2.8 g (61%), m.p. 200° C.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].C(N(CC)CC)C.[CH2:20](Cl)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(Cl)(=[O:42])C=C>CN(C=O)C>[C:11]([OH:12])(=[O:42])[CH:9]=[CH2:7].[CH2:20]([C:2]([C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])=[O:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: C=CC(=O)Cl
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCC/C=C\CCCCCCCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCCC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 8 h

Procedure:
To glucose (10 g) in anhydrous DMF (100 ml) containing excess triethlamine was added freshly distilled oleyl chloride (1 mol. equiv.), followed by acryloyl chloride after one hour reaction. The mixture was stirred overnight and the solvent removed in vacuo. The product was purified by hexane filtration followed by chromatography on silica (1.5% methanol in methylene chloride). We have applied the same transformation technology to a pentahydroxylated sugar, glucose, as depicted in FIG. 37 to yield the glucose-based compound 31, which is a mixture of regio and stereo isomers. This material has three free hydroxyls (on average) per molecule, and has a more hydrophilic character.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:35]=[C:36]([NH2:47])[CH2:37][S:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=[O:40])=[O:39]>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:47]=[C:36]([CH2:37][S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)(=[O:40])=[O:39])[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: NC(CS(=O)(=O)c1ccccc1)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CS(=O)(=O)c2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (300 mg, 1.00 mmol) in dichloromethane (15m) was treated with 1,1′-carbonyidiimidazole (162 mg, 1.00 mmol) and the solution was stirred at room temperature for 2 hours. N′-hydroxy-2-(phenylsulfonyl)ethanimidamide (J.Heterocycl.Chem.; 16; 1979; 1197-1200) (214 mg, 1.00 mmol) was then added and the mixture was stirred for 17 hours. The solvent was removed under reduced pressure and the residue was heated neat at 130° C. under a nitrogen atmosphere for 2 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1) to afford the title compound (78 mg).
Reaction SMILES: [C@@H:1]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][C:20]3[S:21][C:22]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)=[CH:23][CH:24]=3)[CH:13]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].CI.[C:32](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C@@H:1]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][C:20]3[S:21][C:22]([C:25]4[N:29]=[N:28][N:27]([CH3:32])[N:26]=4)=[CH:23][CH:24]=3)[CH:13]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: O=C([O-])[O-]
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4nnn[nH]4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1nnc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(β-D-glucopyranosyl)-4-chloro-3-(5-(1H-tetrazol-5-yl)-2-thienylmethyl)benzene (140 mg) obtained in Example 181 was dissolved in dimethylformamide (5 ml) and added thereto were methyl iodide (100 μl) and potassium carbonate (220 mg). The mixture was stirred at room temperature overnight. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-methyl-2H-tetrazol-5-yl)-2-thienylmethyl)benzene as colorless powder. APCI-Mass m/Z 470/472 (M+NH4).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([Cl:15])=[C:5]([C:7]2([NH2:14])[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=1.[C:16]([O-:19])([O-])=[O:17].[Na+].[Na+].ClC([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=O>C1(C)C=CC=CC=1>[N+:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][NH:14][C:16](=[O:17])[O-:19])=[CH:27][CH:28]=1)([O-:34])=[O:33].[CH:1]1[CH:2]=[CH:3][C:4]([Cl:15])=[C:5]([C:7]2([NH2:14])[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C([O-])[O-]
Agent: NC1(c2ccccc2Cl)CCCCC1=O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C([O-])NOc1ccc([N+](=O)[O-])cc1
Temperature: 85 °C

Procedure:
To a mixture of norketamine (0.05 g, 0.22 mmol) in anhydrous toluene (2 mL) and Na2CO3 (0.082 g) was added a solution of para-nitrophenyl chloroformate (0.129 g, 0.64 mmol) in anhydrous toluene (2 mL). After heating for 8 hours at 85° C., the reaction mixture was cooled to room temperature and filtered. Toluene was evaporated under vacuum and the reaction mixture was diluted with dichloromethane (DCM). The DCM layer was washed 6 times with 50% aqueous NaHCO3 solution to remove the para-nitrophenol side-product and then with brine. The DCM layer was then dried over anhydrous sodium sulfate, filtered, concentrated under vacuum to afford the para-nitrophenoxycarbamate of norketamine as a pale solid. 1H-NMR (CDCl3): δ 8.17 (2H, dd), 7.87 (1H, d), 7.37 (3H, m) 7.23 (2H, dd), 3.84 (1H, d), 2.55-1.71 (8H).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.C(=O)(O)[O-].[Na+].[SH:24][C:25]1[N:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]2=[N:28][N:29]=1.Cl>O.CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:24][C:25]3[N:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]4=[N:28][N:29]=3)[CH2:15][S:14][C@H:9]12
Reactant: Sc1nnc2ccccn12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc4ccccn34)CS[C@H]12
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
2.72 g (0.01 mol) of 7-aminocephalosporanic acid was suspended in 18 ml of water, and a suspension of 2.1 g (0.025 mol) of sodium bicarbonate in 20 ml of water was added dropwise thereto over a period of time of 10 minutes. The inside temperature of the reactor was then increased to 50° C., and a suspension of 1.81 g (0.0125 mol) of 3-mercaptopyrido[2,1-c]-s-triazole in 35 ml of acetone was added dropwise thereto over a period of time of 10 minutes. The resulting mixture was refluxed for 4 hours at a stable inside temperature of the reactor of 63° C. followed by ice cooling the mixture. After the inside temperature of the reactor reached 4° C., the mixture was adjusted to a pH of 3.6 with 6 N hydrochloric acid. One hour after the stirring, the precipitated crystals were filtered and dried over phosphorus pentoxide under reduced pressure to obtain 2.31 g (yield: 61%) of the tilted compound having a melting point (decomposition) of 173° to 175° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.[NH4+].[Cl-]>C1COCC1>[C:1]1([CH2:7][CH2:8][C:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH2:7][CH2:8][C:11]23[CH2:12][CH2:13][CH:14]([CH2:15][CH2:16]2)[C:17](=[O:18])[O:19]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CC=C(CCc2ccccc2)CC1
Product: O=C1OC2(CCc3ccccc3)CCC1CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Slowly add 2-phenylethyl bromide (2.6 g) to a slurry of Mg (0.37 g) in THF (50 mL) and heat at reflux for 4 h. Cool the solution to ambient temperature and add to a solution of ethyl 4-oxo-cyclo-hexanecarboxylate (2.4 g) in THF (50 mL). After 2 h, pour the reaction mixture into a half-saturated solution of NH4Cl and extract with EtOAc. Partially purify the product on a silica gel column, eluting with EtOAc. Dissolve the product in toluene (100 mL), treat with p-TsOH and heat at reflux overnight with azeotropic removal of water. Cool the reaction mixture, wash with saturated NaHCO3 solution and concentrate. Purify the crude product on a silica gel column, eluting with CH2Cl2 to obtain ethyl 4-(2-phenylethyl)-cyclohex-3-enecarboxylate (0.45 g) and 1-(2-phenyl-ethyl)-2-oxabicyclo[2.2.2]octan-3-one (0.71 g). Dissolve 1-(2-phenyl-ethyl)-2-oxabicyclo[2.2.2]octan-3-one in EtOH, treat with conc.HCl (catalytic) and heat at reflux overnight. Dilute the reaction mixture with water and extract with EtOAc. Concentrate the organic layer to obtain additional ethyl 4-(2-phenylethyl)-cyclohex-3-enecarboxylate (0.88 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[NH:11])=[CH:4][CH:3]=1.[NH:20]1[C:28]2[C:23](=[CH:24][C:25](B(O)O)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>COCCOC.O.C(O)C.C([O-])(O)=O.[Na+].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>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10](=[NH:11])[CH:9]=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([C:25]3[CH:24]=[C:23]4[C:28](=[CH:27][CH:26]=3)[NH:20][CH:21]=[CH:22]4)=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: N=C(C=Cc1ccc(Br)cc1)Nc1ccc(Cl)cc1
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: COCCOC
Solvent: O
Solvent: CCO
Product: N=C(C=Cc1ccc(-c2ccc3[nH]ccc3c2)cc1)Nc1ccc(Cl)cc1
Yield: 44 %

Procedure:
A mixture of 0.075 g (0.22 mmol) of 3-(4-bromo-phenyl)-N-(4-chloro-phenyl)-acrylamidine, 0.042 g (0.26 mmol) of 5-indoleboronic acid, and 0.013 g (0.011 mmol) of Pd(PPh3)4 in 3 mL of DME/water/ethanol (4/2/1) in a sealed tube was heated under microwave (45 W, 5 min). The reaction was diluted with 10 mL of saturated NaHCO3, and extracted with three 10 mL portions of ethyl acetate. The combined organic extracts were washed with 10 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC eluting with 60% ethyl acetate in hexanes plus 1% NH4OH to give 0.036 g of N-(4-chloro-phenyl)-3-[4-(1H -indol-5-yl)-phenyl]-acrylamidine. Method M: To a stirred solution of 0.10 g (0.27 mmol) of N-(4-chloro-phenyl)-3-[4-(1H -indol-5-yl)-phenyl]-acrylamidine in 3 mL of DMF was added 0.011 g (0.28 mmol) of 60% NaH at 0° C. After 1 h, 0.018 mL (0.28 mmol) of iodomethane was introduced, the reaction was warmed to room temperature overnight and quenched with 10 mL of saturated NaHCO3. It was extracted with three 10 mL portions of dichloromethane. The combined organic extracts were washed with 10 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed eluting with 40% ethyl acetate in hexanes to give 0.028 g of N-(4-chloro-phenyl)-3-[4-(1-methyl-1H-indol-5-yl)-phenyl]-acrylamidine.