Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6](Br)[CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[NH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([NH:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:7]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:9]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1cc(Br)cc(N2CCCC2=O)c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cc(Nc2ccccc2)cc(N2CCCC2=O)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 32.2 %

Procedure:
A flask was charged under nitrogen with 3-bromo-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D9a) (298 mg, 1 mmol, 1 equiv), Cs2CO3 (488 mg, 1.5 mmol, 1.5 equiv), tris(dibenzylideneacetone)dipalladium(0) (18.3 mg, 0.02 mmol, 0.02 equiv), 2-(di-tert-butylphosphino)biphenyl (18 mg, 0.06 mmol, 0.06 equiv) and DME (8 ml). Aniline (136 μl, 1.5 mmol, 1.5 equiv) was then added via syringe and the resulting mixture was stirred at 100° C. for 16 h then cooled to room temperature, diluted with H2O and AcOEt. The layers were separated and the aqueous phase was extracted with AcOEt. The combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 3/1 to 1/1) gave 3-(2-oxo-pyrrolidin-1-yl)-5-phenylamino-benzoic acid methyl ester (B30) (100 mg, 32%) as a white solid. [M+H]+=311.0, RT=3.14 min
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1Cl
Reactant: NCCc1ccccc1
Product: Cc1sc2nc(-c3ccncc3)nc(NCCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-4-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-phenethylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:19][CH:18]=[C:17]([CH2:20][F:21])[C@@H:7]2[C@H:8]([O:11]C(OCC)C)[O:9][CH:10]=1)=[O:4].Cl.O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:19][CH:18]=[C:17]([CH2:20][F:21])[C@@H:7]2[CH:8]([OH:11])[O:9][CH:10]=1)=[O:4]
Reactant: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(CF)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1=COC(O)[C@H]2C(CF)=CC[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
670 mg of the above (1S,4aS.7aR)-1-[1-(ethoxy) ethoxy]-7-(fluoromethyl)-1,4a,5,7a-tetrahydrocyclopenta [c] pyrane-4-carboxylic acid methylester were dissolved in tetrahydrofuran followed by addition of 2N aqueous hydrochloric acid and stirring for 2 hours at room temperature. The reaction mixture was neutralized after adding water, and then extracted with ethyl acetate. After washing the organic phase with brine, it was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a pale yellow oil from the hexane-ether eluate in the form of (4aS,7aR)-7-(fluoromethyl)-1-hydroxy-1,4a,5,7a-tetrahydrocyclopenta [c] pyrane-4-carboxylic acid methylester (500 mg, yield: 98%). The physicochemical properties of this compound are described below.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]2[CH2:19][C:18]([O:20]C)=[C:17]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[CH3:30])[C:16]2=[O:31])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>CC(C)=O>[ClH:32].[O:31]=[C:16]1[CH:17]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=2[CH3:30])[C:18](=[O:20])[CH2:19][CH:15]1[CH2:14][CH:11]1[CH2:12][CH2:13][NH2+:8][CH2:9][CH2:10]1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(CC2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cc(C)c(C2C(=O)CC(CC3CC[NH2+]CC3)C2=O)c(C)c1

Procedure:
To a solution of 4-[4-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-cyclopent-3-enylmethyl]-piperidine-1-carboxylic acid tert-butyl ester (15.4 g, 36 mmol) in acetone (100 ml) is added 2N HCl (100 ml) and the reaction heated to reflux for 4 hours. The solvent is removed under reduced pressure to give 4-[2,4-dioxo-3-(2,4,6-trimethyl-phenyl)-cyclopentylmethyl]-piperidinium hydrochloride (12.58 g)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[NH4+].[Cl-]>CCO.O.[Zn]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])c1cc(F)cc2cccnc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Nc1cc(F)cc2cccnc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To a mixture of 6-fluoro-8-nitroquinoline (1.6 g, 8.3 mmol), and NH4Cl (2 g, 41.5 mmol) in EtOH/H2O (10 mL/10 mL) in a round bottom flask equipped with a refluxing condenser was added Zn (5.4 g, 16.6 mmol) dust in portions at room temperature, and the resulting mixture was stirred at 60° C. overnight. The reaction mixture was filtered, and the filtrate was extracted with EtOAc. The combined organic layers were dried over Na2SO4, and concentrated to give 1.0 g of crude product, which was used directly for the next step without further purification. LC-MS: m/z 163.2 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]([N:8]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:9][CH2:10][C:11]([O:13]CC)=O)=[O:7])[CH3:2].[O-]CC.[Na+]>C(O)C>[CH:16]1([N:8]2[CH2:9][CH2:10][C:11](=[O:13])[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:22])[C:6]2=[O:7])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)CCN(C(=O)CC(=O)OCC)C1CCCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1C(=O)CCN(C2CCCCC2)C1=O

Procedure:
N-Cyclohexyl-N-(2-ethoxycarbonyl-ethyl)-malonamic acid ethyl ester (5.40 g, 17.2 mmol) was heated with sodium ethoxide (2.34 g, 3.44 mmol) in refluxing ethanol (100 ml) for 3 hours. The cooled solution was concentrated, water (100 ml) was added and the solution washed with ether then isohexane. It was acidified with c. sulphuric acid to pH 2. The oily precipitate was extracted into dichloromethane, wahed with brine, dried (MgSO4) and concentrated to a yellow oil weighing 3.6 g (67%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].[C:15]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][N:18]=1)#[N:16]>CN(C=O)C>[NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:20]2[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[N:18][CH:19]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: N#Cc1ccc(F)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(O[C@@H]2CC[C@H](N)c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.2 %

Procedure:
Intermediate A (300 mg, 1.84 mmol) was added to an ice cold stirred suspension of sodium hydride (60% in mineral oil, 221 mg, 5.52 mmol) in DMF (15 mL) and stirred for 15 min. 2-Cyano-5-fluoropyridine (224 mg, 1.84 mmol) was added and the reaction warmed to RT. After 90 min, the reaction was quenched by dropwise addition of water and the mixture partitioned between EtOAc (75 mL) and water (150 mL). The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM, to give the title compound (255 mg, 0.96 mmol, 52%). LCMS (Method 4): Rt 0.28, 1.73, m/z 266.1 [MH+].
Reaction SMILES: [CH:1]([S:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:8]=[N:7][N:6]=1)([CH3:3])[CH3:2].Br[CH:18]([OH:21])[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH:1]([S:4][C:5]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:20][CH2:19][CH2:18][OH:21])=[CH:14][CH:15]=2)[N:8]=[N:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Sc1nnnn1-c1ccc(O)cc1
Reactant: CCC(O)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Sc1nnnn1-c1ccc(OCCCO)cc1

Procedure:
400 mg of 4-(5-isopropylsulfanyl-tetrazol-1-yl)-phenol, 471 mg of bromopropanol, 473 mg of potassium carbonate and 10 mg of potassium iodide are stirred for 15 hours at reflux in 10 ml of acetone. The reaction mixture is filtered and concentrated. The residue is taken up in ethyl acetate, washed with water and concentrated. Purification over silica gel yields 3-[4-(5-isopropylsulfanyl-tetrazol-1-yl)-phenoxy]-propan-1-ol. 1H-NMR (CDCl3) 300 MHz: 1.50 (d, 6H), 2.09 (m, 2H), 3.90 (t, 2H), 4.12 (m, 1H), 4.19 (t, 2H), 7.03 (d, 2H), 7.43 (d, 2H)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[NH:12]1[C:20]2[C:15](=[C:16]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[CH3:37][CH:36]([CH3:38])[C:35]([NH:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:15]=3[CH:14]=[CH:13][N:12]4[C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=3)[CH2:23][CH2:24]2)[CH:29]=1)=[O:39]
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3cccc(C(F)(F)F)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-3-(trifluoromethyl)benzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 520.2 (M+H)+.
Reaction SMILES: Br[CH:2]([CH2:19][Br:20])[CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[O:11]CC1C=CC=CC=1.[NH4+].[Cl-].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(Cl)Cl>[Br:20][CH2:19][CH:2]1[CH2:3][O:4][C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:10]=2[O:11]1
Reactant: BrCC(Br)COc1cnccc1OCc1ccccc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: BrCC1COc2cnccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.6 %

Procedure:
To a solution of intermediate (46) (0.0166 mol) in DCM (270 ml), FeCl3 (0.033 mol) was added portionwise and the mixture was stirred at room temperature overnight. The reaction mixture was treated with a saturated NH4Cl-solution and with a diluted solution of potassium sodium tartrate and then it was filtered off over celite. The solvent was evaporated until dry and the residue was treated with methanol and then filtered off. The filtrate was evaporated until dry and the residue was treated with 2,3-dihydroxy butaenedioic acid, monopotassium monosodium salt (1 g) in ethanol and refluxed for 18 hours. The cooled reaction mixture was filtered off over celite and the filtrate was evaporated until dry. The residue was washed with water and extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated until dry. The residue was purified by flash column chromatography over silica gel (eluent: ethyl acetate/(MeOH/NH3) 96/4). The product fractions were collected and the solvent was evaporated, yielding 0.52 g of 2-(bromomethyl)-2,3-dihydro-[1,4]dioxino-[2,3-c]pyridine (intermediate 47).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[C:18][Si](C)(C)C)=[C:15]([CH3:23])[N:14]=[C:13]([NH2:24])[N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+]>CO>[C:17]([C:16]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[N:12][C:13]([NH2:24])=[N:14][C:15]=1[CH3:23])#[CH:18]
Reactant: Cc1nc(N)nc(-c2ccc(S(C)(=O)=O)cc2)c1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1c(C)nc(N)nc1-c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 2.7 g (6.0 mmol) 4-(4-methanesulfonyl-phenyl)-6-methyl-5-trimethylsilanylethynyl-pyrimidin-2-ylamine (A-36) and 415 mg (3.0 mmol) potassium carbonate in 40 mL MeOH. After stirring for 2 h at 0° C. the precipitated product is filtered off and dried over night at 40° C. The product is treated with water, filtered off and dried again. Yield: 1.8 g (83%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1>CS(C)=O>[N:1]([CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
8.13 g of sodium azide are added over 5 minutes to a solution of 5.73 g of methyl 4-(bromomethyl)benzoate in 30 ml of DMSO and the mixture is stirred for 3 hours 30 minutes at RT. The reaction mixture is extracted with ether, the organic phase is washed with water and with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. 4.72 g of the expected product are obtained in the form of a colourless oil.
Reaction SMILES: O=[CH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[O:12])[CH2:6][CH2:5]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][C:36]=1[Cl:37])[O:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][C:36]=1[Cl:37])[O:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][C@H:4]2[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[O:12])[CH2:6][CH2:5]2)[CH2:30][CH2:29]1
Reactant: O=CC[C@H]1CC[C@H](NC(=O)c2ccnc3ccccc23)CC1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1)c1ccnc2ccccc12

Procedure:
The title compound was prepared analogously to example 71 using quinoline-4-carboxylic acid trans-[4-(2-oxo-ethyl)-cyclohexyl]-amide and 4-(3,4-dichloro-phenoxy)-piperidine as starting materials.
Reaction SMILES: [Cl-].[Li+].BrCCBr.I[CH:8]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1.[Cl:19][C:20]1[C:21]([F:33])=[C:22](I)[C:23]([O:29][CH2:30][CH3:31])=[C:24]([C:26](=[O:28])[CH3:27])[CH:25]=1>O1CCCC1.[Zn].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.Cl[Si](C)(C)C.II.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2N(C)C)CCCCC1.C1(C)C=CC=CC=1>[C:26]([C:24]1[C:23]([O:29][CH2:30][CH3:31])=[C:22]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)[C:21]([F:33])=[C:20]([Cl:19])[CH:25]=1)(=[O:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1cccc(N(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: BrCCBr
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 44.6 %

Procedure:
A round-bottom flask equipped with a magnetic stir bar and a rubber septum was charged with lithium chloride (3.9 g, 91 mmol). The flask was heated at 140° C. for 10 min under high vacuum and backfilled with nitrogen after cooling to room temperature. Zinc (6.0 g, 91 mmol) was added and the flask was heated at 140° C. for 10 min under high vacuum and backfilled with nitrogen after cooling to room temperature. Tetrahydrofuran (THF) (38 mL) and 1,2-dibromoethane (233 μL, 2.70 mmol) were added via syringe. The mixture was heated at 60° C. for 10 min and then cooled to room temperature. Chlorotrimethylsilane (68 pt, 0.54 mmol) and iodine (69 mg, 0.27 mmol) in THF (1 mL) were added and the resulting mixture was stirred at 60° C. for 10 min then cooled to room temperature. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (12.17 g, 42.99 mmol) in THF (10 mL) was then added and the mixture stirred at 40° C. for 1 h and at room temperature for 1 h. Another flask charged with 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (13.0 g, 38.0 mmol), palladium acetate (170 mg, 0.76 mmol), 2′-(dicyclohexylphosphino)-N,N,N′,N′-tetramethylbiphenyl-2,6-diamine (660 mg, 1.5 mmol), and toluene (35 mL) was evacuated under high vacuum and backfilled with nitrogen. The mixture was cooled to 0° C. and the zinc reagent made above was added slowly via syringe. After addition, the reaction was heated to 50° C. overnight. The reaction solution was partitioned between EtOAc and sat. NH4Cl solution. The layers were separated and the aqueous extracted further with EtOAc (2×). The combined organics were washed with water, brine, then dried over MgSO4, and concentrated. The crude mixture was purified on silica gel column to give the desired product as an orange oil (6.3 g, 45%). LCMS calculated for C18H23ClFNO4Na (M+Na)+: m/z=394.1; Found: 394.1.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([O:10]C2OC(CO)C(O)C(O)C2O)=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+]>>[N+:7]([C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=1[OH:10])([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccccc1OC1OC(CO)C(O)C(O)C1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccccc1O

Procedure:
β-Galactosidase Assay. An aliquot of the 14,000 g supernatant from the lysed transfected cells (15-25 μg protein) was incubated at 28° C. for 15-60 minutes with 0.67 mg/ml o-nitrophenyl-β-D-galactopyranoside in a final volume of 1.2 ml (Lee et al., 1984). Reactions were stopped with 0.5 ml 1M Na2CO3, and the amount of o-nitrophenol formed was measured spectrophotometrically at 420 nm.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@:15]2([O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]2[OH:18])[OH:16])=[CH:11][C:10]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OCC)(=O)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@:15]2([O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]2[OH:18])[OH:16])=[CH:11][C:10]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cc3cc([C@@]4(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(OC4CCNCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2 ml trifluoroacetic acid are added to a solution of 0.19 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(1-tert-butlyoxycarbonylpiperidin-4-yloxy)-benzyl]-benzene in 4 ml dichloromethane. The solution is stirred for 1.5 h at ambient temperature and then diluted with ethyl acetate and made basic with aqueous potassium carbonate solution. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and the solvent is eliminated entirely.
Reaction SMILES: [C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([CH3:27])[CH:19]=2)=[N:5]1)(=[O:3])[CH3:2].O.NN>CO.ClCCl.[Ni]>[C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([CH3:27])[CH:19]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)c(Cl)cc2CC1C
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1N=C(c2ccc(N)c(C)c2)c2cc(Cl)c(Cl)cc2CC1C
Reaction time: 0.75 h
Yield: 86.9 %

Procedure:
4.06 g (10 mmoles) of (±)-3-acetyl-4,5-dihydro-7,8-dichloro-1-(3-methyl-4-nitrophenyl)-4-methyl-3H-2,3-benzodiazepine are dissolved in a mixture of 55 cm3 of methanol and 55 cm3 of dichloromethane, then 3.0 g of wet Raney nickel catalyst and, under vigorous stirring, 1.7 cm3 (35 mmoles) of 98% hydrazine hydrate are added. The reaction mixture is stirred for further 45 minutes, the catalyst is filtered, washed with dichloromethane, the filtrate is evaporated, and the residue is rubbed with 50 cm3 of water to obtain solid matter. The crude product is recrystallized from a mixture of ethyl acetate and hexane. Thus, 3.27 g (87%) of the title compound are obtained in the form of yellow ochre solids melting at 127–129° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][N:5]([CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:21])[C:6](=[O:17])[CH2:7][N:8]1[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]1=[O:10].Cl>[OH-].[Na+].CO.O>[C:22]([N:20]([CH3:21])[CH2:19][CH2:18][N:5]([C:6](=[O:17])[CH2:7][N:8]1[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]1=[O:10])[CH2:4][C:3]([OH:29])=[O:2])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: COC(=O)CN(CCN(C)C(=O)OC(C)(C)C)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cn(CC(=O)N(CCN(C)C(=O)OC(C)(C)C)CC(=O)O)c(=O)[nH]c1=O

Procedure:
N-[(N-Boc)(N-methyl)-2-aminoethyl]-N-[(1-thyminyl)acetyl] glycine methyl ester was dissolved in 1N NaOH in MeOH/H2O 1:1 for 2 hours. The pH was adjusted to 2 with 2N HCl and extracted with ethyl acetate (50 ml). The organic phase was dried with Na2SO4 and evaporated to dryness. The yield of the title compound was 77%.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.CC(C)([O-])C.[Na+].[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]2[CH2:26][C@H:21]1[CH2:22][NH:23]2)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C(OCC)(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]2[CH2:26][CH:21]1[CH2:22][N:23]2[C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Brc1nccs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CC1CN2c1nccs1
Yield: 52 %

Procedure:
A mixture of 2-bromothiazole (200 mg, 1.22 mmol), palladium acetate (15 mg, 0.06 mmol), sodium tert-butoxide (217 mg, 2.26 mmol), (S,S) 2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (280 mg, 1.4 mmol) and 2-Di-t-butylphosphino)-biphenyl (37 mg, 0.118 mmol) was stirred in dioxane (10 ml) at 80° C. for overnight. The reaction was cooled, diluted with ethyl acetate (40 ml) and H2O (50 ml). The organic layer was separated, dried (Na2SO4), filtered and solvent evaporated. The residue was purified by chromatography eluting with 5% MeOH/DCM yielding product as a white solid. (180 mg, 52% yield)