Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18](O)[N:19]([CH2:26][C:27]1[CH:28]=[C:29]([CH2:33][C:34]#[N:35])[CH:30]=[CH:31][CH:32]=1)[C:20]2=[O:25]>ClCCl>[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][N:19]([CH2:26][C:27]1[CH:28]=[C:29]([CH2:33][C:34]#[N:35])[CH:30]=[CH:31][CH:32]=1)[C:20]2=[O:25]
Reactant: N#CCc1cccc(CN2C(=O)c3cccc(N)c3C2O)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCc1cccc(CN2Cc3c(N)cccc3C2=O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
At room temperature, initially 8 ml (50 mmol) of triethylsilane and then dropwise, 20 ml (260 mmol) of TFA are added to a suspension of 5.87 g (20 mmol, purity about 90%) of 2-{3-[(4-amino-3-hydroxy-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}acetonitrile in 200 ml dichloromethane. The mixture is stirred at room temperature for 4 h and then concentrated and dried under high vacuum. The residue is taken up in dichloromethane and the mixture is washed with sat. sodium bicarbonate solution and sat. sodium chloride solution, dried over magnesium sulfate and concentrated to about 50 ml. About 100 ml of ether are added to the crystal slurry, which is then stirred for about 2 h and filtered. Yield: 4.36 g (78.7% of theory);
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[CH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH:26]([CH2:28][C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24][C:23]=3[CH:34]=2)=[O:17])[CH2:10][CH2:9]1.C(O)C.[OH-].[Na+]>C(O)(=O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([CH:14]=[CH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH:26]([CH2:28][C:29]([OH:31])=[O:30])[CH2:25][CH2:24][C:23]=3[CH:34]=2)=[O:17])[CH2:12][CH2:13]1
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)C=CC3CCNCC3)ccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CCc2cc(NC(=O)C=CC3CCNCC3)ccc2O1

Procedure:
0.1 g (0.2 mmol) of the ester from Example 77 were stirred overnight at room temperature in a mixture 2.5 ml ethanol and 0.35 ml 2 N aqueous sodium hydroxide solution. The reaction mixture was cooled with ice and brought to pH 5.5 with 2 N acetic acid. The precipitate of the title acid was filtered with suction, washed with a small amount of cold water, and dried at 50° C. in vacuo. Yield: 42 mg (59%) of beige crystals, m.p. 175-178° C.
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)=[N:6]1)(C)(C)C>C(O)=O.Cl>[NH2:21][C:17]1[CH:16]=[C:15]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[N:12][C:13]=3[NH2:14])[NH:5][N:6]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)n1nc(-c2cccc(N)c2)c2c(N)ncnc21
Agent: Cl
Solvent: O=CO
Product: Nc1cccc(-c2n[nH]c3ncnc(N)c23)c1

Procedure:
1-tert-butyl-3-(3-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was dissolved in a solution of formic acid (2 mL) and conc. HCl (0.2 mL) and heated to reflux for 30 min. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 227.1, found 227.3.
Reaction SMILES: C(N(CC)CC)C.[Cl-].[Mg+2].[Cl-].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([O-:15])=O.[K+].[C:21]1([C:27]2[O:28][C:29](=O)[C:30]([CH:33]([CH3:35])[CH3:34])(C)[N:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>C(#N)C.O>[CH3:29][C:30]([NH:31][C:27](=[O:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH:33]([CH3:34])[CH3:35])[C:13](=[O:15])[CH2:12][C:11]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC(C)C1(C)N=C(c2ccccc2)OC1=O
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CC(=O)C(C)(NC(=O)c1ccccc1)C(C)C
Yield: 26.2 %

Procedure:
1.06 g (0.01 mole) of triethylamine and 0.85 g (0.01 mole) of magnesium chloride were added, at room temperature, to a solution of 0.85 g (0.005 mole) of monopotassium ethyl malonate dissolved in 10 ml of acetonitrile, followed by stirring. Thereto was added 1.1 g (0.005 mole) of 2-phenyl-4-isopropyl-4-methyl-1,3-oxazol-5-one. The mixture was stirred at 60° C. for 8 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was cooled. Thereto were added 50 ml of water and diluted hydrochloric acid to adjust the mixture to a pH of 4 or less. The mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated. The concentrate was subjected to separation by column chromatography to obtain 0.4 g (0.00131 mole) of ethyl 4,5-dimethyl-3-oxo-4-(benzoylamino)hexanoate (yield=26%).
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH2:30][C@@H:31]([CH2:33][OH:34])[N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:34][CH2:33][C@@H:31]1[CH2:30][O:29][C:28]([C:26]2[NH:27][C:23]([C:8]3[CH:7]=[C:6]([CH:11]=[C:10]([O:12][C:13]4[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=4)[CH:9]=3)[O:5][C@@H:4]([CH3:35])[CH2:3][OH:2])=[CH:24][CH:25]=2)=[N:32]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](CO)CO3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](CO)CO3)[nH]2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
{(4R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}methanol (200 mg, 0.40 mmol) synthesized in Example (86c) was dissolved in methylene chloride (5 mL), followed by cooling to −78° C., and boron tribromide (1.0 mol/L methylene chloride solution, 0.80 mL, 0.80 mmol) was added under nitrogen atmosphere. After the temperature was raised naturally and stirring was carried out at room temperature for 30 minutes, a saturated aqueous sodium hydrogencarbonate solution was added to neutralize the reaction solution, followed by extraction with methylene chloride (80 mL). The organic layer was washed with 1N aqueous sodium hydroxide solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-4%) to afford the desired compound (143 mg, 74%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[CH:16]=[CH:17][C:18](O)=[O:19].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>O1CCCC1.C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[CH:16]=[CH:17][C:18]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1)=[O:19]
Reactant: Cc1cc(N)cc(C)c1O
Reactant: COc1cccc(C=CC(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(C=CC(=O)Nc2cc(C)c(O)c(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
Under argon gas stream, to a solution of 600 mg of 4-amino-2,6-dimethylphenol in 20 ml of tetrahydrofuran is added under ice-cooling 779 mg of 3-methoxycinnamic acid, and then 902 mg of dicyclohexylcarbodiimide and 118 mg of 1-hydroxybenzotriazole are added, followed by stirring at room temperature overnight. After ethyl acetate is added to the reaction mixture, the mixture is washed successively with 10 % hydrochloric acid, water, 5 % sodium hydrogen carbonate and water, and dried, followed by concentration. The residue is recrystallized from ethyl acetate-n-hexane to give 890 mg of 4-(3-methoxycinnamoyl)amino-2,6-dimethyl-phenol.
Reaction SMILES: BrBr.[CH2:3]([N:10]1[CH2:19][CH2:18][C:17]2[NH:16][C:15](=[O:20])[CH2:14][CH2:13][C:12]=2[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)(=O)C>[CH2:3]([N:10]1[CH2:19][CH2:18][C:17]2[NH:16][C:15](=[O:20])[CH:14]=[CH:13][C:12]=2[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCC2=C(CCN(Cc3ccccc3)C2)N1
Agent: BrBr
Solvent: CC(=O)O
Product: O=c1ccc2c([nH]1)CCN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 44.9 %

Procedure:
Bromine (750 μl, 14.6 mmol) in glacial acetic acid (5 ml) was added dropwise over 5 minutes to (6-benzyl-3,4,5,6,7,8-hexahydro-1H-[1,6]naphthyridin-2-one (3.37 g, 13.9 mmol) (reference WO9830560) dissolved in glacial acetic acid (50 ml) at 100° C. The mixture was heated at 100° C. for 2.5 hours and then was cooled to room temperature. The solvent was evaporated under reduced pressure and the residue was basified with 10% sodium carbonate solution (50 ml). The aqueous mixture was extracted with chloroform (4×50 ml) and the combined organic solutions were dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane (gradient from 0:100 to 3:97) to give the title compound as yellow crystals (1.5 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:59][CH:60]([CH3:62])[CH3:61])[C:7]([F:58])=[C:8]([CH:10]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[N:56]=[C:55]([CH3:57])[O:54][N:53]=3)=[CH:48][CH:47]=2)[C:11]2[N:12]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH:22]([OH:25])[CH2:23][CH3:24])[N:15]=2)[CH:9]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:59][CH:60]([CH3:62])[CH3:61])[C:7]([F:58])=[C:8]([CH:10]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[N:56]=[C:55]([CH3:57])[O:54][N:53]=3)=[CH:48][CH:47]=2)[C:11]2[N:12]([C:26]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22](=[O:25])[CH2:23][CH3:24])[N:15]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(O)CC)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(=O)CC)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of Intermediate 122.2 and Dess-Martin periodinate (60 mg, 0.12 mmol) in anhydrous CH2Cl2 (2 mL) was stirred at rt for 20 min. The reaction mixture was then partionated between EtOAc and 1 N NaOH, the organic layer was collected and dried over (Na2SO4), filtered and concentrated to afford Intermediate 122.3, which was used in the following step without further purification. LCMS (2 min gradient) RT=2.27 min, 826.4 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C@H:20]([CH2:21][CH:22]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])C(O)=O)[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl-].[Na+].O>CS(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C@H:20]([CH2:21][CH2:22][C:26]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[O:27])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C[C@H]2CC(C(=O)O)C(=O)N2CCOCC2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C[C@H]2CCC(=O)N2CCOCC2)cc1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
To a solution of 7.80 g (16.51 mmol) of the compound obtained in Step C in 100 mL of DMSO there are added 1.16 g (19.83 mmol) of solid sodium chloride (NaCl) and then, dropwise, 5 mL of water. The batch is stirred at 130° C. for 1 hour and then the solution is concentrated to 3/4. The reaction mixture is then diluted with dichloromethane and washed successively with saturated aqueous lithium chloride solution and then with brine. The organic phase is then dried over MgSO4, filtered and concentrated to dryness. After purification by chromatography over silica gel using cyclohexane and ethyl acetate as eluants, the expected product is obtained in the form of an oil.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.[C:30]([O:34][C:35]([NH:37][NH2:38])=[O:36])([CH3:33])([CH3:32])[CH3:31]>[Cu](I)I.CN(C=O)C>[C:30]([O:34][C:35]([N:37]([C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1)[NH2:38])=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: N#Cc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(N)c1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 54.1 %

Procedure:
Copper iodide (18 mg, 0.05 eq, 0.09 mmol), 1,10-phenanthroline (67 mg, 0.2 eq, 0.37 mmol) and caesium carbonate (0.84 g, 1.4 eq, 2.6 mmol) were mixed in a RB flask, placed under vacuum and purged with N2 (g). 4-iodo-benzonitrile (0.5 g, 1.0 eq, 1.85 mmol), hydrazine carboxylic acid tert-butyl ester (0.3 g, 1.2 eq, 2.22 mmol) and DMF (25 ml) were added to the mixture which was then heated to 80° C. with stirring under an inert atmosphere for 16 hours. The reaction mixture was allowed to cool and the solvent was removed in vacuo. The resultant residue was absorbed onto silica and purified by column chromatography using heptane/ethyl acetate (7:3) as eluent to yield the title compound as a pale orange solid (0.23 g, 1.0 mmol, 45%). LCMS: [M+H]+=234, rt=1.94 min, 97% purity.
Reaction SMILES: NC1N=C(N)C2C(=NC=C(CN(C3C=CC=CC=3)C3C=CC=CC=3)N=2)N=1.[CH:27]1[C:40]2[NH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[S:32][C:31]=2[CH:30]=[CH:29][CH:28]=1.[H-].[Na+].Br.[NH2:44][C:45]1[N:54]=[C:53]([NH2:55])[C:52]2[C:47](=[CH:48][CH:49]=[C:50]([CH2:56]Br)[CH:51]=2)[N:46]=1>>[NH2:44][C:45]1[N:54]=[C:53]([NH2:55])[C:52]2[C:47](=[CH:48][CH:49]=[C:50]([CH2:56][C:37]3[CH:36]=[CH:35][CH:34]=[C:33]4[C:38]=3[NH:39][C:40]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[S:32]4)[CH:51]=2)[N:46]=1
Reactant: Nc1nc(N)c2cc(CBr)ccc2n1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: Br
Agent: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Agent: [H-]
Product: Nc1nc(N)c2cc(Cc3cccc4c3Nc3ccccc3S4)ccc2n1

Procedure:
9-[(2,4-Diaminoquinazolin-6-yl)methyl]phenothiazine (Formula I: Ar=2,4-diaminoquinazolin-6-yl; W=CH2; X=N; Z=S; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by using phenothiazine (159 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylquinazoline hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(OCC)(=O)C>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:4][OH:3]
Reactant: CCOC(=O)C1CCCCC1c1ccccc1OC
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1C1CCCCC1CO
Reaction time: 2 h
Yield: 94.9 %

Procedure:
Combine 2-(2-methoxy-phenyl)-cyclohexanecarboxylic acid ethyl ester (2.34 g, 8.9 mmol), lithium aluminum hydride (1.02 g, 26.7 mmol), and tetrahydrofuran (30.0 mL) at room temperature. Stir at rm temperature under nitrogen for 2 hours then add Rochelle's salt and ethyl acetate. Stir 18 hours then separate layers and wash with brine then dry over anhydrous sodium sulfate. Concentrate to yield the titled compound (1.86 g, 95%). TLC Rf=0.08 in 10% ethyl acetate/hexanes. 1H NMR (CDCl3): 7.2 (m, 2H), 6.9 (m, 2H), 3.8 (s, 3H), 3.5 (m, 1H), 3.4 (m, 1H), 3.3 (m, 1H), 2.3 (m, 1H), 1.8 (m, 2H), 1.5 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])[C:12]2[N:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH3:35]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])[C:12]2[N:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([NH2:35])=[O:21])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: N
Reactant: O=C(O)/C=C/c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)/C=C/c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
In dichloromethane (6 ml) was dissolved (E)-3-[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]acrylic acid (370 mg, 0.822 mmol). To the resulting solution were added thionyl chloride (2.00 ml) and N,N-dimethylformamide (one drop). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness. The residue thus obtained was dissolved in dichloromethane (6 ml), followed by the addition of aqueous concentrated ammonia (2.00 ml). After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane. The diluted mixture was washed with water, 0.1N hydrochloric acid and brine, dried over magnesium sulfate, and concentrated. The solid thus obtained was recrystallized from ethanol to give the title compound (250 mg, 0.558 mmol, 68%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH:3]([CH:5]1[C:11](=[O:12])[N:10]2[CH:6]1[CH2:7][C:8]([O:23][S:24]([C:27]1[C:28]([CH3:33])=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25])=[C:9]2[C:13]([O:15]CC1C=CC=CC=1)=[O:14])[OH:4].C(=O)(O)[O-].[Na+:40].O1CCOCC1>[Pd].O>[F:35][C:2]([F:1])([F:34])[CH:3]([CH:5]1[C:11](=[O:12])[N:10]2[CH:6]1[CH2:7][C:8]([O:23][S:24]([C:27]1[C:28]([CH3:33])=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25])=[C:9]2[C:13]([O-:15])=[O:14])[OH:4].[Na+:40]
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(O)C(F)(F)F)C2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)[O-])N2C(=O)C(C(O)C(F)(F)F)C2C1
Reaction time: 0.5 h

Procedure:
A mixture of benzyl 6-(2,2,2-trifluoro-1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (26 mg), 10% palladium on charcoal (25 mg), sodium bicarbonate (4.5 mg), dioxane (2 ml) and water (1 ml) is hydrogenated at 40 psi for 30 mins. The mixture is filtered to remove the catalyst which is washed with several portions of water (3×2 ml). The combined filtrate is extracted with ethyl acetate (2×2 ml), concentrated in vacuo to ca. 2 ml, and lyophilized to provide sodium 6-(2,2,2-trifluoro-1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [C:1]12[CH2:9][CH:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][C:3](C1=CC(OC1=O)=O)([C:10]1([CH:20]3[CH2:25][CH:24]4[CH2:26][C:22]([C:23]4([CH3:28])[CH3:27])=[C:21]3[CH3:29])[CH2:15][CH:14]3[CH2:16][C:12]([C:13]3([CH3:18])[CH3:17])=[C:11]1[CH3:19])[C:2]=2[CH3:37].C1C=CC(/C=C/CO[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)=CC=1.CCCCCCCCCC/C=C/C1C(=O)OC(=O)C1.C1(C=CC(O)=CC=1)O>CO>[C:1]12[CH2:9][CH:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH:3]([C:10]1([CH:20]3[CH2:25][CH:24]4[CH2:26][C:22]([C:23]4([CH3:28])[CH3:27])=[C:21]3[CH3:29])[CH2:15][CH:14]3[CH2:16][C:12]([C:13]3([CH3:17])[CH3:18])=[C:11]1[CH3:19])[C:2]=2[CH3:37]
Reactant: CC1=C2CC(CC1C1(C3(C4=CC(=O)OC4=O)CC4CC(=C3C)C4(C)C)CC3CC(=C1C)C3(C)C)C2(C)C
Agent: CCCCCCCCCC/C=C/C1CC(=O)OC1=O
Agent: *C(F)(F)C(*)(F)F
Agent: OC[C@H]1O[C@@H](OC/C=C/c2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CO
Product: CC1=C2CC(CC1C1(C3CC4CC(=C3C)C4(C)C)CC3CC(=C1C)C3(C)C)C2(C)C
Temperature: 170 °C

Procedure:
A 1 liter Parr reactor equipped with a mechanical stirrer, bottom drain valve and distillation apparatus, was charged with NDC (111.0 g, 0.453 moles, 0.121 eq), PPG (211.0 g, 2.768 moles, 0.508 eq; excess 0.232 eq), terpinene-maleic anhydride adduct (42 g, 0.180 moles, 0.048 eq), Rosin-Ar (88 g, 0.249 moles, 0.0667 eq), DDSA (118 g, 0.445 moles, 0.119 eq), SA (53.0 g, 0.453 moles, 0.121 eq) followed by 1.0 g of both Fascat 4100 and Vertec AC422 titanium catalyst. About 0.4 g of hydroquinone were added as a free radical scavenger to prevent crosslinking of resin. The reactor was blanketed with nitrogen and the temperature of the reactor was slowly raised to 170° C. with stirring (once the solids melted). The reaction mixture was maintained for 15 hours under nitrogen at 205° C. while methanol was continuously collected in a collection flask. The reaction mixture was heated to 215° C. and low vacuum was applied. A higher vacuum (<0.1 Torr) was applied. During that time, propylene glycol distilled off and when the softening point of the resin reached 97.8° C., the reactor temperature was reduced to 180° C. and the second portion of terpinene-maleic anhydride (14 g, 0.058 moles, 0.0154 eq) was added. The reaction mixture temperature was slowly raised to 225° C. while under high vacuum for another 10 hours until a softening point of 103.5° C. was achieved. The temperature was then lowered to 190° C. and the polymer was discharged onto a polytetrafluoroethylene (Teflon) pan.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[NH:4][C@@H:5]1[C@@H:12]([OH:13])[C@H:11]([OH:14])[C@@H:10]([CH3:15])[O:9][C@H:6]1[O:7][CH3:8].[N:17]([O-])=[O:18].[Na+]>C(O)(=O)C.O>[CH3:1][N:2]([N:17]=[O:18])[C:3](=[O:16])[NH:4][C@@H:5]1[C@@H:12]([OH:13])[C@H:11]([OH:14])[C@@H:10]([CH3:15])[O:9][C@H:6]1[O:7][CH3:8]
Reactant: CNC(=O)N[C@H]1[C@H](OC)O[C@H](C)[C@@H](O)[C@@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CO[C@@H]1O[C@H](C)[C@@H](O)[C@H](O)[C@H]1NC(=O)N(C)N=O
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Methyl 2,6-dideoxy-2-(N'-methyl-ureido)-β-D-glucopyranoside (124 mg) of the formula: ##STR35## was dissolved in a mixture of 0.5 ml of glacial acetic acid and 2.5 ml of water, and the resulting solution was admixed with 55 mg of sodium nitrite at ambient temperature and under agitation to effect the nitrosation. The reaction mixture so obtained was then allowed to stand overnight in a refrigerator, so that a crystalline product was deposited. This crystalline product was collected by filtration and then washed with ethanol, affording 80 mg of methyl 2,6-dideoxy-2-(N'-methyl-N'-nitroso-ureido)-β-D-glucopyranoside as the desired product. The mother liquor was then treated with Amberlite IR-120 (H+ form) to remove the sodium ion, and the mother liquor so treated was concentrated by distilling off the solvent under reduced pressure. Crystallization of the residue from ethanol gave 45 mg of the desired product as a second crop. Yield 125 mg (90%). [α]D28 -14° (c 0.52, H2O).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]([CH3:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])C.CO.[OH-].[Li+].Cl>O1CCCC1>[C:16]([O:15][C:13]([N:8]1[CH2:9][CH2:10][C@@H:11]([CH3:12])[C@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a flask containing (+/−)-4-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.12 g, 4.1 mmol; from example 8 above) was taken up in tetrahydrofuran (12 mL) and methanol (3 mL) and cooled to 0° C. (ice bath). A solution of lithium hydroxide (4.5 mL, 1M) was added and the mixture was warmed to ambient over 3 hours. Extra methanol (2 mL) was added and the material was heated to 60° C. (oil bath) for 5.5 hours. The mixture was cooled to ambient and treated with 1N hydrochloric acid solution (4.7 mL) with vigorous stirring. The solvent was stripped and the remainder was dried under high vacuum for several hours, providing 1.06 g of mainly trans-(+/−)-4-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester: as a off-white solid. MS (M−H)−=242.