Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[CH2:45]([N:47]([CH2:50]C)CC)C.CN>CN(C1C=CN=CC=1)C.C1COCC1.ClCCl>[C:18]([C:8]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[N:4]2[N:3]=[C:2]([NH:1][C:45]([NH:47][CH3:50])=[O:34])[N:31]=[C:5]2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)[C:7]=1[CH3:20])#[N:19]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: CN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (13 mg, 28 μmol) was initially charged in abs. dichloromethane (2 ml). At −78° C., 4-nitrophenyl chloroformate (28.6 mg, 142 μmol, 5 eq.), triethylamine (14.7 mg, 145 μmol, 5.1 eq.) and DMAP (3.5 mg, 28 μmol) were added. After 2 h of stirring at −78° C., the reaction mixture was allowed to thaw initially to −20° C. (2 h) and then to 0° C. (2 h). The mixture was then once more cooled to −78° C., and a 2 M solution of methylamine in THF (102 μl, 7.2 eq.) was added. The mixture was then warmed to −10° C. and stirred overnight. A 2 M solution of methylamine in THF (1 ml) was then added, the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (5.9 mg, 43% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH:12]([CH3:14])[C:11](=[O:15])[N:10]([C@@H:16]([CH2:26][CH3:27])[CH2:17][N:18]([CH3:25])[S:19]([CH:22]3[CH2:24][CH2:23]3)(=[O:21])=[O:20])[C@@H:9]2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:44][CH2:45][CH:46]=[CH2:47]>C1COCC1>[CH2:44]([C:12]1([CH3:14])[CH2:13][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:9]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:10]([C@@H:16]([CH2:26][CH3:27])[CH2:17][N:18]([CH3:25])[S:19]([CH:22]2[CH2:23][CH2:24]2)(=[O:21])=[O:20])[C:11]1=[O:15])[CH2:45][CH:46]=[CH2:47]
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)C(C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C=CCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-((2S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-methyl-6-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide (2618 mg, 5.0 mmol; Example 201, Step B) in degassed THF (10 mL) was added lithium diisopropylamide (5.00 mL, 10.00 mmol) at −15° C. After stirring at −15° C. for 30 min, the reaction mixture was cooled to −74° C. 4-Bromobut-1-ene (1.066 mL, 10.50 mmol) was added slowly. The reaction mixture was stirred at −74° C. for 3 h before warming up to rt and then stirred at rt for 66 h. Filtered and purified by HPLC (C18 column, eluted with 10 to 95% CH3CN in water, with 0.1% TFA) to give the title compound as the first eluting isomer Its stereoisomer is obtained as the later eluting isomer.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:14])[O:5][C:6]2[C:11]([C:12]=1[CH3:13])=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[C:3]=1[C:1]1[NH:17][N:16]=[N:15][N:2]=1
Reactant: Cc1c(C#N)c(=O)oc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2nnn[nH]2)c(=O)oc2ccccc12

Procedure:
A solution of 3-cyano-4-methyl coumarin (7.94 g; 0.043 mole) in cimethylformamide (DMF) (45 ml) was added to a mixture of sodium azide (2.92 g; 0.044 mole) and ammonium chloride (2.36 g; 0.044 mole) and the stirred mixture heated on a steam bath for 24 hours. After removal of the solvent under reduced pressure, water (100 ml) was added and the solid filtered off. Acidification of the filtrate, and further aqueous extracts, afforded the title compound; m.p. (EtOH) 213°-4° C (Found: C, 57.58; H, 3.51; N, 24.41; C11H8N4O2 requires; C, 57.89; H, 3.53; N, 24.55%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH2:14][C:15]([CH3:18])([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.[I-].[Na+].[Na].[CH3:22][CH:23]1[CH2:27][CH2:26][CH:25]([CH3:28])[NH:24]1>C(#N)C.C(OCC)(=O)C.O>[CH3:22][CH:23]1[CH2:27][CH2:26][CH:25]([CH3:28])[N:24]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH2:14][C:15]([CH3:18])([CH3:17])[N:16]=2)=[CH:8][CH:7]=1
Reactant: CC1CCC(C)N1
Reactant: CC1(C)COC(c2ccc(OCCCCl)cc2)=N1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC1CCC(C)N1CCCOc1ccc(C2=NC(C)(C)CO2)cc1
Yield: 41 %

Procedure:
2-[4-(3-chloropropoxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole ax10 (500 mg, 1.87 mmol, 1 eq), sodium iodide (0.56 mg, 3.74 mmol, 2 eq), sodium hydrogenocarbonate (0.31 mg, 3.74 mmol, 2 eq) and 2,5-dimethylpyrrolidine (0.24 ml, 2.8 mmol, 1.5 eq) are stirred at reflux overnight in dry acetonitrile (10 ml). Water and ethyl acetate are added to the mixture and the layers are separated. The organic layer is dried with brine, sodium sulfate and evaporated under vacuum. Flash chromatography over silica with ethyl acetate as the eluent gives 0.253 g of 2-(4-{3-[2,5-dimethylpyrrolidin-1-yl]propoxy}phenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole 18 as a free base.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH3:22])[CH:18]=3)[CH:13]2[CH3:23])[C:9]2[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>CN(C)C=O>[ClH:1].[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:2]2[N:11]=[C:10]([N:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([CH3:22])[CH:18]=4)[CH:13]3[CH3:23])[C:9]3[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:29][CH:28]=1
Reactant: COc1cccc2c(N3CCc4cc(C)ccc4C3C)nc(Cl)nc12
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4cc(C)ccc4C3C)nc(Nc3ccc(F)cc3)nc12
Product: Cl
Yield: 61 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 2.50 g of the compound (7.06 mM) prepared in Example 15 and 10 ml of dimethyl-formamide, 1.40 ml of 4-fluoroaniline(4.8 mM) was added, 2.0 g of the title compound was prepared.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>C(N(CC)CC)C>[CH2:7]([O:6][C:1](=[O:5])[C@@H:2]([O:3][S:10]([CH3:9])(=[O:12])=[O:11])[CH3:4])[CH3:8]
Reactant: CCOC(=O)[C@H](C)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)OS(C)(=O)=O

Procedure:
An equal molar solution of (S)-ethyl lactate and triethylamine in dry methylene was treated with an equal molar amount of methane sulfonylchloride at 5°-10° C. After the addition was complete, the mixture was filtered to remove triethylamine hydrochloride. The filtrate was then washed with water, dried over MgSO4, and concentrated to give a high yield of ethyl-(S)-2[(methylsulfonyl)oxy]propionate.
Reaction SMILES: [CH3:1][Mg+].[Br-].[F:4][C:5]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:6]=1[C:7]([NH:9]/[CH:10]=[CH:11]\I)=[O:8].Cl>[Br-].[Zn+2].[Br-].C(OCC)C.C1COCC1.CN(C=O)C>[F:4][C:5]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:6]=1[C:7]([NH:9]/[CH:10]=[CH:11]\[CH3:1])=[O:8]
Reactant: C[Mg+]
Reactant: O=C(N/C=C\I)c1c(F)cccc1F
Agent: Cl
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C/C=C\NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Yield: 86 %

Procedure:
Zinc bromide (1.68 g, 7.48 mmol) was added in portions to a solution of MeMgBr in diethyl ether (3M, 2.4 ml, 7.23 mmol).After stirring at room temperature there was a thick prepicipitate. Some DMF and THF was added to improve solubility and aid stirring. 2,6-difluoro-N—[(Z)-2-iodovinyl]benzamide (746 mg, 2.41 mmol) was added and then dichloro-bisacetonitrile palladium (12.5 mg, 0.048 mmol) was added, and the mixture stirred overnight at RT and then shaken between diethyl ether and HCl (1 M), dried with MgSO4, evaporated and chromatographed with EtOAc/cyclohexane to yield pure 2,6-difluoro-N—[(Z)-prop-1-enyl]benzamide (406 mg, 86%) m.p. 71-74° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([NH2:12])[C:7]([O:10][CH3:11])=[N:8][CH:9]=1.[Cl:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[C:16](Cl)[N:15]=1>O1CCCC1>[Cl:13][C:14]1[N:15]=[C:16]([NH:12][C:6]2[C:7]([O:10][CH3:11])=[N:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)[C:17]([N+:21]([O-:23])=[O:22])=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)nc1Cl
Reactant: COc1ncc(Cl)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncc(Cl)cc1Nc1nc(Cl)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.23 g, 5.80 mmol) was added to a stirred solution of 5-chloro-2-methoxypyridin-3-amine (Preparation 23b, 1.15 g, 7.25 mmol) in tetrahydrofuran (11 mL) and the resulting mixture was stirred at ambient temperature for 30 minutes. A solution of 2,6-dichloro-3-methyl-5-nitropyridine (prepared according to the method described in WO2010/094645(A1), 1.0 g, 4.83 mmol) in tetrahydrofuran (10 mL) was then added and the reaction mixture was heated at reflux overnight and then stirred at ambient temperature for 3 days. Solvent was evaporated under reduced pressure and the resulting residue was treated with methanol, filtered, washed with additional methanol and dried to yield the title compound (1.18 g, 74%) as an orange solid.
Reaction SMILES: [NH2:1][C:2]([O:4][CH2:5][C@@H:6]1[CH2:11][C:10]([C:12]2[N:13]=[C:14]([S:17]CC3C=CC(OC)=CC=3)[S:15][CH:16]=2)=[CH:9][CH2:8][N:7]1[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])=[O:3].C1(OC)C=CC=CC=1.C(N)(=S)C1C=CN=CC=1>FC(F)(F)C(O)=O>[NH2:1][C:2]([O:4][CH2:5][C@@H:6]1[CH2:11][C:10]([C:12]2[N:13]=[C:14]([SH:17])[S:15][CH:16]=2)=[CH:9][CH2:8][N:7]1[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])=[O:3]
Reactant: C=CCOC(=O)N1CC=C(c2csc(SCc3ccc(OC)cc3)n2)C[C@H]1COC(N)=O
Agent: NC(=S)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CCOC(=O)N1CC=C(c2csc(S)n2)C[C@H]1COC(N)=O
Yield: 65.6 %

Procedure:
Allyl (2S)-2-{[(aminocarbonyl)oxy]methyl}-4-{2-[(4-methoxybenzyl)sulfanyl]-1,3-thiazol-4-yl}-3,6-dihydro-1(2 H)-pyridinecarboxylate (74.5 mg, 0.16 mmol) and anisole (35 ml, 0.32 mmol) were dissolved in trifluoroacetic acid (6 ml). And then thioisonicotinamide (3 mg) was added to the solution and the mixture was refluxed at 80–90° C. Four hours later the solvent was removed in vacuo. To the residue was added an aqueous 1N NaOH solution to make the solution alkaline. To the solution were added ethyl acetate and hexane, and the solution was separated with a separating funnel. To the aqueous layer was added 6N hydrochloric acid and the solution was separated with a separating funnel by addition of ethyl acetate. The aqueous layer was extracted with ethyl acetate and the organic layer was washed twice with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo to give allyl (2S)-2-{[(aminocarbonyl)oxy]methyl}-4-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2 H)-pyridinecarboxylate (37.3 mg, 67%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[C:13]1([S:19][CH2:20][CH:21]([OH:24])[CH2:22]O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=2[Cl:12])[O:24][CH:21]([CH2:20][S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:22][O:4]1
Reactant: OCC(O)CSc1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: O
Solvent: c1ccccc1
Product: Clc1ccc(C2(CBr)OCC(CSc3ccccc3)O2)c(Cl)c1

Procedure:
A mixture of 13.6 parts of 2-bromo-1-(2,4-dichlorophenyl)-1-ethanone, 11.1 parts of 3-(phenylthio)-1,2-propanediol, 3 parts of 4-methylbenzenesulfonic acid, 80 parts of butanol and 180 parts of benzene is stirred and refluxed for 24 hours with water-separator. The reaction mixture is evaporated and the residue is dissolved in trichloromethane. The solution is stirred with silica gel for 30 minutes. The latter is filtered off and the filtrate is evaporated, yielding A+B 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(phenylthiomethyl)-1,3-dioxolane as a residue.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[Cl:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][N:30]=1)[C:25](O)=[O:26].O1CC(C2C3SC(NC(C4SC(C)=CC=4)=O)=NC=3C(OC)=CC=2)COCC1>>[Cl:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][N:30]=1)[C:25]([NH:17][C:14]1[S:15][C:16]2[C:8]([CH:6]3[CH2:5][O:4][CH2:3][CH2:2][O:1][CH2:7]3)=[CH:9][CH:10]=[C:11]([O:18][CH3:19])[C:12]=2[N:13]=1)=[O:26]
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Reactant: O=C(O)c1ccnc(CCl)c1
Agent: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 2-chloromethyl-isonicotinic acid, the title compound was prepared in the same manner as described for 5-methyl-thiophene-2-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide and obtained as brown solid. MS: m/e=435(M+H+).
Reaction SMILES: [P:1](Cl)([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])([O:3][CH2:4][CH:5]([CH3:7])[CH3:6])=[O:2].N1C=CC=CC=1.[CH2:20]([OH:24])[CH2:21][CH2:22][CH3:23]>ClCCl>[P:1]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])([O:3][CH2:4][CH:5]([CH3:7])[CH3:6])([O:24][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2]
Reactant: CCCCO
Reactant: CC(C)COP(=O)(Cl)OCC(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOP(=O)(OCC(C)C)OCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diisobutyl chlorophosphate (130.3 g, 0.57 mole) in 600 mL of dichloromethane and 55.37 g (0.70 mole) of pyridine was cooled to 0° C. n-Butanol (42.25 g, 0.57 mole) was added dropwise over 1 hour. The formation of a white precipitate was immediately observed. The reaction mixture was then stirred for 24 hours at room temperature. The pyridinium hydrochloride was filtered off and the solution washed with water (2×250 mL), aqueous 0.5 N HCl (2×250 mL) and water (2×250 mL). The organic phase was dried over anhydrous magnesium sulfate for 12 hours. Filtration of the drying agent, followed by the removal of the solvent using a Roto-vap, yielded n-butyl diisobutyl phosphate as a clear colorless liquid. Distillation of the crude product (68° C. at 0.02 torr) gave 125 g of 96% n-butyl diisobutyl phosphate (BDIBP).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Li]CCCC.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:37]([C:39]4[N:43]([CH3:44])[CH:42]=[N:41][CH:40]=4)=[O:38])[CH:35]=3)[N:30]([CH3:45])[C:29](=[O:46])[CH:28]=2)[CH:24]=[CH:25][CH:26]=1>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:37]([OH:38])([C:3]4[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=4)[C:39]4[N:43]([CH3:44])[CH:42]=[N:41][CH:40]=4)[CH:35]=3)[N:30]([CH3:45])[C:29](=[O:46])[CH:28]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Cn1cncc1C(=O)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: Cn1ccnc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C)c1nccn1C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A mixture of 1-methyl-1H-imidazole (0.0054 mol) in THF (10 ml) was cooled to −70° C. BuLi 1.6M (3.4 ml) was added dropwise and the mixture stood at −70° C. for 30 min. Chlorotriethylsilane (0.0054 mol) was added. The mixture was allowed to warm to 10° C. and then cooled to −70° C. BuLi 1.6M (3.4 ml) was added dropwise. The mixture stood at −70° C. for 1 hour, brought quickly to −15° C. and cooled to −70° C. THF (20 ml) and then intermediate 29) (0.0045 mol) were added. The mixture was allowed to warm to room temperature, stirred at room temperature overnight, stirred and refluxed for 24 hours, then hydrolized and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (2.7 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.5; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone/DIPE. The precipitate was filtered off and dried, yielding 0.6 g (28%) of 4-(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-2-yl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone, melting point 130° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccc(C#N)cn1
Yield: 44.2 %

Procedure:
(S)-2-Aminomethyl pyrrolidine-1-carboxylic acid tert-butyl ester (0.3 g), 6-chloronicotinonitrile (0.21 g), potassium carbonate (0.41 g) and diisopropylethylamine (0.78 ml) were heated in xylene at 130° C. for 26 h, cooled and the mixture filtered through kieselguhr. The filtrate was evaporated and the residue chromatographed on silica gel, eluting with ethyl acetate-hexane mixtures to afford the title compound (0.2 g). Mass Spectrum (API+): Found 303 (MH+). C16H22N4O2 requires 302.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[N+:11]([O-])([O-:13])=[O:12].[K+]>OS(O)(=O)=O>[CH3:1][N:2]1[C:7]([CH3:8])=[C:6]([N+:11]([O-:13])=[O:12])[C:5](=[O:9])[NH:4][C:3]1=[O:10]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(=O)[nH]c(=O)n1C
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c([N+](=O)[O-])c(=O)[nH]c(=O)n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of 1,6-dimethylpyrimidine-2,4(1H,3H)-dione (5 g, 0.035 mol) in H2SO4 (20 mL) at 0° C. was added dropwise a solution of KNO3 (4.69 g, 0.046 mol) in H2SO4 (10 mL). The reaction was stirred 0° C. for 2 h, warmed to RT, stirred for 18 h, poured into ice then extracted with EA (5×50 mL). The combined organic layers were dried over Na2SO4, and concentrated to give 1,6-dimethyl-5-nitropyrimidine-2,4(1H,3H)-dione (4.3 g, 68.1% yield) as a yellow solid. 1H NMR (DMSO-d6) δ: 12.09 (s, 1H), 3.32 (s, 3H), 2.36 (s, 3H) LCMS: MH+ 186 and TR=0.610 min. Used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11]([CH3:13])=[O:12].[N-:14]=[N+]=[N-].[Na+].S(=O)(=O)(O)O.O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11]([CH3:13])(=[NH:14])=[O:12]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc([N+](=O)[O-])ccc1S(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1S(C)(=N)=O
Temperature: 25 °C

Procedure:
1.5 g (7.5 mmol) of (RS)-2-methyl-1-(methylsulfinyl)-4-nitrobenzene and 1.1 g (17.1 mmol) of sodium azide in 10.0 ml of CHCl3 are carefully mixed at 0° C. with 2.2 ml of concentrated sulfuric acid. The batch is heated first to room temperature and then to 45° C. while being stirred vigorously. It is stirred for 116 hours at this temperature. After cooling, it is mixed with water and extracted from DCM (2×). The aqueous phase is made basic with 2N NaOH solution and extracted from DCM. The combined organic phases are filtered through a Whatman filter and concentrated by evaporation. The crude product that is obtained is recrystallized from ethyl acetate. 1.3 g (6.1 mmol, corresponding to 81% of theory) of the product is obtained.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:35])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][CH:26]=2)=[O:21])[CH2:16][C:17](=[O:19])[NH2:18])(=[O:13])=[O:12])=[C:6]([CH3:42])[C:5]=1[CH3:43].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[C@@H:69]1(N)[O:77][C@H:76]([CH2:78][OH:79])[C@H:74]([OH:75])[C@H:72]([OH:73])[C@H:70]1[OH:71]>CN(C=O)C.ClCCl>[ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:35])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31](=[NH:32])[NH2:33])=[CH:29][CH:30]=2)=[O:21])[CH2:16][C:17](=[O:19])[NH:18][C@@H:69]2[O:77][C@H:76]([CH2:78][OH:79])[C@H:74]([OH:75])[C@H:72]([OH:73])[C@H:70]2[OH:71])(=[O:13])=[O:12])=[C:6]([CH3:42])[C:5]=1[CH3:43]
Reactant: N[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](Cc2ccc(C(=N)N)cc2)C(=O)N2CCCCC2)c(C)c1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)N[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)C(=O)N[C@H](Cc2ccc(C(=N)N)cc2)C(=O)N2CCCCC2)c(C)c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-N-(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-L-asparaginyl-4-amidino-D-phenylalanine-piperidide hydrochloride (1.0 g), HOBt (0.23 g) and DCCI (0.37 g) were dissolved in DMF and dichloromethane 1:1 (50 mL) and, after 0.5 h of stirring, β-D-galactopyranosyl-amine (1.0 g) was added. The reaction mixture was stirred for 48 h at room temperature and then filtered and concentrated by evaporation in vacuo. The residue was dissolved in ethyl acetate and washed with water. The crude product was purified by column chromatography on silica gel with chloroform/methanol 5:1. Yield: 1.2 g. TLC analysis: Rf=0.73 (chloroform/methanol 3:1). Barium oxide (0.25 g) was added to a solution of the intermediate compound (1.2 g) in chloroform/methanol 2:1 (100 mL), and the mixture was stirred for 2 h and then filtered. The flitrate was neutralized with methanolic HCl and concentrated by evaporation in vacuo. The residue was purified by column chromatography (Sephadex LH 20). Yield: 1.0 g. TLC analysis: Rf=0.042 (chloroform/methanol 3:1). [α]D +19.3° (c=1 in methanol). M.p. 186°-190° C.