Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][Cl:39]>CN(C)C=O>[Cl:39][CH2:38][CH2:37][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:14][C:15]3[C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=4)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: ClCCBr
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol (compound 443) (30 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (107 mg) and 1-bromo-2-chloroethane (0.03 ml) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (37 mg, yield 100%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].C(N(CC)CC)C.[C:32](Cl)(=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>ClCCl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32](=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)NCCOCCn1c(CCOC)nc2c(N)nc3ccccc3c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
Under a nitrogen atmosphere, a suspension of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (140.5 mg, 0.428 mmol) in a mixture of dichloromethane (3.5 mL) and triethylamine (150 μL, 1.07 mmol) was cooled to 0° C. Palmitoyl chloride (130 μL, 0.428 mmol) was slowly added. The reaction mixture was allowed to stir at 0° C. for 2 hours at which time analysis by thin layer chromatography indicated that there was no starting material left. The reaction mixture was diluted with dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (2×5 mL), dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (12 g of silica gel eluted with 2% methanol in dichloromethane) to provide 183 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)hexadecanamide as a white powder.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=3[CH:32]=2)[C:11]=1[CH3:12])[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO.C1COCC1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[O:20][C:16]3[CH:15]=[CH:14][C:13]([C:10]4[CH:9]=[C:4]([CH:3]=[CH:2][C:11]=4[CH3:12])[C:5]([OH:7])=[O:6])=[CH:32][C:17]=3[C:18]=2[C:28](=[O:31])[NH:29][CH3:30])=[CH:22][CH:23]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)cc(F)c3C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Temperature: 60 °C

Procedure:
To a mixture of methyl 3-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoate (0.3 g, 0.68 mmol, 1 eq) in a 1:1 mixture of MeOH/THF at ambient temperature was added 5 eq. of NaOH and heated to 60° C. for 5 h. The mixture was cooled to ambient temperature and then cooled in an ice-water bath. It was acidified slowly with 1.5 N HCl and then concentrated. The mixture with white precipitates was diluted with water and filtered to get the solid. It is further washed with water and dried in vacuum. Yield: 0.2 g (60%). 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 2.82-2.84 (d, 3H, J=4.6 Hz), 7.39-7.43 (m, 3H,), 7.61 (s, 1H), 7.66-7.70 (d, 1H, J=8.6 Hz), 7.66-7.70 (m, 1H), 7.78-7.80 (d, 1H, J=8.5 Hz), 8.01-8.03 (m, 2H), 8.49-8.51 (d, 1H, J=4.76 Hz), 13.2 (s, 1H). LCMS: (ES−) m/z=420.0 (M−H) Chromolith SpeedROD C18 (4.6×3.0 mm-5.0 μm) Mphase A: 10% CH3OH-90% H2O-0.1% TFA Mphase B: 90% CH3OH-10% H2O-0.1% TFA.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=O)=[CH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28].C(=O)([O-])O.[Na+]>CO.O>[OH:28][N:27]=[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[CH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CC=C(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CC=C(C(=NO)c1ccc(OC)cc1)c1ccc(OC)cc1
Yield: 89.9 %

Procedure:
A mixture of 24.5 g of methyl 4,5bis(4-methoxyphenyl)-5-oxo-3-pentenoate and 51.5 g of hydroxylamine hydrochloride in a mixture of 650 ml of methanol and 72 ml of water was heated under reflux for 3 hours. During this procedure, 0.9 equivalent of sodium hydrogen carbonate was added portionwise to the reaction mixture as the reaction progressed. After completion of the reaction, the methanol was distilled off under reduced pressure. Water and ethyl acetate were added to the residue for dissolution thereof, the organic layer was separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The organic layer was then concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:4) to give 23 g (yield 90%) of methyl 5-hydroxyimino-4,5-bis(4-methoxyphenyl)-3-pentenoate as an oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([C:32]1[N:33]=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.N1CCC[C@@H]1C#N>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:24][C@@H:23]2[C:32]#[N:33])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Agent: N#C[C@H]1CCCN1
Product: CC(C)(C)c1nc(N2CCC[C@@H]2C#N)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-pyrrolidine-2-carbonitrile hydrochloride and isolated as light-yellow solid (9.7 mg, 52%). MS (m/e): 396.4 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=[O:7])[CH2:4][NH:5][CH3:6].C(OCC)(=O)C.C(=O)([O-])O.[Na+].[CH2:20]([O:27][CH2:28][C:29](Cl)=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH2:20]([O:27][CH2:28][C:29]([N:5]([CH3:6])[CH2:4][C:3](=[O:7])[CH:2]([CH3:8])[CH3:1])=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CNCC(=O)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C(=O)CN(C)C(=O)COCc1ccccc1
Temperature: 0 °C
Yield: 41.6 %

Procedure:
A mixture of 6.1 g (52.9 mmol) of 3-methyl-1-methylamino-2-butanone, 70.0 ml of ethyl acetate and 41.0 ml of water was stirred at 0° C. Added was 7.1 g (84.6 mmol) of sodium hydrogen carbonate, and the mixture was stirred for 10 minutes. There was added 8.5 ml (54.0 mmol) of benzyloxyacetylchloride over 30 minutes. After stirring at room temperature for 10 hours, the ethyl acetate layer was seperated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (hexane/ethyl acetate 1:1) to give 5.8 g of 2-benzyloxy-N-methyl-N-(3-methyl-2-oxobutyl)-acetamide (18a') (yield 42%).
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[C:12]2[C:7](=[N:8][C:9]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][C:11]=2[OH:13])[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1)[CH3:3].C(OC([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)=O)(C)(C)C.Cl>>[ClH:1].[N:17]1([CH:36]2[CH2:37][CH2:38][NH:33][CH2:34][CH2:35]2)[CH2:16][CH2:15][CH:14]([C:9]2[N:8]=[C:7]3[N:6]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:5]=[C:4]([CH2:2][CH3:3])[C:12]3=[C:11]([OH:13])[N:10]=2)[CH2:19][CH2:18]1
Reactant: CCc1nn(-c2ccccc2)c2nc(C3CCNCC3)nc(O)c12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Product: CCc1nn(-c2ccccc2)c2nc(C3CCN(C4CCNCC4)CC3)nc(O)c12

Procedure:
The title compound was prepared according to the procedure as described in Example 88 reacting via reductive amination 3-ethyl-1-phenyl-6-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-ol hydrochloride and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester followed by de-protection of the adduct with HCl.
Reaction SMILES: Cl.[CH2:2]([NH2:5])[CH2:3][CH3:4].[O:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[C:10]=2[O:9][CH:8]=[CH:7]1.C(Cl)CCl>CN(C)C=O>[CH2:2]([NH:5][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:15]1[C:10]2[O:9][CH:8]=[CH:7][O:6][C:11]=2[CH:12]=[CH:13][CH:14]=1)[CH2:3][CH3:4]
Reactant: CCCN
Reactant: O=C(O)CCCc1cccc2c1OC=CO2
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCNC(=O)CCCc1cccc2c1OC=CO2
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A suspension of 0.29 g (2.6 mmol) of n-propylamine hydrochloride in 7 ml of anhydrous N,N-dimethylformamide is cooled to 0° C. and then 0.33 g (3.54 mmol) of N,N-dimethylaminopyridine are added to the mixture. After the addition of 0.41 g (2.36 mmol) of the acid obtained in Step F of Example 40, 0.5 g (2.6 mmol) of EDC is added to the mixture. The solution is stirred for 12 hours under argon at room temperature and then the solvent is evaporated off in vacuo. The residue is taken up in a water/ethyl acetate (1/1) mixture and then the aqueous phase is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. Chromatography over silica gel (eluant:AcOEt/PE:70/30) yields the title amide in the form of a clear syrup.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:15]([N:18]([CH2:28]C(O)=O)[C:19]1C=[CH:26][CH:25]=[CH:24][C:20]=1C(O)=O)(=[O:17])[CH3:16]>O>[C:15]([N:18]1[C:19]2[C:6](=[CH:26][CH:25]=[CH:24][CH:20]=2)[C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:28]1)(=[O:17])[CH3:16]
Reactant: CC(=O)N(CC(=O)O)c1ccccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cn(C(C)=O)c2ccccc12
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a stirred mixture of acetic anhydride (46.29 g, 0.45 mol) and triethylamine (13.77 g, 0.14 mol), 2-(N-acetylcarboxymethylamino)benzoic acid of Example 1b (11.36 g, 0.048 mol) was added at room temperature. The mixture was refluxed for 20 min and concentrated in vacuum to give an oily residue. Water (350 mL) was added under vigorous stirring, and the mixture was refrigerated overnight. The solid product was collected, washed with water and air-dried to give 9.0 g (86%) of the product which was used in the next step without purification.
Reaction SMILES: [OH:1][N:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[C:5]([O:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[C:3]1=[O:29].[O:30]1[CH:34]=[CH:33][CH2:32][CH2:31]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:13][O:12][N:9]1[CH2:10][CH2:11][C:6]2([N:2]([O:1][CH:31]3[CH2:32][CH2:33][CH2:34][O:30]3)[C:3](=[O:29])[C:4]([C:20]3[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[C:5]2[O:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])[CH2:7][CH2:8]1
Reactant: C1=COCC1
Reactant: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(O)C12CCN(OC)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(OC2CCCO2)C12CCN(OC)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of carbonic acid ethyl ester 1-hydroxy-8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (150 mg, 0.37 mmol) in dichloromethane (3 ml) under argon atmosphere was added 2,3-dihydro-furan (56 μl, 52 mg, 0.74 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (2 mg). The reaction mixture was stirred at room temperature for 4 hours, diluted with dichloromethane, washed twice with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/hexane 2:1). Yield: 114 mg of carbonic acid ethyl ester 8-methoxy-2-oxo-1-(tetrahydro-furan-2-yloxy)-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (title compound P1ii.9) as a colorless gum.
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1([S:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[C:18]23[O:29][CH2:28][CH2:27][CH2:26][O:25]2)(=[O:14])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.Cl[CH2:31][C:32]([CH3:36])([CH3:35])[C:33]#[N:34].O>CS(C)=O>[CH3:31][C:32]([CH3:36])([CH2:35][N:20]1[C:21]2[C:17](=[CH:16][C:15]([S:12]([N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)(=[O:13])=[O:14])=[CH:23][CH:22]=2)[C:18]2([O:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:19]1=[O:24])[C:33]#[N:34]
Reactant: CC(C)(C#N)CCl
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCCC3)cc2C12OCCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C#N)CN1C(=O)C2(OCCCO2)c2cc(S(=O)(=O)N3CCCC3)ccc21
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
At room temperature, to a stirred solution of potassium t-butoxide (0.287 g, 2.56 mmol, 1.2 eq) in anhydrous DMSO (4 mL) was added 5′-(pyrrolidin-1-ylsulfonyl)spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (0.72 g, 2.13 mmol). After stirring 20 minutes, 3-chloro-2,2-dimethylpropionitrile (3 eq) was added drop-wise and the reaction was heated at 130° C. for 20 hr. The reaction mixture was heated at 126° C. for 16 h. After cooling to room temperature, the reaction was poured into H2O (100 mL) and extracted with Et2O (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH H4OH (97/2/1) followed by a second chromatography eluting with 50/50 Pet. ether/EtOAc to give the title compound as a white solid (0.69 g, 77% yield). NMR: consistent.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[F:7][C:8]1[CH:9]=[C:10]([N:20]2[CH2:24][CH:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1.C[OH:32]>O>[F:7][C:8]1[CH:9]=[C:10]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:11]=[CH:12][C:13]=1[N:14]1[CH2:15][CH2:16][S:17](=[O:32])[CH2:18][CH2:19]1
Reactant: CC(=O)NCC1CN(c2ccc(N3CCSCC3)c(F)c2)C(=O)O1
Reactant: CO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCS(=O)CC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Sodium metaperiodate (42 mg, 0.196 mmol) was dissolved in water (1 mL) and then cooled to 0° C. (ice bath). Next, the N-[[3-[3-fluoro-4-(4-thiomorpholinyl) phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (66 mg, 0.187 mmol) was added. Methanol (3 mL) was added to increase solubility. The reaction was stirred at 0° C. for an additional 4 hours under N2 before being stoppered and stored in the freezer (65 hours). The reaction was filtered through a medium-porosity sintered glass funnel, rinsing the flask and filter cake with CHCl3 (5 mL). The filtrate was transferred to a separatory funnel, the layers separated, and the water layer further extracted with more CHCl3 (3×5 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure to yield 80 mg of a gummy solid. The material was chromatographed on silica gel (10 g silica, packed with 10% CH3CN/CHCl3), eluting with a gradient of 1-5% MeOH in 10% CH3CN/CHCl3 to give 49 mg (71%) of the title compound as an off-white solid with amp of 159°-161° C. and a HRMS (M+) calculated for C16H20N3O4FS 369.1158, found 369.1182.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([N:22]2[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:25][C:24]([CH:33]=O)=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([N:22]2[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:25][C:24]([CH2:33][NH:15][CH2:14][CH2:13][N:10]3[CH2:9][CH2:8][N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:12][CH2:11]3)=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCN1CCN(c2ccccc2)CC1
Reactant: O=Cc1cc(-c2ccccc2)n(-c2ccccc2)n1
Product: c1ccc(-c2cc(CNCCN3CCN(c4ccccc4)CC3)nn2-c2ccccc2)cc1
Yield: 78.8 %

Procedure:
Compound 9 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 1,5-diphenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3](C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2N=N1.CN1CCOCC1.CN(C=O)C.[C:49]1([CH3:67])[CH:54]=[CH:53][C:52]([S:55]([NH:58][C@H:59]([C:64]([OH:66])=[O:65])[C:60]([CH3:63])([CH3:62])[CH3:61])(=[O:57])=[O:56])=[CH:51][CH:50]=1>>[C:49]1([CH3:67])[CH:50]=[CH:51][C:52]([S:55]([NH:58][C@H:59]([C:64]([OH:66])=[O:65])[C:60]([CH3:62])([CH3:63])[CH3:61])(=[O:56])=[O:57])=[CH:53][CH:54]=1.[C:49]1([CH3:67])[CH:50]=[CH:51][C:52]([S:55]([NH:58][C@H:59]([C:64]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:66])[C:60]([CH3:61])([CH3:62])[CH3:63])(=[O:56])=[O:57])=[CH:53][CH:54]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)(C)C)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C(=O)O)C(C)(C)C)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-tert-butylglycine was prepared from L-tert-butylglycine using the procedure described in Method 1. The title compound was prepared by coupling in DMF N-(toluene-4-sulfonyl)-L-tert-butylglycine with an L-phenylalanine ester in the presence of BOP and NMM. Conventional deesterification provided the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26](Br)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[CH2:37]([N:44]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[N:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[F-].[Cs+]>COCCOC.CO.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>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:47]3[CH:46]=[N:45][N:44]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:48]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1-c1cnn(Cc2ccccc2)c1

Procedure:
A mixture of EXAMPLE 1D (0.113 g), 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.063 g), tetrakis(triphenylphosphine)palladium(0) (0.023 g) and CsF (0.091 g) in 1,2-dimethoxyethane (2 mL) and methanol (1 mL) was heated at 120° C. for 30 minutes under microwave heating conditions. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 35% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][NH2:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CCN)cc1OC1CCCC1
Solvent: c1ccncc1
Product: COc1ccc(CCNC(C)=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of crude 2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine (0.5 g, 2.1 mmol) in pyridine (1.8 mL) under an argon atmosphere was added acetic anhydride (1.25 mL). The resulting solution was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was dissolved in methylene chloride, washed with water and dried (sodium sulfate). The solvent was removed in vacuo, the residue was purified by flash chromatography, eluting with 4% methanol/ether, and then triturated with ether to provide the acetamide: m.p. 87°-88° C.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[CH3:27][C:28]1[N:29]2[CH:35]=[N:34][CH:33]=[C:30]2[S:31][CH:32]=1>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:34]3[CH:33]=[C:30]4[S:31][CH:32]=[C:28]([CH3:27])[N+:29]4=[CH:35]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: Cc1csc2cncn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: Cc1csc2cn(CC3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)c[n+]12
Yield: 22.9 %

Procedure:
The same procedure as in Example 1 was repeated except that 187 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 212 mg of 3-methylimidazo[5,1-b]thiazole were used, thereby obtaining 42.4 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][CH2:25][CH2:26][NH2:27]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:27][CH2:26][CH2:25][NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCNc1ccccn1
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccccn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and N1-pyridin-2-yl-ethane-1,2-diamine in DME. ES-MS m/e (%): 322 (M+H+, 100).